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miR-193a-5p as a promising therapeutic candidate in colorectal cancer by reducing 5-FU and Oxaliplatin chemoresistance by targeting CXCR4
International Immunopharmacology ( IF 4.8 ) Pub Date : 2021-01-08 , DOI: 10.1016/j.intimp.2020.107355
Mohammad Reza Mohammad Hoseini Azar 1 , Hamed Aghazadeh 2 , Halgurd Nadhim Mohammed 3 , Mehdi Rezai Seghin Sara 4 , Arezoo Hosseini 5 , Navid Shomali 6 , Rozita Tamjidifar 7 , Saeed Tarzi 7 , Mahmoud Mansouri 8 , Sahar Pashaei Sarand 9 , Faroogh Marofi 10 , Morteza Akbari 5 , Huaxi Xu 11 , Siamak Sandoghchian Shotorbani 12
Affiliation  

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. The role of microRNAs (miRNAs/miRs) as small (19–25 nucleotides in length) non-coding RNA molecules that modify gene expression has been shown in several types of cancer. 5-Fluorouracil (5-FU) and oxaliplatin (Ox) are two common chemotherapeutic agents used to treat cancer. The present study aimed to evaluate the expression levels of miR-193a-5p in CRC, and its effect on the C-X-C Motif Chemokine Receptor 4 (CXCR4) target gene alone and in combination with chemotherapeutic drugs, to determine its possible role in chemoresistance. CRC tissues and adjacent non-cancerous tissue were obtained from 67 patients who had undergone surgery to determine the expression levels of miR-193a-5p and CXCR4. Subsequently, qPCR and Western blotting were performed to determine the effect of miR-193a-5p and chemotherapy drugs on CXCR4. َAlso, MTT assay, and flow cytometry was performed to determine their role in cell viability and apoptosis. Besides, the relationship between miR-193a-5p and CXCR4 with patients' clinical features was investigated. The results of the present study showed that miR-193a-5p was significantly downregulated, whereas CXCR4 was significantly upregulated in tumor tissues obtained from patients with CRC compared with the adjacent non-tumor healthy controls. In addition, the upregulation of miR-193-5p reduced the expression levels of CXCR4, particularly in combination with 5-FU and OX. Besides, using rescue experiments, the present study showed that miR-193a-5p replacement was able to suppress CXCR4-induced CRC cell proliferation by directly targeting CXCR4. Furthermore, there was a significant association between miR-193a-5p and CXCR4 with certain clinicopathological characteristics, particularly with metastasis-related features. These results suggest that miR-193a-5p serves a tumor-suppressive function in CRC and can directly target CXCR4 and decrease its mRNA and protein expression levels. Additionally, miR-193a-5p in combination with 5-FU and Ox potentiated reducing CXR4 expression, which may reveal its contribution to tumor chemoresistance. In conclusion, miR-193-5p may be applicable as a prognostic and diagnostic marker, and also serve as a therapeutic factor by reducing CXCR4 in combination with chemotherapeutic drugs.



中文翻译:

通过靶向CXCR4降低5-FU和奥沙利铂的化学耐药性,miR-193a-5p在结直肠癌中有望成为有希望的治疗候选药物

结直肠癌(CRC)是全世界与癌症相关的死亡的最常见原因之一。在几种类型的癌症中,已经证明了微小的RNA(miRNA / miRs)小(长度为19–25个核苷酸)非编码RNA分子可以改变基因的表达。5-氟尿嘧啶(5-FU)和奥沙利铂(Ox)是用于治疗癌症的两种常见化疗药物。本研究旨在评估miR-193a-5p在CRC中的表达水平及其对CXC基序趋化因子受体4(CXCR4)目标基因的作用以及与化疗药物联合使用的作用,以确定其在化学耐药性中的作用。从67位接受手术以确定miR-193a-5p和CXCR4表达水平的患者中获得了CRC组织和邻近的非癌性组织。后来,进行qPCR和Western印迹以确定miR-193a-5p和化疗药物对CXCR4的作用。َ还进行了MTT测定和流式细胞术以确定它们在细胞活力和凋亡中的作用。此外,还研究了miR-193a-5p和CXCR4与患者临床特征之间的关系。本研究的结果表明,与邻近的非肿瘤健康对照组相比,在患有CRC的患者的肿瘤组织中miR-193a-5p显着下调,而CXCR4显着上调。此外,miR-193-5p的上调降低了CXCR4的表达水平,特别是与5-FU和OX联合使用时。此外,利用救援实验 本研究表明,通过直接靶向CXCR4,替代miR-193a-5p能够抑制CXCR4诱导的CRC细胞增殖。此外,miR-193a-5p和CXCR4与某些临床病理特征(尤其是与转移相关的特征)之间存在显着关联。这些结果表明,miR-193a-5p在CRC中具有肿瘤抑制功能,可以直接靶向CXCR4,并降低其mRNA和蛋白质表达水平。此外,miR-193a-5p与5-FU和Ox的组合可增强CXR4表达,这可能表明其对肿瘤化学耐药性的贡献。总之,miR-193-5p可以用作预后和诊断标志物,还可以通过与化学治疗药物联合使用降低CXCR4来作为治疗因素。miR-193a-5p和CXCR4与某些临床病理特征(尤其是与转移相关的特征)之间存在显着关联。这些结果表明,miR-193a-5p在CRC中具有肿瘤抑制功能,可以直接靶向CXCR4,并降低其mRNA和蛋白质表达水平。此外,miR-193a-5p与5-FU和Ox的组合可增强CXR4表达,这可能表明其对肿瘤化学耐药性的贡献。总之,miR-193-5p可以用作预后和诊断标志物,还可以通过与化学治疗药物联合使用降低CXCR4来作为治疗因素。miR-193a-5p和CXCR4与某些临床病理特征(尤其是与转移相关的特征)之间存在显着关联。这些结果表明,miR-193a-5p在CRC中具有肿瘤抑制功能,可以直接靶向CXCR4,并降低其mRNA和蛋白质表达水平。此外,miR-193a-5p与5-FU和Ox的组合可增强CXR4表达,这可能表明其对肿瘤化学耐药性的贡献。总之,miR-193-5p可以用作预后和诊断标志物,还可以通过与化学治疗药物联合使用降低CXCR4来作为治疗因素。这些结果表明,miR-193a-5p在CRC中具有肿瘤抑制功能,可以直接靶向CXCR4,并降低其mRNA和蛋白质表达水平。此外,miR-193a-5p与5-FU和Ox的组合可增强CXR4表达,这可能表明其对肿瘤化学耐药性的贡献。总之,miR-193-5p可以用作预后和诊断标志物,还可以通过与化学治疗药物联合使用降低CXCR4来作为治疗因素。这些结果表明,miR-193a-5p在CRC中具有肿瘤抑制功能,可以直接靶向CXCR4,并降低其mRNA和蛋白质表达水平。此外,miR-193a-5p与5-FU和Ox的组合可增强CXR4表达,这可能表明其对肿瘤化学耐药性的贡献。总之,miR-193-5p可以用作预后和诊断标志物,还可以通过与化学治疗药物联合使用降低CXCR4来作为治疗因素。

更新日期:2021-01-08
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