Unraveling diverse roles of noncoding RNAs in various human papillomavirus negative cancers
Introduction
Since the late half of this century, the understanding of the correlation between cancer and pathogen infection has been deepen increasingly with the cancer prevention moving forward. Among these related infections, human papillomavirus (HPV), as a noteworthy risk factor, is considered to have a direct relationship with carcinogenesis (Dunne & Park, 2013). According to HPV infection status, tumors in these anatomical sites were divided into two broad categories, HPV-associated and HPV-independent tumors (Lechner, Liu, Masterson, & Fenton, 2022). Although the sensitivity of HPV screening techniques is improving gradually, people found that there is always a fraction of cancer samples that are negative for HPV (Negri, Rigo, Vittadello, Mian, & Egarter-Vigl, 2007; De Sanjose et al., 2010; Rodriguez-Carunchio et al., 2015). Due to popularization of the cytological screening, colposcopy and an increase of HPV vaccination rate, the HPV infection rate is declining (Chabeda et al., 2018). Therefore, the occurrence of HPV-negative tumors may increase relatively. Because of the great difference in molecular mechanisms of tumorigenesis between the two cancer types, the sensitivity to chemoradiotherapy and the survival outcomes of HPV negative cancer were distinct from HPV positive cancer clinically (Costa, Boroni, & Soares, 2018). In addition, a large number of surveys consistently showed that HPV negative tumor was more likely to relapse and distant metastasize, and thought to be connected with worse prognosis (Riou et al., 1990; Higgins et al., 1991; Rodriguez-Carunchio et al., 2015).
In recent years, the regulatory functions of noncoding RNAs (ncRNAs) in various cellular processes have caused people's attention (Anastasiadou, Jacob, & Slack, 2018), and gradually been recognized as the important regulatory factors in the occurrence of various cancers (Martens-Uzunova et al., 2014; Chen, Lin, Shu, He, & Gao, 2020). Currently, HPV negative tumor regarded as an independently classified tumor has no definitive studies on its pathogenic mechanism, whereas multiply researches indicated that ncRNAs have the special connection with HPV negative cancer. Thus, it is urgent for us to explore the specialness of ncRNAs in gene expression levels and downstream signaling pathway as well as to identify the prognostic biomarkers and therapeutic targets in HPV negative tumor. In this review, we summarized the abnormally expressed ncRNAs in HPV negative tumors and their mechanisms of tumorigenesis and progression.
Section snippets
Occurrence and types of HPV negative cancer
HPV, a double-stranded DNA virus family, has a tropism for squamous epithelial cells of the skin, genital tract, as well as oral mucosa (Tommasino, 2014). Low-risk HPV types lead to warts and benign tumors, while persistent infection with high-risk types of HPV is a driving factor in some squamous origin malignancies. HPV has been proved to be a leading cause of the cervical cancer, mainly cervical squamous cell carcinoma (Munoz et al., 1992; Walboomers et al., 1999; Bosch, Lorincz, Munoz,
Noncoding RNAs
At one time, noncoding regions were considered as useless sequences in genome regulation. People only pay attention to the protein coding part that accounts for 2% of the entire genome (Alexander, Fang, Rozowsky, Snyder, & Gerstein, 2010). Since microRNAs (miRNAs), a family of small ncRNAs (sncRNAs), were discovered in Caenorhabditis elegans and played a critical role in developmental transitions (Pasquinelli & Ruvkun, 2002), the functions of noncoding RNAs in regulation of various cell life
Noncoding RNAs in HPV negative cervical cancer
Cervical cancer, one of the largest gynecological malignancies, is the primary cause of cancer death among females around the world. It is estimated that there will be about 14,480 new cases and account for 4290 deaths this year in the United States (Siegel, Miller, Fuchs, & Jemal, 2021). Based on the understanding of HPV infection and cancer development, HPV vaccines have been widely inoculated and self-awareness of HPV screening has been improved. The overall incidence of HPV-related cancer
NcRNAs in HPV-negative head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma(HNSCC)refers to a general term, which includes tumors arisen from epithelium of oral cavity, pharynx and larynx (Johnson et al., 2020). It is estimated approximately 870,000 new cases and 440,000 deaths in 2021, and ranked the sixth largest tumor in the world (Sung et al., 2021). Unfortunately, the survival rates of HNSCC were not improved, although the tumors were surgically resected or treated with adjuvant chemoradiotherapy (Hunter, Parkinson, &
NcRNAs in HPV negative pharyngeal squamous cell carcinoma (PSCC)
Although the vast majority of pharyngeal cancers are caused by HPV infection, one study found that there were 21 miRNAs with differential expressions between HPV-positive PSCC and HPV-negative PSCC (Lajer et al., 2011). HPV-negative cancers show a much higher degree of genome-wide hypomethylation. It has been suggested that HPV negative cancers are far less genomically stable relative to their HPV-positive counterparts (Richards et al., 2009; Sartor et al., 2011; Van Kempen et al., 2014),
NcRNAs in HPV-negative oral squamous cell carcinoma (OSCC)
In HNSCC, oral carcinoma is a typical type of cancer associated with high risk factors such as tobacco and alcohol, and 95% of these are HPV-negative (Panarese et al., 2019). It is estimated that there are about 35,500 new cases and 7000 deaths in America in 2021 (Siegel et al., 2021). The 5-year survival rate for diagnosed patients is less than 50%, even after the treatment of surgery, radiation, chemotherapy and targeted drugs (Califano et al., 1996). Previous experimental evidence has been
NcRNAs in other HPV negative carcinomas
There is a small percentage of HPV negative tumors occurring in areas other than the uterine cervix or head and neck, which is strongly associated with tobacco and alcohol exposure. It has been widely reported that cigarette smoke may affect the regulation of ncRNAs to reduce the dysregulation and damage of genetic or epigenetic (Calin & Croce, 2006; Russ & Slack, 2012). Liu et al. detected cellular miRNAs in plasma and serum, and found that the relative expression of circulating miR-155 and
Conclusions and perspectives
In conclusions, ncRNAs are involved in the huge regulatory network, effecting gene expression. These ncRNAs play significant roles through regulating multiple pathways in driving cell physiology and etiopathology reaction, especially the occurrence and carcinogenesis of various tumors. HPV negative carcinoma is an independent type of tumor, characterized by poor prognosis and obstacle in early diagnosis. It has been widely accepted that lncRNAs can serve as competing endogenous RNAs, binding to
Funding
This work was supported by a grant from the Natural Science Foundation of Zhejiang Province (No. LY21H160060).
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
References (180)
- et al.
TGF-beta signaling in cancer – a double-edged sword
Trends in Cell Biology
(2001) - et al.
Head and neck cancer
Lancet
(2008) - et al.
Long noncoding RNAs: Cellular address codes in development and disease
Cell
(2013) - et al.
Therapeutic vaccines for high-risk HPV-associated diseases
Papillomavirus Research
(2018) - et al.
MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma
Oral Oncology
(2013) - et al.
Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma
The American Journal of Pathology
(2009) - et al.
miR-211 promotes the progression of head and neck carcinomas by targeting TGFbetaRII
Cancer Letters
(2013) - et al.
Long non-coding RNA: Classification, biogenesis and functions in blood cells
Molecular Immunology
(2019) - et al.
Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis
The Lancet Global Health
(2020) - et al.
Human papillomavirus genotype attribution in invasive cervical cancer: A retrospective cross-sectional worldwide study
The Lancet Oncology
(2010)
Long non-coding RNAs regulate the hallmarks of cancer in HPV-induced malignancies
Critical Reviews in Oncology/Hematology
HPV and HPV-associated diseases
Infectious Disease Clinics of North America
Increased expression of the long non-coding RNA UCA1 in tongue squamous cell carcinomas: A possible correlation with cancer metastasis
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology
LncRNA-CTS promotes metastasis and epithelial-to-mesenchymal transition through regulating miR-505/ZEB2 axis in cervical cancer
Cancer Letters
HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer
Oral Oncology
Long noncoding RNAs in cell-fate programming and reprogramming
Cell Stem Cell
Increased age and mortality associated with cervical carcinomas negative for human papillomavirus RNA
Lancet
Association between the rs2910164 polymorphism in pre-mir-146a and oral carcinoma progression
Oral Oncology
miR-29b suppresses proliferation, migration, and invasion of tongue squamous cell carcinoma through PTEN-AKT signaling pathway by targeting Sp1
Oral Oncology
Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs
Drug Resistance Updates
High-risk human papillomavirus is transcriptionally active in a subset of sinonasal squamous cell carcinomas
Modern Pathology
Long non-coding RNA linc00460 promotes epithelial-mesenchymal transition and cell migration in lung cancer cells
Cancer Letters
LncRNA, TUG1 regulates the oral squamous cell carcinoma progression possibly via interacting with Wnt/beta-catenin signaling
Gene
miR-140-3p impedes the proliferation of human cervical cancer cells by targeting RRM2 to induce cell-cycle arrest and early apoptosis
Bioorganic & Medicinal Chemistry
Long noncoding RNA in prostate, bladder, and kidney cancer
European Urology
Expressions of miR-30c and let-7a are inversely correlated with HMGA2 expression in squamous cell carcinoma of the vulva
Oncotarget
Annotating non-coding regions of the genome
Nature Reviews. Genetics
Non-coding RNA networks in cancer
Nature Reviews. Cancer
MicroRNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis
Journal of Oral Pathology & Medicine
Non-coding RNAs in development and disease: Background, mechanisms, and therapeutic approaches
Physiological Reviews
RNA meets chromatin
Genes & Development
The causal relation between human papillomavirus and cervical cancer
Journal of Clinical Pathology
Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. International biological study on cervical cancer (IBSCC) Study group
Journal of the National Cancer Institute
Genetic progression model for head and neck cancer: Implications for field cancerization
Cancer Research
MicroRNA signatures in human cancers
Nature Reviews. Cancer
Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia
Proceedings of the National Academy of Sciences of the United States of America
MiR-23b-3p reduces the proliferation, migration and invasion of cervical cancer cell lines via the reduction of c-met expression
Scientific Reports
Integrated genomic and molecular characterization of cervical cancer
Nature
HPV involvement in Head and Neck cancers: Comprehensive assessment of biomarkers in 3680 patients
Journal of the National Cancer Institute
Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer
Oncology Reports
miR-375-3p inhibits the progression of laryngeal squamous cell carcinoma by targeting hepatocyte nuclear factor-1beta
Oncology Letters
MicroRNA15a5ptargeting oncogene YAP1 inhibits cell viability and induces cell apoptosis in cervical cancer cells
International Journal of Molecular Medicine
Plant and animal small RNA communications between cells and organisms
Nature Reviews. Molecular Cell Biology
Interaction between N(6)-methyladenosine (m(6)A) modification and noncoding RNAs in cancer
Molecular Cancer
Long non-coding RNA ZEB1-AS1 promotes cell invasion and epithelial to mesenchymal transition through inducing ZEB1 expression in cervical cancer
Oncotargets and Therapy
Impacts of microRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer
PLoS One
LINC00460 is a dual biomarker that acts as a predictor for increased prognosis in basal-like breast Cancer and potentially regulates immunogenic and differentiation-related genes
Frontiers in Oncology
Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq
Oncotarget
Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer
Scientific Reports
Long noncoding RNA MEG3, a potential novel biomarker to predict the clinical outcome of cancer patients: A meta-analysis
Oncotarget
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