MicroRNA in Cervical Carcinogenesis: Window of Therapeutic Potential

Author(s): Shiksha Sharma , Minakshi Vashist* .

Journal Name: Current Women`s Health Reviews

Volume 15 , Issue 3 , 2019

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Graphical Abstract:


Background: Cervical cancer is the second leading malignancy for women. In developing countries, it is becoming a public health trouble in adult women. Persistent cervical infection with high-risk human papillomavirus (HPV) may contribute to the development of cervical cancer. The danger is in the fact that woman with HPV can go unnoticed for years. So, women with early cervical cancer and pre-malignant neoplastic disease show no symptoms, until cancer becomes invasive and grows into the nearby tissue. A large number of females die from the disease each year due to late diagnosis and resistance to conventional treatment. In particular, in advanced tumor stage, low response to chemotherapy results in poor prognosis and recurrence. Therefore, new therapies and indicators are needed to overcome chemo-resistance as well as early diagnosis of cancer. There is a continuous search for prognostic and predictive markers in order to help optimize and personalize treatment for improvement in the outcome of cervical cancer.

Recent Findings: Non-coding regulatory RNAs that control gene expression at the posttranscriptional level are seeking the attention of scientists in this area. Certain microRNAs have been located near cancer susceptibility loci that correlate tumorgenesis. Multiple profiling studies have revealed a significant change in miRNA expression in cervical cancer patients. A number of miRNAs have shown a consistent up-regulation or down regulation throughout the different stages of cervical cancer.

Conclusion: Investigation of microRNAs involved in carcinogenesis and progression of cervical cancer in tissue-specific manner is opening a window in early diagnosis and therapeutics.

Keywords: Cervical cancer, carcinogenesis, microRNA, oncomir, tumor suppressor RNA and therapeutics, chemotherapy.

Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide IARC Cancer Base No 5Lyon, France. International Agency for Research on Cancer 2001.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. Cancer J Clin 2005; 55: 74-108.
De Villiers EM, Fauquet C, Broker TR. Classification of papillomaviruses. Virology 2004; 324: 17-27.
Moodley M, Moodley J, Chetty R, Herrington CS. The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: A review. Int J Gynecol Cancer 2003; 13(2): 103-10.
Shields TS, Brinton LA, Burk RD, et al. A case-control study of risk factors for invasive cervical cancer among U.S. women exposed to oncogenic types of human papillomavirus. Cancer Epidemiol Biomarkers Prev 2004; 13(10): 1574-82.
Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997; 350: 535-40.
Quinn MA, Benedet JL, Odicino F, et al. Carcinoma of the cervix uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006; 95(1): S43-S103.
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75(5): 843-54.
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med 2006; 12(12): 580-7.
Calin GA. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999-3004.
Calin GA, Croce CM. Chromosomal rearrangements and microRNAs: A new cancer link with clinical implications. J Clin Invest 2007; 117: 2059-66.
Sevignani C. MicroRNA genes are frequently located near mouse cancer susceptibility loci. Proc Natl Acad Sci USA 2007; 104: 8017022.
Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524-9.
Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis: A primer. Am J Pathol 2007; 171(3): 728-38.
Bandyopadhyay S, Mitra R, Maulik U, Zhang MQ. Development of the human cancer microRNA network. Silence 2010; 1(1): 6.
Lee Y, Ahn C, Han J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425(6956): 415-9.
Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the microprocessor complex. Nature 2004; 432(7014): 231-5.
Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 2006; 13(12): 1097-101.
Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 2004; 10(2): 185-91.
He L, Wang HY, Zhang L, et al. Prognostic significance of low DICER expression regulated by miR-130a in cervical cancer. Cell Death Dis 2014; 5(5): e1205.
Sandra LRC, Ivan SG, Alfredo HM. miRNA biogenesis: Biological impact in the development of cancer. Cancer Biol Ther 2014; 15(11): 1444-55.
Bahrami A, Hasanzadeh M, Hassanian SM, et al. The potential value of the PI3K/Akt/mTOR signaling pathway for assessing prognosis in cervical cancer and as a target for therapy. J Cell Biochem 2017; 118(12): 4163-9.
Teng P, Jiao Y, Hao M, Tang X. microRNA-383 suppresses the PI3K-AKT-MTOR signaling pathway to inhibit development of cervical cancer via down-regulating PARP2: Role of miR-383 in cervical cancer. J Cell Biochem 2017; 11(7): 5243-52.
Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435(7043): 834-8.
Haraguchi T, Ozaki Y, Iba H. Vectors expressing efficient RNA decoys achieves the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res 2009; 37(6): e43.
Zhang J, Zhao X, Zhang J, Zheng X, Li F. Circular RNA hsa_circ_0023404 exerts an oncogenic role in cervical cancer through regulating miR-136/TFCP2/YAP pathway. Biochem Biophys Res Commun 2018; 501(2): 428-33.
Zhao S, Yao D, Chen J, Ding N. Circulating miR-20 and miR-203 for screening lymph node metastasis in early stage cervical cancer. Genet Test Mol Biomarkers 2013; 17: 631-6.
Wang X, Tang S, Le SY, et al. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One 2008; 3(7): e2557.
Pereira PM, Marques JP, Soares AR, Carreto L, Santos MA. MicroRNA expression variability in human cervical tissues. PLoS One 2010; 5(7): e11780.
Yao Q, Xu H, Zhang QQ, et al. MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun 2009; 388: 539-42.
Kang HW, Wang F, Wei Q. miR-20a promotes migration and invasion by regulating TNKS2 in human cervical cancer cells. FEBS Lett 2012; 586: 897-904.
Qin W, Dong P, Ma C. MicroRNA-133b is a key promoter of cervical carcinoma development through the activation of the ERK and AKT1 pathways. Oncogene 2011; 31: 4067-75.
Lao G, Liu P, Wu Q, et al. Mir-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1. Tumour Biol 2014; 35(12): 11933-8.
Zhou C, Li G, Zhou J, Han N, Liu Z, Yin J. miR-107 activates ATR/Chk1 pathway and suppress cervical cancer invasion by targeting MCL1. PLoS One 2014; 9(11): e111860.
Liu P, Xin F, Ma CF. Clinical significance of serum miR-196a in cervical intraepithelial neoplasia and cervical cancer. Genet Mol Res 2015; 14: 17995-8002.
Vojtechova Z, Sabol L, Salakova M, et al. Comparison of the miRNA profiles in HPV-positive and HPV-negative tonsillar tumors and a model system of human keratinocyte clones. BMC Cancer 2016; 16: 382.
Li J, Hu L, Tian C, Lu F, Wu J, Liu L. microRNA-150 promotes cervical cancer cell growth and survival by targeting FOXO4. BMC Mol Biol 2015; 16: 24.
Hou T, Ou J, Zhao X, Huang X, Huang Y, Zhang Y. MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. Br J Cancer 2014; 110: 1260-8.
Zhang Y, Zhang D, Wang F, Xu D, Guo Y, Cui W. Serum miRNAs panel (miR-16-2*, miR-195, miR-2861, miR-497) as novel non-invasive biomarkers for detection of cervical cancer. Sci Rep 2015; 5: 17942.
Huang N, Wu J, Qiu W. MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of camptothecin. Cancer Biol Ther 2015; 16: 941-8.
Yang YK, Xi WY, Xi RX, Li JY, Li Q, Gao YE. MicroRNA-494 promotes cancer prolifiratio through ht regulation of PTEN. Oncol Rep 2015; 33(5): 2393-401.
Fei L, Shimeng Z, Zhen Z, et al. MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer. Oncotarget 2016; 7(15): 19666-79.
Li GC, Cao XY, Li YN, et al. MicroRNA-374b inhibits cervical cancer cell proliferation and induces apoptosis through the p38/ERK signaling pathway by binding to JAM-2. J Cell Physiol 2018; 233(9): 7379-90.
Jaceline G, Pires S, Yunchao X, Iddrisu BY, Min L, Ying L. miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. Chem Biol Interact 2018; 285: 85-95.
Chakrabarti M, Banik NL, Ray SK. miR-138 overexpression is more than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo. Exp Cell Res 2013; 319: 1575-85.
Pang RT, Leung CO, Ye TM, et al. MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. Carcinogenesis 2010; 31: 1037-44.
Wei Q, Li YX, Liu M, Li X, Tang H. miR-17-5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells. IUBMB Life 2012; 64(8): 697-704.
Rao Q, Shen Q, Zhou H, Peng Y, Li J, Lin Z. Aberrant microRNA expression in human cervical carcinomas. Med Oncol 2012; 29: 1242-8.
Zou D, Zhou Q, Wang D, Guan L, Yuan L, Li S. The downregulation of microRNA-10b and its role in cervical cancer. Oncol Res 2016; 24: 99-108.
Hesselink AT, Heideman DA, Steenbergen RD. Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy. Int J Cancer 2014; 135: 880-6.
Snellenberg S, de Strooper LM, Hesselink AT. Development of a multiplex methylation-specific PCR as candidate triage test for women with an HPV-positive cervical scrape. BMC Cancer 2012; 12: 551.
Wilting SM, Van Boerdonk RA, Henken FE, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer 2010; 9: 167.
Song X, Shi B, Huang K, Zhang W. miR-133a inhibits cervical cancer growth by targeting EGFR. Oncol Rep 2015; 34: 1573-80.
Liu S, Zhang P, Chen Z, Liu M, Li X, Tang H. MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett 2013; 587: 2247-53.
Hao Z, Yang J, Wang C, et al. MicroRNA-7 inhibits metastasis and invasion through targeting focal adhesion kinase in cervical cancer. Int J Clin Exp Med 2015; 8: 480-7.
Zhou LL, Shen Y, Gong JM, Sun P, Sheng JH. MicroRNA-466 with tumor markers for cervical cancer screening. Oncotarget 2017; 8(41): 70821-7.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall LO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9.
Xu J, Li Y, Wang F, et al. Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene 2013; 32(8): 976-87.
Gocze K, Gombos K, Juhasz K. Unique microRNA expression profiles in cervical cancer. Anticancer Res 2013; 33(6): 2561-7.
Wang F, Zhang QW, Fu XH, Wang HF, Liu YL. Expressions and clinic significance of miRNA-143, miRNA-34A, miRNA-944, miRNA-101 and miRNA-218 in cervical cancer tissues. Trop J Pharm Res 2016; 15(7): 1387-92.
Osaki M, Takeshita F, Ochiya T. MicroRNAs as biomarkers and therapeutic drugs in human cancer. Biomarkers 2008; 13: 658-70.
Liu L, Yu X, Guo X. miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep 2012; 5(3): 753-60.
Lee JW, Choi CH, Choi JJ, et al. Altered microRNA expression in cervical carcinomas. Clin Cancer Res 2008; 14: 2535-42.
Phuah NH, In LL, Azmi MN, Ibrahim H, Awang K, Nagoor NH. Alterations of MicroRNA expression patterns in human cervical carcinoma cells (Ca Ski) toward 1′S-1′-acetoxychavicol acetate and cisplatin. Reprod Sci 2013; 20(5): 567-78.
Zhang J, Zheng F, Yu G, Yin Y, Lu Q. MiR-196a targets netrin 4 and regulates cell proliferation and migration of cervical cancer cells. Biochem Biophys Res Commun 2013; 440: 582-8.
Wang JM, Ju BH, Pan CJ, et al. MiR-214 inhibits cell migration, invasion and promotes the drug sensitivity in human cervical cancer by targeting FOXM1. Am J Transl Res 2017; 9(8): 3541-57.
Chen Y, Ke G, Han D, Liang S, Yang G, Wu X. MicroRNA-181a enhances the chemoresistance of human cervical squamous cell carcinoma to cisplatin by targeting PRKCD. Exp Cell Res 2014; 320: 12-20.

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Year: 2019
Page: [171 - 178]
Pages: 8
DOI: 10.2174/1573404814666181102150558
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