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  • Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-17
    Tatevik R. Broutian; Bo Jiang; Jingfeng Li; Keiko Akagi; Shanying Gui; Zhengqiu Zhou; Weihong Xiao; David E. Symer; Maura L. Gillison

    Human papillomavirus (HPV) insertions in cancer genomes have been linked to various forms of focal genomic instability and altered expression of neighboring genes. Here we tested the hypothesis that investigation of HPV insertions in a head and neck cancer squamous cell carcinoma (HNSCC) cell line would identify targetable driver genes contributing to oncogenesis of other HNSCC. In the cell line UPCI:SCC090, HPV16 integration amplified PIM1 serine/threonine kinase gene ∼16-fold, thereby increasing transcript and protein levels. We used genetic and pharmacological approaches to inhibit PIM kinases in this and other HNSCC cell lines. Knockdown of PIM1 transcripts by transfected short hairpin RNAs reduced UPCI:SCC090 viability. CRISPR/Cas9-mediated mutagenesis of PIM1 caused cell cycle arrest and apoptosis. Pharmacological inhibition of PIM family kinases decreased growth of UPCI:SCC090 and additional HNSCC cell lines in vitro and a xenograft UPCI:SCC090 model in vivo. Based on established interactions between intracellular signaling pathways and relatively high levels of gene expression in almost all HNSCC, we also evaluated combinations of PIM kinase and epidermal growth factor receptor (EGFR) inhibitors. Dual inhibition of these pathways resulted in supra-additive cell death. These data support clinical testing of PIM inhibitors alone or in combination in HNSCC.

    更新日期:2020-01-17
  • Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-17
    Karrie Mei-Yee Kiang; Pingde Zhang; Ning Li; Zhiyuan Zhu; Lei Jin; Gilberto Ka-Kit Leung

    Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.

    更新日期:2020-01-17
  • ShRNA-based POLD2 expression knockdown Sensitizes Glioblastoma to DNA-Damaging Therapeutics
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Qingfu Xu; Chengchen Hu; Yan Zhu; Kimberly Wang; Bachuchu Lal; Lichao Li; Junhai Tang; Shuang Wei; Guohao Huang; Shuli Xia; Shengqing Lv; John Laterra; Yugang Jiang; Yunqing Li

    Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133+ and SSEA-1+ cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.

    更新日期:2020-01-16
  • The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Huiying Huang; Michael Zepp; Rania Georges; Mostafa Jarahian; Maryam Kazemi; Ergül Eyol; Martin R. Berger

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and novel therapeutic strategies are urgently needed. Recently, expression of the C-C chemokine receptor 5 (CCR5) and its ligands has been found to play an important role in cancer progression and metastasis. In this study, we blocked the CCR5 receptor by the FDA approved antagonist maraviroc (MVC) in Suit2-007 and MIA-PaCa-2 human PDAC cells. The treatment significantly inhibited their proliferation and induced apoptosis of exposed cells as evidenced by caspases activation and increased Bax levels. Moreover, MVC inhibited the cell cycle by down regulating the proteins of the complexes of cyclin dependent kinase (CDK) 4/6 - Cyclin D and CDK2 - Cyclin E, as well as by increasing the protein levels of CDK inhibitors p18, p21 and p27. In line with this, MVC caused significant retardation of Suit2-007 cells growing in a PDAC liver metastasis xenograft model (p<0.05). These results suggest that maraviroc could be a promising treatment strategy for PDAC patients with liver metastases.

    更新日期:2020-01-16
  • Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Yunjiang Zhou; Yang Zhou; Keke Wang; Tao Li; Mengdi Yang; Rui Wang; Yaxin Chen; Mengran Cao; Rong Hu

    Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, participates in protecting cells from electrophilic or oxidative stresses through regulating expression of cytoprotective and antioxidant genes. It has become one of the emerging targets for cancer chemosensitization, and small molecule inhibitors of Nrf2 can enhance the efficacy of chemotherapeutic drugs. Here, we found that flumethasone, a glucocorticoid, inhibited Nrf2 signaling in A549 and H460 cells by promoting Nrf2 protein degradation. Moreover, flumethasone significantly increased the sensitivity of A549 and H460 cells to chemotherapeutic drugs including cisplatin, doxorubicin and 5-FU. In mice bearing A549-shControl cells-derived xenografts, the size and weight of xenografts in the flumethasone and cisplatin combination group had a significant reduction compared with those in the cisplatin group, while in mice bearing A549-shNrf2 cells-derived xenografts, the size and weight of the xenografts in the combination group had no significant difference compared with those in the cisplatin group, demonstrating that chemosensitization effect of flumethasone is Nrf2-dependent. This work suggests that flumethasone can potentially be used as an adjuvant sensitizer to enhance the efficacy of chemotherapeutic drugs in lung cancer.

    更新日期:2020-01-16
  • Disruption of the EGFR-SQSTM1 Interaction by a Stapled Peptide Suppresses Lung Cancer via Activating Autophagy and Inhibiting EGFR Signaling
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-10
    Jiao-jiao Yu; Dan-dan Zhou; Bing Cui; Cheng Zhang; Feng-wei Tan; Shan Chang; Ke Li; Xiao-xi Lv; Xiao-wei Zhang; Shuang Shang; Yu-Jin Xiang; Fei Chen; Jin-mei Yu; Shan-shan Liu; Feng Wang; Zhuo-Wei Hu; Fang Hua

    Despite the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, intrinsic or acquired resistance remains the major obstacle to long-term disease remission. Defective autophagy has been reported as an EGFR-TKI resistance mechanism. However, how EGFR regulate autophagic flux are still not fully understood. Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturb the sequestration function of SQSTM1 and cause autophagic flux blocking. SAH-EJ2, a staple optimized EGFR-derived peptide, showed enhanced in vitro and in vivo antitumor activity against NSCLC than the prototype regardless of EGFR mutation status. Mechanistically, SAH-EJ2 disrupts the EGFR-SQSTM1 interaction and protects against EGFR-induced SQSTM1 phosphorylation, which hinders the dimerization of the SQSTM1 UBA domains and restores SQSTM1 cargo function. Moreover, SAH-EJ2 suppresses EGFR activity by blocking its dimerization and reducing its protein stability, which reciprocally activates the core autophagy machinery. Our observations reveal that disturbing the EGFR-SQSTM1 interaction by SAH-EJ2 confers a potential strategy in the treatment of NSCLC through suppressing EGFR signalling and activating autophagy simultaneously.

    更新日期:2020-01-11
  • Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-10
    Dong Wang; Xiaohui Wang; Mahan Si; Juan Yang; Shiyue Sun; Haochen Wu; Shuxiang Cui; Xianjun Qu; Xinfeng Yu

    Tumor-associated macrophages (TAMs) are important immunocytes associated with cancer metastasis. However, whether TAMs play a dominant role in mediating CXCL12/CXCR4-induced liver metastasis of colorectal cancer (CRC) remains unexplored. Herein, we found that CD206+ TAMs, which infiltrated at the invasive front, were correlated with CXCR4 expression and liver metastasis of CRC in clinical specimens. Several miRNAs (miR-25-3p, miR-130b-3p, miR-425-5p), upregulated in CRC cells by activation of the CXCL12/CXCR4 axis, could be transferred to macrophages via exosomes. These exosomal miRNAs induced M2 polarization of macrophages by regulating PTEN through activation of PI3K/Akt signaling pathway. In turn, M2 polarized macrophages promoted cancer metastasis by enhancing epithelial-mesenchymal transition (EMT) and secreting vascular endothelial growth factor (VEGF). Co-culture of CRC cells with macrophages transfected with these miRNAs or treated with exosomes enhanced their metastatic capacity both in vitro and in vivo. Clinically, the serum levels of exosomal miR-25-3p, miR-130b-3p and miR-425-5p were correlated with progression and metastasis of CRC. In conclusion, these results reveal a crucial role of exosomal miRNAs in mediating the crosstalk between CXCR4 overexpressing cancer cells and TAMs, providing potential therapeutic targets for circumventing liver metastasis of CRC.

    更新日期:2020-01-11
  • Gut microbiota: a new piece in understanding hepatocarcinogenesis
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-07
    An Zhou; Li Tang; Shuo Zeng; Yuanyuan Lei; Shiming Yang; Bo Tang

    The gut microbiota forms a symbiotic relationship with the host and benefits the body in many critical aspects of life. However, immune system defects, alterations in the gut microbiota and environmental changes can destroy this symbiotic relationship and may lead to diseases, including cancer. Due to the anatomic and functional connection of the gut and liver, increasing studies show the important role of the gut microbiota in the carcinogenesis of hepatocellular carcinoma (HCC). In this manuscript, we review the available evidence and analyze some potential mechanisms of the gut microbiota, including bacterial dysbiosis, lipopolysaccharide (LPS), and genotoxins, in the progression and promotion of HCC. Furthermore, we discuss the possible therapeutic applications of probiotics, chemotherapy modulation, immunotherapy, targeted drugs and fecal microbiota transplantation (FMT) in targeting the gut microbiota.

    更新日期:2020-01-07
  • Dysregulation Of Metabolic Enzymes In Tumor And Stromal Cells: Role In Oncogenesis And Therapeutic Opportunities
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-07
    Mohammad Aslam Khan; Haseeb Zubair; Shashi Anand; Sanjeev Kumar Srivastava; Seema Singh; Ajay Pratap Singh

    Altered cellular metabolism is a hallmark of cancer. Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways. Furthermore, altered metabolism is also reported in tumor-corrupted stromal cells as a result of their interaction with cancer cells or due to their adaptation in the dynamic tumor microenvironment. Metabolic alterations are associated with dysregulation of metabolic enzymes and tumor-stromal metabolic crosstalk is vital for the progressive malignant journey of the tumor cells. Therefore, several therapies targeting metabolic enzymes have been evaluated and/or are being investigated in preclinical and clinical studies. In this review, we discuss some important metabolic enzymes that are altered in tumor and/or stromal cells, and focus on their role in supporting tumor growth. Moreover, we also discuss studies carried out in various cancers to target these metabolic abnormalities for therapeutic exploitation.

    更新日期:2020-01-07
  • TAZ target gene ITGAV regulates invasion and feeds back positively on YAP and TAZ in liver cancer cells
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-03
    Sofia M.E. Weiler; Teresa Lutz; Michaela Bissinger; Carsten Sticht; Maria Knaub; Norbert Gretz; Peter Schirmacher; Kai Breuhahn

    The Hippo pathway effectors yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ/WWTR1) support tumor initiation and progression in various cancer entities including hepatocellular carcinoma (HCC). However, to which extent YAP and TAZ contribute to liver tumorigenesis via common and exclusive molecular mechanisms is poorly understood. RNAinterference (RNAi) experiments illustrate that YAP and TAZ individually support HCC cell viability and migration, while for invasion we observed additive effects. Comprehensive expression profiling revealed partly overlapping YAP/TAZ target genes as well as exclusively regulated genes. Integrin-αV (ITGAV) is a novel TAZ-specific target gene, whose overexpression in human HCC patients correlates with poor clinical outcome, TAZ expression, and the abundance of YAP/TAZ target genes. Functionally, ITGAV contributes to actin stress fiber assembly, tumor cell migration and invasion. Perturbation of ITGAV diminishes actin fiber formation and nuclear YAP/TAZ protein levels. We describe a novel Hippo downstream mechanism in HCC cells, which is regulated by TAZ and ITGAV and that feedbacks on YAP/TAZ activity. This mechanism may represent a therapeutic target structure since it contributes to signal amplification of oncogenic YAP/TAZ signaling in hepatocarcinogenesis.

    更新日期:2020-01-04
  • LOXL2 Promotes Oncogenic Progression in Alveolar Rhabdomyosarcoma Independently of its Catalytic Activity
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-03
    Olga Almacellas-Rabaiget; Paola Monaco; Juan Huertas-Martinez; Silvia García-Monclús; Mariona Chicón-Bosch; Susana Maqueda-Marcos; Isabel Fabra-Heredia; David Herrero-Martín; Santiago Rello-Varona; Enrique de Alava; Roser López-Alemany; Paloma H. Giangrande; Oscar M. Tirado
    更新日期:2020-01-04
  • ARID1A deficiency and immune checkpoint blockade therapy: from mechanisms to clinical application
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-03
    Guangyuan Hu; Wei Tu; Liu Yang; Guang Peng; Lin Yang

    The AT-rich interaction domain 1A (ARID1A, also known as BAF250a) is a chromatin remodeling gene, which frequently mutates across a broad spectrum of cancers with loss expression of the ARID1A protein. Recently, the association between ARID1A deficiency and immune checkpoint blockade (ICB) therapy has been reported. ARID1A deficiency contributes to the high microsatellite instability phenotype, increases tumor mutation burden, elevates expression of programmed cell death ligand 1 (PD-L1), and modulates the immune microenvironment, supporting the view that ARID1A loss might serve as a predictive biomarker for ICB. Furthermore, the therapeutic targeting strategies, which show “synthetic lethality” with ARID1A deficiency, exhibit potential synergy with ICB. We collectively reviewed the mechanisms underlying the correlation between ARID1A deficiency and ICB, the predictive function of ARID1A deficiency for ICB, and potential combined strategies of targeting agents, vulnerable for ARID1A deficiency, with ICB in cancer treatment.

    更新日期:2020-01-04
  • Circular RNAs and their Emerging Roles as Diagnostic and Prognostic Biomarkers in Ovarian Cancer
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Rong Sheng; Xiaoduan Li; Ziliang Wang; Xipeng Wang

    Ovarian cancer (OC), one of the gynecologic malignancies with high invasive and metastatic potential, has a low survival rate in females. Although cytoreductive surgery combined with chemotherapy is the principal treatment for OC, the prognosis remains poor, and the recurrence rate of OC remains high. It is urgent to explore novel biomarkers for the diagnosis and prognosis of OC, as well as therapeutic targets. Circular RNAs (circRNAs) are a class of highly conserved, stable and abundant noncoding RNAs (ncRNAs). Recent studies have shown that circRNAs participate in OC progression by regulating various processes, including cell proliferation, migration, invasion and apoptosis. In addition, circRNAs are potential biomarkers for OC diagnosis and prognosis. This review provides an overview of recent findings on circRNAs in OC, including their functions and molecular mechanisms, and discusses their potential roles as diagnostic and prognostic biomarkers, as well as therapeutic targets for OC.

    更新日期:2020-01-02
  • Exosomes in Triple Negative Breast Cancer: Garbage Disposals or Trojan Horses?
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Chia Yin Goh; Cathy Wyse; Matthew Ho; Ellen O’Beirne; Jane Howard; Sinéad Lindsay; Pamela Kelly; Michaela Higgins; Amanda McCann

    Triple Negative Breast Cancer (TNBC) is a breast cancer subtype which is particularly aggressive and invasive. The treatment of TNBC has been limited due to the lack of well-defined molecular targets. Exosomes are nano-sized extracellular vesicles that are released from virtually all cell types into the extracellular space. Due to their endocytic origin, exosomes carry valuable information from their cells of origin. Exosomes were first thought to serve as “garbage disposals” that eliminate unwanted cellular components. Later, they were found to be involved in the pathology of many diseases including cancer. Despite their established roles in multiple diseases, only a small number of studies have focused on the role of exosomes in TNBC. In this review, we outline the roles of exosomes in cancer progression, metastasis and drug resistance in this breast cancer subtype. We then further illustrate the potential roles of exosomes as diagnostic tools, therapeutic targets and delivery systems.

    更新日期:2020-01-02
  • Inhibition of Fatty Acid Catabolism Augments the Efficacy of Oxaliplatin-based Chemotherapy in Gastrointestinal Cancers
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Yun Wang; Jia-Huan Lu; Feng Wang; Ying-Nan Wang; Ming-Ming He; Qi-Nian Wu; Yun-Xin Lu; Hong-En Yu; Zhan-Hong Chen; Qi Zhao; Jia Liu; Yan-Xing Chen; De-Shen Wang; Hui Sheng; Ze-Xian Liu; Zhao-Lei Zeng; Rui-Hua Xu; Huai-Qiang Ju

    Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.

    更新日期:2020-01-02
  • VCAM-1 Secreted from Cancer-Associated Fibroblasts Enhances the Growth and Invasion of Lung Cancer Cells through AKT and MAPK Signaling
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Zhuan Zhou; Qin Zhou; Xia Wu; San Xu; Xiaohong Hu; Xuxiu Tao; Bo Li; Jinwu Peng; Dan Li; Liangfang Shen; Ya Cao; Lifang Yang

    Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

    更新日期:2020-01-02
  • All-Trans Retinoic Acid Exerts Selective Anti-FLT3-ITD Acute myeloid leukemia Efficacy through Downregulating Chk1 Kinase
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Wenliang Wang; Zongru Jiang; Li Wang; Aoli Wang; Juan Liu; Cheng Chen; Kailin Yu; Fengming Zou; Wenchao Wang; Jing Liu; Qingsong Liu

    All-trans retinoic acid (ATRA) is known to be a potent inhibitor of FLT3-ITD acute myeloid leukemia (AML) cells, although the exact mechanism remains unclear. In this work, we report that ATRA causes fatal mitotic catastrophe in FLT3-ITD AML cells by degrading Chk1 kinase, and therefore preventing DNA damage repair. In order to explore a further enhancement in the inhibitory effect of ATRA on FLT3-ITD AML cells, we investigated the suitability of a combination of ATRA and DNA damage drug SN38. In vitro experiments showed that this combinatorial approach effectively inhibited the proliferation of FLT3-ITD cells and induced cell apoptosis in AML. In vivo experiments confirmed that the combination could substantially improve the anti-tumor effect of SN38. Taken together, our results indicate that ATRA down-regulates Chk1 in FLT3-ITD AML cells, and the combination of ATRA and SN38 significantly improves the anti-tumor effect of either ATRA or SN38 when used alone.

    更新日期:2020-01-02
  • LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like Polarization of Tumor-Associated Macrophages of CPEB4
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Dong Yang; Kaiyuan Liu; Lin Fan; Wenqing Liang; Tianyang Xu; Wenwei Jiang; Hengli Lu; Junjie Jiang; Chi Wang; Guodong Li; Xiaoping Zhang

    Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.

    更新日期:2020-01-02
  • Natural killer T cell cytotoxic activity in cervical cancer is facilitated by the LINC00240/microRNA-124-3p/STAT3/MICA axis
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Yan Zhang; Xin Li; Jun Zhang; Hua Liang

    Long noncoding RNAs play significant roles in diverse cancers. In this study, we found that LINC00240 expression was markedly increased in cervical cancer. Functional in vitro assays in cervical cancer cells showed that LINC00240 enhanced the growth, migration, and invasion of cervical cancer cells. The target of LINC00240 was confirmed as microRNA(miR)-124-3p. Inhibition of miR-124-3p significantly enhanced cervical cancer progression via targeting of STAT3, which is greatly activated in tumor-infiltrating immune cells. LINC00240 expression was able to induce STAT3 expression via sponging of miR-124-3p, and showed a positive association with STAT3 expression in cervical cancer tissues. MHC class I-related chain (MIC)-A plays a key role in activating natural killer T (NKT) cells and serves as a downstream target of STAT3. Here, MICA was inhibited by up-regulation of LINC00240, and could be rescued by STAT3 knockdown. In addition, LINC00240 overexpression suppressed the cytotoxic activity of NKT cells by affecting the STAT3/MICA axis. Subsequently, we found that LINC00240 expression promoted cervical cancer progression via induction of miR-124-3p/STAT3/MICA-mediated NKT cell tolerance. Considering these findings, we conclude that LINC00240 might be a novel target for cervical cancer.

    更新日期:2020-01-02
  • ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Mark Barok; Vadim Le Joncour; Ana Martins; Jorma Isola; Marko Salmikangas; Pirjo Laakkonen; Heikki Joensuu

    The majority of HER2-positive breast or gastric cancers treated with T-DM1 eventually show resistance to this agent. We compared the effects of T-DM1 and ARX788, a novel anti-HER2 antibody-drug conjugate, on cell growth and apoptosis in HER2-positive breast cancer and gastric cancer cell lines sensitive to T-DM1, gastric cancer cell lines resistant to T-DM1, HER2-negative breast cancer cell lines, and T-DM1-resistant xenograft models. ARX788 was effective in T-DM1-resistant in vitro and in vivo models of HER2-positive breast cancer and gastric cancer. ARX788 showed a pronounced growth inhibitory effect on all five HER2-positive cell lines tested, of which two gastric cancer cell lines had acquired resistance to T-DM1. ARX788 evoked more apoptotic events compared to T-DM1. While JIMT-1 and RN-87 xenograft tumors progressed on T-DM1 treatment, all such tumors responded to ARX788, and four out of the six JIMT-1 tumors and nine out of the twelve RN-87 tumors disappeared during the ARX788 treatment. Mice treated with ARX788 survived longer than those treated with T-DM1. The data support evaluation of ARX788 in patients with HER2-positive breast cancer or gastric cancer including cancers that progress during T-DM1 therapy.

    更新日期:2020-01-02
  • TRIM8 interacts with KIF11 and KIFC1 and controls bipolar spindle formation and chromosomal stability
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-02
    Santina Venuto; Laura Monteonofrio; Flora Cozzolino; Maria Monti; Irene Appolloni; Tommaso Mazza; Diana Canetti; Vincenzo Giambra; Patrizio Panelli; Carmela Fusco; Gabriella Maria Squeo; Anna Irma Croce; Pietro Pucci; Paolo Malatesta; Silvia Soddu; Giuseppe Merla; Lucia Micale

    The faithful inheritance of chromosomes is essential for the propagation of organisms. In eukaryotes, central to this process is the mitotic spindle. Recently, we have identified TRIM8 as a gene aberrantly expressed in gliomas whose expression reduces the clonogenic potential in the patient’s glioma cells. TRIM8 encodes an E3 ubiquitin ligase involved in various pathological processes, including hypertrophy, antiviral defense, encephalopathy, and cancer development. To gain insights into the TRIM8 functions, we characterized the TRIM8 interactome in primary mouse embryonic neural stem cells using proteomics. We found that TRIM8 interacts with KIFC1, and KIF11/Eg5, two master regulators of mitotic spindle assembly and cytoskeleton reorganization. By exploring the TRIM8 role in the mitotic spindle machinery, we showed that TRIM8 localizes at the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis with a subsequent delay of the mitotic progression and impact on chromosomal stability.

    更新日期:2020-01-02
  • Proprotein convertases: Key players in inflammation-related malignancies and metastasis
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-30
    Geraldine Siegfried; Jean Descarpentrie; Serge Evrard; Abdel-Majid Khatib

    Many cancers occur from locations of inflammation due to chronic irritation and/or infection. Tumor microenvironment contains various different inflammatory cells and mediators that orchestrate diverse neoplastic processes, including proliferation, survival, adhesion and migration. In parallel, tumor cells have adapted some of the signaling molecules used by inflammatory cells, such as selectins and chemokines as well as their receptors for invasion, extravasation and subsequently metastasis. Expression and/or activation of the majority of these molecules is mediated by the proprotein convertases (PCs); proteases expressed by both tumor cells and inflammatory cells. This review analyzes the potential role of these enzymatic system in inflammation-associated cancer impacting on the malignant and metastatic potential of cancer cells, describing the possible use of PCs as a new anti-inflammatory therapeutic approach to tumor progression and metastasis.

    更新日期:2019-12-30
  • Tackling hepatocellular carcinoma with individual or combinatorial immunotherapy approaches
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Maria Tagliamonte; Angela Mauriello; Beatrice Cavalluzzo; Concetta Ragone; Carmen Manolio; Annacarmen Petrizzo; Luigi Buonaguro

    Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, there is a single drug approved as first-line systemic therapy in advanced unresectable HCC, providing a very limited survival benefit. In earlier stages, 5-year survival rates after surgical and loco-regional therapies are extremely variable depending on the stage of disease. Nevertheless, HCC is considered an immunogenic tumor arising in chronically inflamed livers. In such a scenario, immunotherapy strategies for HCC, in particular combinations including cancer vaccines, may represent a key therapeutic tool to improve clinical outcome in HCC patients. However, a lot of improvement is needed given the disappointing results obtained so far.

    更新日期:2019-12-23
  • TRIM59 promotes tumor growth in hepatocellular carcinoma and regulates the cell cycle by degradation of protein phosphatase 1B
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Hanning Ying; Lin Ji; Zhiyao Xu; Xiaoxiao Fan; Yifan Tong; Hui Liu; Jia Zhao; Xiujun Cai

    Tripartite motif 59 (TRIM59) is a member of Tripartite motif protein family, which is frequently increased in many human cancers. However, the molecular mechanism of TRIM59 in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we report that TRIM59 plays an essential role in growth of HCC. We analyzed RNA sequencing data to explore abnormally expressed TRIM59 in HCC. The effects of TRIM59 on HCC were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, xenograft model, immunohistochemistry, immunofluorescence and western blot). The mechanism of TRIM59 action was explored through co-immunoprecipitation, immunofluorescence, mass spectrometry and bioinformatics. TRIM59 expression is up-regulated in HCC tissues. A high level of TRIM59 expression is correlated with poor overall and disease-free survival of HCC patients. Knockdown of TRIM59 attenuated proliferation, induced cells arrested at G1/S phase and reduced tumor growth in the mouse xenograft model. Ectopic expression of TRIM59 had the opposite results. Mechanistically, TRIM59 promoted growth and regulated cell cycle. Further studies indicated that TRIM59 might interacted physically with PPM1B, which has been reported to negatively regulate CDKs phosphorylation. We also discovered that TRIM59 increased degradation of PPM1B. TRIM59 overexpression in HCC patients correlated with reduced expression of PPM1B and increased CDKs phosphorylation and cell cycle proteins. Our findings demonstrate that TRIM59 promotes growth by PPM1B/CDKs signaling pathway, indicating a new prognostic biomarker candidate and a potential antitumor target for HCC.

    更新日期:2019-12-23
  • ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Nuozhou Wang; Ming-yue Li; Yi Liu; Jianqing Yu; Jianwei Ren; Zhiyuan Zheng; Shanshan Wang; Shucai Yang; Sheng-li Yang; Li-ping Liu; Bao-guang Hu; Charing CN. Chong; Juanita L. Merchant; Paul BS. Lai; George Gong Chen

    Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer stemness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC stemness via inhibiting the Notch1 signaling.

    更新日期:2019-12-23
  • miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Jessica Ray; Charles Haughey; Christianne Hoey; Jouhyun Jeon; Ross Murphy; Lara Dura-Perez; Nuala McCabe; Michelle Downes; Suneil Jain; Paul C. Boutros; Ian G. Mills; Stanley K. Liu

    Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.

    更新日期:2019-12-23
  • Heat-killed Mycobacterium paragordonae therapy exerts an anti-cancer immune response via enhanced immune cell mediated oncolytic activity in xenograft mice model
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    So-Young Lee; Soo-Bin Yang; Yu-Min Choi; Song-Ji Oh; Byung-Jun Kim; Yoon-Hoh Kook; Bum-Joon Kim

    A therapeutic strategy capable of skewing toward a Th1-type immune response is crucial for cancer treatment. Recently, we reported Mycobacterium paragordonae (Mpg) as a potential live vaccine for mycobacterium infections. In this study, we explored the immunotherapeutic potential of heat-killed Mpg (HK-Mpg) in a mouse tumor xenograft model and elucidated its underlying antitumor mechanisms. MC38 cells derived from murine colon adenocarcinoma were implanted by subcutaneously injecting mice. The anticancer effects of HK-Mpg therapy were compared with HK-M. bovis BCG, an effective adjuvant for cancer immunotherapy. HK-Mpg treatment enhanced tumor reduction and mouse survival. Furthermore, HK-Mpg treatment synergistically enhanced the anticancer therapeutic effect of cisplatin. In addition, HK-Mpg enhanced inflammatory cytokine production and immune cell recruits into tumor-infiltrating sites and splenocytes in vaccinated mice. Our mechanistic study demonstrates that HK-Mpg therapy elicits a strong antitumor immune response in mice, mainly through natural killer cell-mediated oncolytic activity via the activation of dendritic cells (DCs) and by enhancing inflammatory cytokines such as IL-12 from DC. Hence, HK-Mpg can be a potential immunotherapy adjuvant, enhancing the effect of cancer chemotherapy.

    更新日期:2019-12-23
  • A selective Aurora-A 5’-UTR siRNA inhibits tumor growth and metastasis
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Chien-Hsien Lai; Ruo-Yu Chen; Hsing-Pang Hsieh; Shaw-Jenq Tsai; Kung-Chao Chang; Chia-Jui Yen; Yu-Chuan Huang; Yao-Wen Liu; Jenq-Chang Lee; Yi-Chien Lai; Liang-Yi Hung; Bo-Wen Lin

    Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5’-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.

    更新日期:2019-12-23
  • Long noncoding RNA GMAN promotes hepatocellular carcinoma progression by interacting with eIF4B
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-23
    Jianbo Xu; Yijun Lu; Qiaoyu Liu; Anliang Xia; Jian Zhao; Xiaoliang Xu; Qikai Sun; Fuzhen Qi; Beicheng Sun

    Gastric cancer metastasis associated long noncoding RNA (GMAN), a long noncoding RNA, is associated with metastasis in gastric cancer. However, its underlying mechanisms in hepatocellular carcinoma (HCC) are unclear. We found that lncRNA-GMAN was significantly overexpressed in HCC tissues. GMAN expression is associated with vascular invasion, histological grade, tumor, node, metastasis (TNM) stage, short overall survival, and disease-free survival. Knockdown of GMAN induced apoptosis and suppressed invasive and migration potential in vitro and vivo, whereas ectopic GMAN expression produced the opposite effect. We also found that the inhibition of apoptosis, rather than promotion of proliferation, was responsible for GMAN-enhanced cellular viability. Mechanistic analyses indicated that GMAN directly combined with eukaryotic translation initiation factor 4B (eIF4B) and promoted its phosphorylation at serine-422 by preventing eIF4B binding and dephosphorization of the protein phosphatase 2A subunit B. The results demonstrated the stability of p-eIF4B and the elevation of mRNA translation and anti-apoptosis-related protein expression, which further induced proliferation and metastasis of HCC. The current study demonstrates that GMAN regulates the progression of HCC by inhibiting apoptosis and promoting the survival of cancer cells.

    更新日期:2019-12-23
  • Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-19
    Wan Liu; Wenjing Wang; Xinran Wang; Cong Xu; Ning Zhang; Wen Di

    Despite the high response rate after surgery and platinum-combination chemotherapy, treatment of ovarian cancer remains challenging due to tumor recurrence and metastasis. Tumor-associated macrophages (TAMs) have been linked to cancer progression and metastasis. However, the impact of the crosstalk between chemotherapy and TAMs on ovarian cancer progression remains unclear. Here, we demonstrated that cisplatin-stimulated classically activated macrophages (CAMs) promote ovarian cancer cell migration by increasing CCL20 production, which activates its receptor CCR6 on ovarian cancer cells, triggering epithelial-to-mesenchymal transition. In clinical ovarian cancer samples, high CCR6 expression on ovarian cancer cells positively correlates with cancer metastasis, leading to poor prognosis. Pharmacological blockage of CCL20 on cisplatin-stimulated CAMs and siRNA-mediated inactivation of CCR6 on cancer cells effectively abrogated ovarian cancer cell migration induced by cisplatin-stimulated CAMs. Collectively, our results reveal a novel pro-migration mechanism driven by the crosstalk between cisplatin and CAMs, and implicate the CCL20-CCR6 axis as a potential therapeutic target to reduce chemotherapy-induced metastasis in advanced stage ovarian cancer.

    更新日期:2019-12-20
  • WEE1 Inhibitor, AZD1775, Overcomes Trastuzumab Resistance by Targeting Cancer Stem-like Properties in HER2-positive Breast Cancer
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-19
    Andrea Sand; Mitchel Piacsek; Deborah L. Donohoe; Aspen T. Duffin; Geoffrey T. Riddell; Chaoyang Sun; Ming Tang; Richard A. Rovin; Judy A. Tjoe; Jun Yin

    Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.

    更新日期:2019-12-19
  • HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-17
    Michael J. Hamilton; Matthew Young; Kay Jang; Silvia Sauer; Vanessa E. Neang; Alexia T. King; Thomas Girke; Ernest Martinez

    HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HM1-3 isoform and that HM1-3 is downregulated in >90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.

    更新日期:2019-12-18
  • Dendritic cell activation by an E. coli-derived monophosphoryl lipid A enhances the efficacy of PD-1 blockade
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-17
    Youngmin Jeong; Gi Beom Kim; Yuhyun Ji; Gi-Jung Kwak; Gi-Hoon Nam; Yeonsun Hong; Seohyun Kim; Jinsu An; Sun Hwa Kim; Yoosoo Yang; Hak Suk Chung; In-San Kim

    Cancer immunotherapy is a powerful approach for cancer treatment, but its clinical effects rely on the tumor’s immune conditions. In particular, low response rates to PD-1 blockades are highly correlated with impaired T cell priming. Here, we demonstrate that E. coli-derived monophosphoryl lipid A (EcML) activates dendritic cells in a toll-like receptor-4 (TLR-4)-dependent manner and increases the sensitivity of cancer cells to anti-PD-1 immunotherapy. EcML is a mixture of 4'-monophosphoryl lipids A (MPLAs) produced directly by an engineered Escherichia coli strain; it has a unique congener composition that differentiates it from the well-established MPLA adjuvants, 3-O-desacyl-4'-monophosphoryl lipid A and glucopyranosyl lipid A. Given that active dendritic cells initiate adaptive immune responses, we investigated the anti-tumor activity of an aqueous formulation of EcML. Upon sensing EcML via TLR-4, dendritic cells matured into powerful antigen-presenting cells that could stimulate naïve T cells. EcML reduced tumor growth in the B16F10 mouse model via dendritic cell activation and potentiated PD-1 blockade therapy in the B16F10-OVA melanoma model. These data identify EcML as a promising TLR-4 agonist that can induce anti-tumor immune responses and potentiate PD-1 blockade therapy against tumors.

    更新日期:2019-12-18
  • Developing more sensitive genomic approaches to detect radioresponse in precision radiation oncology: From tissue DNA analysis to circulating tumor DNA
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-16
    Kewen He; Shaotong Zhang; Liang L. Shao; Jiani C. Yin; Xue Wu; Yang W. Shao; Shuanghu Yuan; Jinming Yu

    Despite the common application and considerable efforts to achieve precision radiotherapy (RT) in several types of cancer, RT has not yet entered the era of precision medicine; the ability to predict radiosensitivity and treatment responses in tumors and normal tissues is lacking. Therefore, development of genome-based methods for individual prognosis in radiation oncology is urgently required. Traditional DNA sequencing requires tissue samples collected during invasive operations; therefore, repeated tests are nearly impossible. Intra- and inter-tumoral heterogeneity may undermine the predictive power of a single assay from tumor samples. In contrast, analysis of circulating tumor DNA (ctDNA) allows for non-invasive and near real-time sampling of tumors. By investigating the genetic composition of tumors and monitoring dynamic changes during treatment, ctDNA analysis may potentially be clinically valuable in prediction of treatment responses prior to RT, surveillance of responses during RT, and evaluation of residual disease following RT. As a biomarker for RT response, ctDNA profiling may guide personalized treatments. In this review, we will discuss approaches of tissue DNA sequencing and ctDNA detection and summarize their clinical applications in both traditional RT and in combination with immunotherapy.

    更新日期:2019-12-17
  • MUC-1 recognition-based activated drug nanoplatform improves doxorubicin chemotherapy in breast cancer
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-16
    Pilei Si; Jinjin Shi; Pei Zhang; Cao Wang; Haijun Chen; Xuefang Mi; Wenling Chu; Baoping Zhai; Wentao Li

    Tumor-targeted drug delivery systems with stimuli-response drug release have been increasingly used to improve the therapeutic efficacy of antitumor drugs. Here, we report a specific molecular recognition activation drug nanoplatform based on specially designed DNA sensor-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs), designated as specific molecular recognition-activated nanoparticle (SMRAN). DNA sensors on the targeted nanoparticles can trigger DOX release through a conformational switch induced by MUC-1. This causes a significant difference in cell viability between breast cancer MCF-7 and normal breast Hs578bst cells (24.8% and 86.0%). In vivo experiments showed that the tumor volume was reduced 1.5-times in the SMRAN treatment group. compared with that in the DOX group, due to significantly improved tumor accumulation and retention of DOX. The strategy of the MUC-1 activated drug delivery system is expected to provide a new perspective for clinical application.

    更新日期:2019-12-17
  • Loss of legumain in macrophages activates senescence of tumor cells by sustaining M1 polarization
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-16
    Long Shen; Lichun Kang; Dekun Wang; Jing Xun; Chuan’ai Chen; Lingfang Du; Mianzhi Zhang; Junbo Gong; Xue Mi; Shijing Yue; Yuying Zhang; Xiangrong Song; Rong Xiang; Zhujun Zhang; Xiaoyue Tan

    Clarifying the interplay between macrophage and tumor cells is urgently needed for developing novel macrophage-based strategy against tumor. Here, we show that deletion of legumain in macrophages activates senescence of tumor cells. Macrophage derived IL-1β mediates the pro-senescent effect of Lgmn-/- macrophages since blockage of IL-1β reverses the senescence induced by downregulation of legumain, in either coculture model of macrophage and tumor cells or orthotopic mouse model of breast cancer. Sustained activation of JAK1/STAT1 signaling and increased iNOS in the tumor cell-cocultured Lgmn-/- macrophages was found compared with the wild type control. Specific STAT1 agonist mimics the inductive effect of Lgmn-/- on IL-1β in macrophages, and the effect could be rescued via inhibition of iNOS. Moreover, legumain and integrin αvβ3 colocalizes on macrophages and blockage of integrin αvβ3 stimulates the activation of STAT1 signaling. Therapeutically, transplantation of bone marrow from Lgmn-/- mice suppresses the malignant growth of tumor with upregulated level of tumor cell senescence. Therefore, our finding highlights the legumain in macrophages as a potential therapeutic target for tumors.

    更新日期:2019-12-17
  • Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-16
    Kai Wang; Yifan Zhan; Nhi Huynh; Chelsea Dumesny; Xiao Wang; Khashayer Asadi; David Herrmann; Paul Timpson; Yang Yang; Katrina Walsh; Graham S. Baldwin; Mehrdad Nikfarjam; Hong He

    Immunotherapies have not yielded significant clinical benefits for pancreatic ductal adenocarcinoma (PDA) because of the existence of an immunosuppressive tumour microenvironment (TME) characterised by a desmoplastic stroma containing infiltrated immune cells and activated pancreatic stellate cells (PSCs). This study aims to investigate the involvement of PAK1 in anti-tumour immunity. In PDA patients low PAK1 expression, low activation of PSC and high CD8+ T cell/PAK1 ratios correlated with longer overall survival. In a murine PDA model PAK1 knockout increased intra-tumoral CD4+ and CD8+ T cells, inhibited PSCs activation and extended survival. Inhibition of PAK1 reduced PSC-stimulated PDA cell proliferation and migration, blocked PSC-mediated protection of PDA cells from killing by cytotoxic lymphocytes and decreased intrinsic and PSC-stimulated PD-L1 expression in PDA cells, which further sensitized PDA cells to cytotoxic lymphocytes. Inhibition of PAK1 stimulates anti-tumour immunity by increasing intra-tumoral CD4+ and CD8+ T cells, and by sensitizing PDA cells to killing by cytotoxic lymphocytes via down-regulation of intrinsic and PSC-stimulated PD-L1 expression. PAK1 inhibitors, especially in combination with immune checkpoint inhibitors may result in improved efficacy of immunotherapy of PDA.

    更新日期:2019-12-17
  • Androgen receptor reverses the oncometabolite R-2-hydroxyglutarate-induced prostate cancer cell invasion via suppressing the circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-14
    Hua Xu; Yin Sun; Bosen You; Chi-Ping Huang; Dingwei Ye; Chawnshang Chang

    IDH1 (Isocitrate dehydrogenase 1) mutation occurring at codon 132 (R132) in prostate cancer (PCa) is considered as a classifier for a subgroup of PCas with accumulation of oncometabolite R-2HG (R-2-hydroxyglutarate). Here we found that adding R-2HG or the mutant IDH1 R132H could promote PCa cell invasion in androgen receptor (AR)-negative PC3 cells or suppressing the AR in AR-positive C4-2 cells. Mechanism dissection revealed that R-2HG could increase circRNA-51217 expression to increase the sponge miRNA-646, which might then lead to increase TGFβ1 expression and thus induce TGFβ1/p-Smad2/3 signaling to increase PCa cell invasion. AR can then suppress this R-2HG/circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling-increased PCa cell invasion via repressing TGFβ1 transcription and inhibiting circRNA-51217 expression through regulating ADAR2 expression. Preclinical studies with an in vivo xenograft mouse model also revealed that PCa cells with the IDH1 R132H mutation have more invasive metastasis. This study demonstrates that IDH1 R132H mutation with increased oncometabolite R-2HG in PCa cells may play important roles to increase PCa cell invasion.

    更新日期:2019-12-17
  • Androgen receptor suppresses prostate cancer metastasis but promotes bladder cancer metastasis via differentially altering miRNA525-5p/SLPI-mediated vasculogenic mimicry formation
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-13
    Zhao Yang; Jiaqi Chen; Hongjun Xie; Tianjie Liu; Yule Chen; Zhenkun Ma; Xinqi Pei; Wenjie Yang; Lei Li

    Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography–mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.

    更新日期:2019-12-13
  • Androgen-induced expression of DRP1 regulates mitochondrial metabolic reprogramming in prostate cancer
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-12
    Yu Geon Lee; YeJi Nam; Kyeong Jin Shin; Sora Yoon; Weon Seo Park; Jae Young Joung; Jeong Kon Seo; Jin Ho Jang; Semin Lee; Dougu Nam; M. Cecilia Caino; Pann-Ghill Suh; Young Chan Chae

    Androgen receptor (AR) signaling plays a central role in metabolic reprogramming for prostate cancer (PCa) growth and progression. Mitochondria are metabolic powerhouses of the cell and support several hallmarks of cancer. However, the molecular links between AR signaling and the mitochondria that support the metabolic demands of PCa cells are poorly understood. Here, we demonstrate increased levels of dynamin-related protein 1 (DRP1), a mitochondrial fission mediator, in androgen-sensitive and castration-resistant AR-driven PCa. AR signaling upregulates DRP1 to form the VDAC-MPC2 complex, increases pyruvate transport into mitochondria, and supports mitochondrial metabolism, including oxidative phosphorylation and lipogenesis. DRP1 inhibition activates the cellular metabolic stress response, which involves AMPK phosphorylation, induction of autophagy, and the ER unfolded protein response, and attenuates androgen-induced proliferation. Additionally, DRP1 expression facilitates PCa cell survival under diverse metabolic stress conditions, including hypoxia and oxidative stress. Moreover, we found that increased DRP1 expression was indicative of poor prognosis in patients with castration-resistant PCa. Collectively, our findings link androgen signaling-mediated mitochondrial dynamics to metabolic reprogramming; moreover, they have important implications for understanding PCa progression.

    更新日期:2019-12-13
  • Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-12
    Béatrice Vanbervliet-Defrance; Tiphaine Delaunay; Thomas Daunizeau; Vahan Kepenekian; Olivier Glehen; Kathrin Weber; Yann Estornes; Audrey Ziverec; Leila Djemal; Marion Delphin; Sylvie Lantuéjoul; Guillaume Passot; Marc Grégoire; Olivier Micheau; Christophe Blanquart; Toufic Renno; Jean-François Fonteneau; Serge Lebecque; Karène Mahtouk

    Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cells isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.

    更新日期:2019-12-13
  • Nerve growth factor (NGF)-TrkA axis in head and neck squamous cell carcinoma triggers EMT and confers resistance to the EGFR inhibitor erlotinib
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-12
    Chengzhong Lin; Zhenhu Ren; Xi Yang; Rong Yang; Yiming Chen; Zheqi Liu; Zhenlin Dai; Yu Zhang; Youya He; Chunye Zhang; Xu Wang; Wei Cao; Tong Ji

    Understanding the molecular mechanisms regulating tumor dissemination and therapeutic resistance is of central importance for effective cancer therapies. Here, we report that nerve growth factor (NGF) and its receptor TrkA facilitate epithelial-mesenchymal transition (EMT) and EGFR inhibitor resistance via STAT3 activation in head and neck squamous cell carcinoma (HNSCC). Both NGF and TrkA expression were elevated in HNSCC, indicating poor clinical outcomes. NGF was highly expressed in cancer cells and nerves in perineural niche, whereas TrkA expression was higher in cancer cells with perineural invasion. The NGF/TrkA axis could promote HNSCC cell dissemination and trigger EMT via STAT3 activation. Moreover, we discovered that the NGF/TrkA axis conferred resistance to the EGFR inhibitor erlotinib via EMT processes in HNSCC cells. Blocking TrkA signaling markedly reversed EMT and sensitized HNSCC cells to erlotinib in both in vitro and in vivo models. Overall, our results demonstrate novel evidence that the paracrine NGF/TrkA axis favors EMT and confers EGFR-targeted therapeutic resistance in HNSCC.

    更新日期:2019-12-13
  • WDR74 induces nuclear β-catenin accumulation and activates Wnt-responsive genes to promote lung cancer growth and metastasis
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-12
    Yumei Li; Fan Chen; Weiyu Shen; Bifei Li; Rong Xiang; Lijuan Qu; Chen Zhang; Gao Li; Huanzhang Xie; Vladimir L. Katanaev; Lee Jia

    Lung cancer has been notorious for its lack of advance in clinical therapy, urging for effective therapeutic targets. WD repeat-containing protein 74 (WDR74) has previously been implicated in tumorigenesis, but its mechanistic functions remain not well understood. Herein, WDR74 expression was observed to be increased upon lung cancer progression from healthy normal tissues to the primary cancer and further to the metastatic cancer. Through gain- and loss-of-function approaches, we found that WDR74 regulated lung cancer cell proliferation, cell cycle progression, chemoresistance and cell aggressiveness in vitro. Moreover, a xenograft mouse model disclosed that WDR74 knockout inhibited lung cancer growth and metastasis, whereas WDR74 overexpression reciprocally enhanced these characteristics. Mechanistically, WDR74 promoted nuclear β-catenin accumulation and drove downstream Wnt-responsive genes, thus revealing that WDR74 activated the Wnt/β-catenin signaling pathway. Collectively, WDR74 inducing nuclear β-catenin accumulation and driving the downstream Wnt-responsive genes expression facilitates lung cancer growth and metastasis. WDR74 can serve as a candidate target for the prevention and treatment of lung cancer in clinic.

    更新日期:2019-12-13
  • Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-11
    Pranav Gupta, Guan-Nan Zhang, Anna Maria Barbuti, Zhang Xin, Nishant Karadkhelkar, Jingfeng Zhou, Ke Ding, Jingxuan Pan, Sabesan Yoganathan, Dong-Hua Yang, Zhe-Sheng Chen

    Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the BCR-ABL fusion gene that produces the constitutively active protein, BCR-ABL. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of of mutations in the BCR-ABL kinase domains. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant BCR-ABL. S116836 was efficacious in BaF3 cells with WT or T315I mutated BCR¬ABL genotypes. S116836 inhibits the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces apoptosis increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant BCR-ABL without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I BCR-ABL mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

    更新日期:2019-12-11
  • Chromosome fragility in the buccal epithelium in patients with Fanconi anemia
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-10
    María José Ramírez, Jordi Minguillón, Sara Loveless, Kelly Lake, Estela Carrasco, Neda Stjepanovic, Judith Balmaña, Albert Català, Parinda A. Mehta, Jordi Surrallés

    Fanconi anemia (FA) is a rare genome instability syndrome characterized by progressive bone marrow failure and predisposition to cancer, especially head and neck squamous cell carcinoma. Surgical resection is the standard of care for solid tumors, as patients with FA do not tolerate genotoxic chemotherapies or radiation, leading to poor prognosis. It is therefore imperative to develop chemoprevention strategies such as the identification of novel biomarkers to detect the formation of the tumor before its emergence and to use them in clinical trials aimed to counteract genome instability of patients with FA in tissues at risk. Micronuclei (MN) are chromosome fragments that are left behind in anaphase and appear in daughter cells as small additional nuclei. In this work, we analyzed MN frequencies in exfoliated buccal cells from 40 patients with FA and 24 controls. We found that MN frequency was significantly increased in the FA cohort indicating that we can detect chromosome fragility in patients with FA in basal conditions and in a tissue that is divided in vivo. Consequently, the MN assay in exfoliated buccal cells of patients with FA could be used in cancer risk studies and clinical trials aimed to identify cancer chemopreventive drugs.

    更新日期:2019-12-11
  • Artificial intelligence in cancer diagnosis and prognosis: Opportunities and challenges
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-10
    Shigao Huang, Jie Yang, Simon Fong, Qi Zhao

    Cancer is an aggressive disease with a low median survival rate. Ironically, the treatment process is long and very costly due to its high recurrence and mortality rates. Accurate early diagnosis and prognosis prediction of cancer are essential to enhance the patient’s survival rate. Developments in statistics and computer engineering over the years have encouraged many scientists to apply computational methods such as multivariate statistical analysis to analyze the prognosis of the disease, and the accuracy of such analyses is significantly higher than that of empirical predictions. Furthermore, as artificial intelligence (AI), especially machine learning and deep learning, has found popular applications in clinical cancer research in recent years, cancer prediction performance has reached new heights. This article reviews the literature on the application of AI to cancer diagnosis and prognosis, and summarizes its advantages. We explore how AI assists cancer diagnosis and prognosis, specifically with regard to its unprecedented accuracy, which is even higher than that of general statistical applications in oncology. We also demonstrate ways in which these methods are advancing the field. Finally, opportunities and challenges in the clinical implementation of AI are discussed. Hence, this article provides a new perspective on how AI technology can help improve cancer diagnosis and prognosis, and continue improving human health in the future.

    更新日期:2019-12-11
  • Acetylcholine promotes the self-renewal and immune escape of CD133+ thyroid cancer cells through activation of CD133-Akt pathway
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-10
    Zhenglin Wang, Wei Liu, Cong Wang, Yinan Li, Zhilong Ai

    Nerves infiltrate the tumor microenvironment and stimulate the growth of cancer cells through the secretion of neurotransmitters. However, the contributions of nerves to the self-renewal capacity of cancer stem cells (CSCs) remain largely unknown. In this study, we found that CD133+ cancer cells were responsible for the initiation of thyroid cancer. Neurons were juxtaposed with CD133+ cells in thyroid cancer tissues. Acetylcholine, one of the most abundant neurotransmitters, promoted CD133 Y828 phosphorylation, and subsequently increased the interaction between CD133 and PI3K regulatory subunit p85, resulting in the activation of the PI3K-Akt pathway. Acetylcholine increased the self-renewal ability of CD133+ thyroid cancer cells through activation of CD133-Akt pathway. Furthermore, acetylcholine promoted the expression of the immune regulator PD-L1 through the activation of the CD133-Akt pathway, resulting in the resistance of CD133+ thyroid cancer cells to CD8+ T cells. However, acetylcholine receptor antagonist 4-DAMP blocked the positive effects of acetylcholine on the self-renewal and immune escape of CD133+ thyroid cancer cells. Taken together, these data suggest that acetylcholine increases the self-renewal and immune escape abilities of CD133+ thyroid cancer cells through the activation of the CD133-Akt pathway.

    更新日期:2019-12-11
  • Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-10
    Adrian D. Schubert, Esther Channah Broner, Nishant Agrawal, Nyall London, Alexander Pearson, Anuj Gupta, Neha Wali, Tanguy Y. Seiwert, Sarah Wheelan, Mark Lingen, Kay Macleod, Hailey Allen, Aditi Chatterjee, Saloura Vassiliki, Daria Gaykalova, Mohammad O. Hoque, David Sidransky, Karthik Suresh, Evgeny Izumchenko

    Mutations in mitochondrial DNA (mtDNA) have been linked to risk, progression, and treatment response of head and neck squamous cell carcinoma (HNSCC). Due to their clonal nature and high copy number, mitochondrial mutations could serve as powerful molecular markers for detection of cancer cells in bodily fluids, surgical margins, biopsies and lymph node (LN) metastasis, especially at sites where tumor involvement is not histologically apparent. Despite a pressing need for high-throughput, cost-effective mtDNA mutation profiling system, current methods for library preparation are still imperfect for detection of low prevalence heteroplasmic mutations. To this end, we have designed an ultra-deep amplicon-based sequencing library preparation approach that covers the entire mitochondrial genome. We sequenced mtDNA in 28 HNSCCs, matched LNs, surgical margins and bodily fluids, and applied multiregional sequencing approach on 14 primary tumors. Our results demonstrate that this quick, sensitive and cost-efficient method allows obtaining a snapshot on the mitochondrial heterogeneity, and can be used for detection of low frequency tumor-associated mtDNA mutations in LNs, sputum and serum specimens. These findings provide the foundation for using mitochondrial sequencing for risk assessment, early detection, and tumor surveillance.

    更新日期:2019-12-11
  • ATP citrate lyase: a central metabolic enzyme in cancer
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-09
    Philippe Icard, Zherui Wu, Ludovic Fournel, Antoine Coquerel, Hubert Lincet, Marco Alifano

    ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these molecules supports protein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+ (consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies.

    更新日期:2019-12-11
  • The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-06
    Po-Ming Chow, Shing-Hwa Liu, Yu-Wei Chang, Kuan-Lin Kuo, Wei-Chou Lin, Kuo-How Huang

    Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC. However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.

    更新日期:2019-12-06
  • Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-05
    Jun Lu, Yao-hui Wang, Changhwan Yoon, Xiao-yan Huang, Yu Xu, Jian-wei Xie, Jia-bin Wang, Jian-xian Lin, Qi-yue Chen, Long-long Cao, Chao-hui Zheng, Ping Li, Chang-ming Huang

    The biological functions of circular RNAs (circRNAs) in gastric cancer (GC) remain largely unexplored. Here, we identified that circ-RanGAP1 was significantly upregulated in both GC tissues and exosomes from the plasma of GC patients. High circ-RanGAP1 expression was closely associated with an advanced TNM stage, lymph node metastases, and worse survival. Inhibition of circ-RanGAP1 decreased GC cell invasion and migration in vitro. Overexpression of circ-RanGAP1 had the opposite effect. Additionally, circ-RanGAP1 silencing remarkably suppressed tumor growth and metastasis of GC in vivo. Mechanistically, circ-RanGAP1 sponged miR-877-3p to upregulate VEGFA expression. Overexpression of miR-877-3p reversed the biological functions mediated by circ-RanGAP1 in GC cells. Interestingly, we demonstrated that circ-RanGAP1 was upregulated in plasma exosomes from preoperative GC patients. More importantly, the plasma exosomes derived from these patients enhanced the migration and invasion potential of GC cells. Overall, the circ-RanGAP1-mediated miR-877-3p/VEGFA axis promotes GC progression. Our findings suggest that circ-RanGAP1 might act as a potential prognostic biomarker and therapeutic target for GC treatment.

    更新日期:2019-12-05
  • Human papillomavirus vaccine against cervical cancer: opportunity and challenge
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-05
    Renjie Wang, Wei Pan, Lei Jin, Weiming Huang, Yuehan Li, Di Wu, Chun Gao, Ding Ma, Shujie Liao

    Cervical cancer is one of the most common cancers threatening women's health, and the persistent infection of high-risk human papillomavirus (HPV) is closely related to the pathogenesis of cervical cancer and many other cancers. The carcinogenesis is a complex process from precancerous lesion to cancer, which provides an excellent window for clinical prevention, diagnosis, and treatment. However, despite the various preventions and treatments such as HPV screening, prophylactic HPV vaccines, surgery, radiotherapy, and chemotherapy, the disease burden remains heavy worldwide. Currently, three types of prophylactic vaccines, quadrivalent HPV vaccine, bivalent HPV vaccine, and a new nonavalent HPV vaccine, are commercially available. Although these vaccines are effective in protecting against 90% of HPV infection, they provide limited benefits to eliminate pre-existing infections. Therefore, new progress has been made in the development of therapeutic vaccines. Therapeutic vaccines differ from prophylactic vaccines in that they aim to stimulate cell-mediated immunity and kill the infected cells rather than neutralizing antibodies. This review aims at systematically covering the progress, current status and future prospects of various vaccines in development for the prevention and treatment of HPV-associated lesions and cancers and laying foundations for the development of the new original vaccine.

    更新日期:2019-12-05
  • Acidosis-induced metabolic reprogramming in tumor cells enhances the anti-proliferative activity of the PDK inhibitor dichloroacetate
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-05
    C.A. Schoonjans, N. Joudiou, D. Brusa, C. Corbet, O. Feron, B. Gallez

    Altered metabolic pathways in cancer such as exacerbated glycolytic flux and increased glutamine metabolism are promising targets for anti-cancer therapies. While commonly observed in glycolytic tumors, extracellular acidosis has never been considered as a potential modulator of anti-metabolic drug activity such as dichloroacetate (DCA). Using cancer cells from various origins selected for their ability to proliferate under acidic conditions, we found that DCA exerts greater inhibitory effects on the growth of these acid-adapted cells than in parental cells. Moreover, daily DCA administration to mice led to a significant decrease in tumor growth from acid-adapted cells but not from parental cells. 13C-tracer studies revealed that DCA induced a double metabolic shift, diminishing glycolysis and increasing intracellular glutamine in acid-adapted cells. As a consequence, DCA reduced the pentose phosphate pathway activity more extensively and increased apoptosis in acid-adapted cells. Finally, the combination of DCA with a glutaminase inhibitor significantly enhanced the cytotoxic effects of DCA. Overall, the interplay between acidosis and DCA exposure leads to metabolic reprogramming that considerably alters cellular fitness.

    更新日期:2019-12-05
  • Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-05
    Junhui Xue, Zhengyi Cao, Yuning Cheng, Jiyin Wang, Yujuan Liu, Ruixiang Yang, Hui Li, Wei Jiang, Gang Li, Wenhui Zhao, Xiaowei Zhang

    Alpha-fetoprotein (AFP) is a well-established biomarker for hepatocellular carcinoma (HCC). Here, we investigated the acetylation state of AFP in vivo. AFP acetylation was regulated by the acetyltransferase CBP and the deacetylase SIRT1. Acetylation of AFP at lysines 194, 211, and 242 increased the stability of AFP protein by decreasing its ubiquitination and proteasomal degradation. AFP acetylation promoted its oncogenic role by blocking binding to the phosphatase PTEN and the pro-apoptotic protein caspase-3, which increased signaling for proliferation, migration, and invasion and decreased apoptosis. High levels of acetylated AFP in HCC tissues were associated with HBV infection and correlated with poor prognosis and decreased patient survival. In HCC cells, hepatitis B virus X protein (HBx) and palmitic acid (PA) increased the level of acetylated AFP by disrupting SIRT1-mediated deacetylation. AFP acetylation plays an important role in HCC progression and provides a new potential prognostic marker and therapeutic target for HCC.

    更新日期:2019-12-05
  • Harnessing altered oxidative metabolism in cancer by augmented prooxidant therapy
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-04
    Malgorzata Firczuk, Malgorzata Bajor, Agnieszka Graczyk-Jarzynka, Klaudyna Fidyt, Agnieszka Goral, Radoslaw Zagozdzon

    Deregulated metabolism of oxygen with increased generation of reactive oxygen species (ROS) is characteristic for a majority of cancers. The elevated ROS levels are in part responsible for further progression of cancer, but when produced in a large excess, they endanger the viability of the cancer cells. To protect themselves from ROS-mediated toxicity, many types of cancers enhance the intrinsic antioxidant defenses, which make them dependent on the efficacy of a given ROS-detoxifying system. This poses an attractive target for anticancer therapy by two main approaches: the use of ROS-generating agents (i.e., prooxidants) or by inhibition of a chosen antioxidant system. However, the clinical efficacy of either of these approaches used alone is modest at best. The solution may rely on combining these strategies into an advanced prooxidant therapy (APoT) in order to produce a synergistic and cancer-specific effect. Indeed, such strategies have proven efficient in preclinical models, e.g., in B cell malignancies and breast cancer. Following promising experimental reports on APoT, this approach needs to be further extensively tested in order to become a potential alternative or an enhancement for classical chemotherapy.

    更新日期:2019-12-04
  • FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-04
    Chao Liu, Yan Zhao, Jianing Wang, Yan Yang, Yan Zhang, Xinliang Qu, Sishi Peng, Zhaoying Yao, Shuli Zhao, Bangshun He, Qiongyu Mi, Yubing Zhu, Xiuting Liu, Jianjun Zou, Xu Zhang, Qianming Du

    5-fluorouracil (5-FU) is widely used in chemotherapy for colorectal cancer (CRC), but a high rate of chemoresistance reduces its effectiveness in clinical treatment. We found remarkably decreased expression of forkhead box 3 (FoxO3) protein, a tumor inhibitor, in 5-FU-resistant SW620 and HCT-8 (SW620/5-FU and HCT-8/5-FU) cells. Moreover, FoxO3 overexpression sensitized SW620/5-FU and HCT-8/5-FU cells to 5-FU. Mechanistically, FoxO3 inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway by directly binding to Keap1 promoter. Thioredoxin reductase 1 (TR1), a pivotal target gene of Nrf2, was observed to promote 5-FU resistance by reducing intracellular ROS levels. Clinical data also revealed that significant upregulation of TR1 was associated with poor outcome in CRC patients. Auranofin (AUR), a FoxO3 agonist and TR1 inhibitor, enhanced the sensitivity of HCT-8/5-FU and SW620/5-FU cells to 5-FU in vitro and in vivo. Taken together, our results suggest that FoxO3 could reverse 5-FU resistance in CRC via inhibiting the Nrf2/TR1 signaling pathway, and increasing the level of intracellular reactive oxygen species. Chemotherapeutic agents targeting FoxO3 and/or TR1, including AUR, might be promising adjuvant sensitizers to reverse chemoresistance in 5-FU-resistant CRC.

    更新日期:2019-12-04
  • 2'-Hydroxyflavanone inhibits the progression of pancreatic cancer cells and sensitizes the chemosensitivity of EGFR inhibitors via repressing STAT3 signaling
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-04
    Yangyang Yue, Weikun Qian, Jie Li, Shiqi Wu, Mengzhao Zhang, Zheng Wu, Qingyong Ma, Zheng Wang

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and chemotherapy is still an important treatment. It is urgent to develop new medicines because of the limitation and side effects of chemotherapy. 2'-Hydroxyflavanone (2HF) is a citrus-bioflavonoid that is considered to have anti-cancer efficacy. Compared to human pancreatic ductal epithelial cells hTERT-HPNE, more significant growth-inhibitory effects were seen in PDAC cells BxPC-3 and MIA PaCa-2. We showed that apoptosis was induced and that the cell cycle was arrested when cells were treated with 2HF. The expression of the molecular proteins cleaved PARP, cleaved caspase3, BAX, BCL2, CyclinD1, and P27 changed correspondingly. Also, we observed anti-metastatic effects and changes in MMP9, E-cadherin, N-cadherin and Vimentin when cells were treated with a low dose of 2HF. Suppression of STAT3 and EGFR phosphorylation was also identified as a result of treatment with a combination of 2HF and EGFR inhibitors. The in vivo antitumor effects in KPC mice were consistent with those observed in vitro. 2HF has impactful anti-cancer efficacy and sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3.

    更新日期:2019-12-04
  • Immunotherapy for hepatocellular carcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-04
    Yin Zongyi, Li Xiaowu

    Despite significant research efforts, only a few treatment approaches have been developed for hepatocellular carcinoma (HCC). In recent years, immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies) have exhibited potential therapeutic effects for advanced HCC. With the development of gene-editing technologies, gene-sequencing technologies, big data strategies, and artificial intelligence algorithms, engineered immune cell infusion and personalized cancer vaccine therapy have emerged as important directions for anti-HCC treatment. Combining different immunotherapies or combining immunotherapies with conventional therapeutic approaches may provide synergistic effects and facilitate the development of personalized medicine. In this study, we provide an overview of the liver immunoanatomy, the potential immune mechanisms of HCC, and current (pre)clinical developments in this field.

    更新日期:2019-12-04
  • Radiomics model of magnetic resonance imaging for predicting pathological grading and lymph node metastases of extrahepatic cholangiocarcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-03
    Chunmei Yang, Mengping Huang, Shupan Li, Jianqiang Chen, Yao Yang, Na Qin, Deqing Huang, Jian Shu

    The aim of this study was to evaluate diagnostic performance of radiomics models of MRI in the detection of differentiation degree (DD) and lymph node metastases (LNM) of extrahepatic cholangiocarcinoma (ECC). We retrospectively enrolled 100 patients with ECC confirmed by pathology from January 2011 to December 2018. Three hundred radiomics features were extracted from each region of interest using MaZda software. Next, the radiomics model was developed by incorporating the optimal radiomics signatures and ADC values of tumors to predict DD (model A) and LNM (model B) of ECC, respectively, through the random forest algorithm. After which, the performance of the radiomics models were further evaluated. The model A showed better performance in both training and testing cohorts to discriminate high and medium-low differentiation groups of ECC, with an average AUC of 0.78 and 0.80, respectively. The model B also yielded the good average AUC of 0.80 and 0.90 to predict the LNM of ECC in training and testing cohorts. The radiomics models based on MRI performed well in predicting DD and LNM of ECC and have significant potential in clinical noninvasive diagnosis and in the prediction of ECC.

    更新日期:2019-12-04
  • VERU-111 suppresses tumor growth and metastatic phenotypes of cervical cancer cells through the activation of p53 signaling pathway
    Cancer Lett. (IF 6.508) Pub Date : 2019-12-03
    Vivek K. Kashyap, Nirnoy Dan, Neeraj Chauhan, Qinghai Wang, Saini Setua, Prashanth K.B. Nagesh, Shabnam Malik, Vivek Batra, Murali M. Yallapu, Duane D. Miller, Wei Li, Bilal B. Hafeez, Meena Jaggi, Subhash C. Chauhan

    In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the expression of phosphorylation of Jak2 (TyR1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the G2/M phase and modulated cell cycle regulatory proteins (cyclin B1, p21 p34cdc2 and pcdk1). Moreover, VERU-111 treatment induced apoptosis and modulated the expression of Bid, Bcl-xl, Survivin, Bax, Bcl2 and cleavage in PARP. In functional assays, VERU-111 markedly reduced the tumorigenic, migratory, and invasive potential of cervical cancer cells via modulations of MMPs. VERU-111 treatment also showed significant (P<0.05) inhibition of orthotopic xenograft tumor growth in athymic nude mice. Taken together, our results demonstrate the potential anti-cancer efficacy of VERU-111 in in vitro and in vivo. VERU-111 can be explored as a potent therapeutic agent for the treatment of cervical cancer.

    更新日期:2019-12-03
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