miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6

Hu,Qiming; Song,Jiacheng; Ding,Bo; Cui,Yugui; Liang,Jiale; Han,Suping

doi:10.3892/or.2018.6391

miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6

Authors:
- Qiming Hu
- Jiacheng Song
- Bo Ding
- Yugui Cui
- Jiale Liang
- Suping Han
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Affiliations: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China, Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China, Department of Obstetrics and Gynecology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
Published online on: April 23, 2018 https://doi.org/10.3892/or.2018.6391
Pages: 3015-3024

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Abstract

Cervical cancer is the third most common type of cancer in women, and microRNAs play an important role in this type of cancer. The elevated expression of miR-146a is involved in the pathogenesis of cancers generally, but its role in cervical cancer has not been fully elucidated. In the present study, we assessed the expression of miR-146a in G>C polymorphisms and confirmed that the overexpression of miR-146a promoted cervical cancer cell viability. The recombinant expression plasmids pre-miR-146a-G or pre-miR-146a-C including single nucleotide polymorphisms (SNP) were successfully constructed. Pre-miR-146a-G or pre-miR-146a-C was transfected into cervical cancer cells or immortalized non-tumorigenic cells and the expression of miR-146a was evaluated by real-time PCR. The cell viability, cell-cycle analysis and apoptosis were assessed using Cell Counting Kit-8 assay (CCK-8), flow cytometry and cleaved caspase-3 protein expression, respectively. The expression of interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and cyclin D1 was assessed following the transfection with a miR-146a mimic or a negative control. The cell viability and the number of S-phase cells increased after transfection with miR-146a mimic or an IRAK1 or TRAF6 interference fragment. After transfection, IRAK1 and TRAF6 protein expression was downregulated and the expression of cyclin D1 was upregulated, however apoptosis and cleaved caspase-3 were not affected. Polymorphisms in miR-146a precursor may be linked to the expression of miR-146a and may be a potential target for cervical cancer therapy.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	de Freitas AC, Gomes Leitão MC and Coimbra EC: Prospects of molecularly-targeted therapies for cervical cancer treatment. Curr Drug Targets. 16:77–91. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
4	Schiffman M, Castle PE, Jeronimo J, Rodriguez AC and Wacholder S: Human papillomavirus and cervical cancer. Lancet. 370:890–907. 2007. View Article : Google Scholar : PubMed/NCBI
5	Scheurer ME, Tortolero-Luna G and Adler-Storthz K: Human papillomavirus infection: Biology, epidemiology, and prevention. Int J Gynecol Cancer. 15:727–746. 2005. View Article : Google Scholar : PubMed/NCBI
6	Castellsagué X, Naud P, Chow SN, Wheeler CM, Germar MJ, Lehtinen M, Paavonen J, Jaisamrarn U, Garland SM, Salmerón J, et al: Risk of newly detected infections and cervical abnormalities in women seropositive for naturally acquired human papillomavirus type 16/18 antibodies: Analysis of the control arm of PATRICIA. J Infect Dis. 210:517–534. 2014. View Article : Google Scholar : PubMed/NCBI
7	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
8	Murchison EP, Stein P, Xuan Z, Pan H, Zhang MQ, Schultz RM and Hannon GJ: Critical roles for Dicer in the female germline. Genes Dev. 21:682–693. 2007. View Article : Google Scholar : PubMed/NCBI
9	Magnusson PK, Lichtenstein P and Gyllensten UB: Heritability of cervical tumours. Int J Cancer. 88:698–701. 2000. View Article : Google Scholar : PubMed/NCBI
10	Wu M, Jolicoeur N, Li Z, Zhang L, Fortin Y, L'Abbe D, Yu Z and Shen SH: Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs. Carcinogenesis. 29:1710–1716. 2008. View Article : Google Scholar : PubMed/NCBI
11	Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR and de la Chapelle A: Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA. 105:7269–7274. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zavala V, Pérez-Moreno E, Tapia T, Camus M and Carvallo P: miR-146a and miR-638 in BRCA1-deficient triple negative breast cancer tumors, as potential biomarkers for improved overall survival. Cancer Biomark. 16:99–107. 2016. View Article : Google Scholar : PubMed/NCBI
13	Liu R, Liu C, Chen D, Yang WH, Liu X, Liu CG, Dugas CM, Tang F, Zheng P, Liu Y, et al: FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells. Cancer Res. 75:1703–1713. 2015. View Article : Google Scholar : PubMed/NCBI
14	Zhang S, Liu F, Mao X, Huang J, Yang J, Yin X, Wu L, Zheng L and Wang Q: Elevation of miR-27b by HPV16 E7 inhibits PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells. Int J Oncol. 47:1759–1766. 2015. View Article : Google Scholar : PubMed/NCBI
15	Liu F, Zhang S, Zhao Z, Mao X, Huang J, Wu Z, Zheng L and Wang Q: MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer. Oncotarget. 7:19666–19679. 2016.PubMed/NCBI
16	Peralta-Zaragoza O, Deas J, Meneses-Acosta A, De la O-Gómez F, Fernández-Tilapa G, Gómez-Cerón C, Benítez-Boijseauneau O, Burguete-García A, Torres-Poveda K, Bermúdez-Morales VH, et al: Relevance of miR-21 in regulation of tumor suppressor gene PTEN in human cervical cancer cells. BMC Cancer. 16:2152016. View Article : Google Scholar : PubMed/NCBI
17	Leung CO, Deng W, Ye TM, Ngan HY, Tsao SW, Cheung AN, Pang RT and Yeung WS: miR-135a leads to cervical cancer cell transformation through regulation of β-catenin via a SIAH1-dependent ubiquitin proteosomal pathway. Carcinogenesis. 35:1931–1940. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zhou X, Yue Y, Wang R, Gong B and Duan Z: MicroRNA-145 inhibits tumorigenesis and invasion of cervical cancer stem cells. Int J Oncol. 50:853–862. 2017. View Article : Google Scholar : PubMed/NCBI
19	Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, Yang CY, Tsai YP, Lin CH, Wang HW, et al: MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nat Cell Biol. 16:268–280. 2014. View Article : Google Scholar : PubMed/NCBI
20	Park H, Huang X, Lu C, Cairo MS and Zhou X: MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 290:2831–2841. 2015. View Article : Google Scholar : PubMed/NCBI
21	Perry MM, Moschos SA, Williams AE, Shepherd NJ, Larner-Svensson HM and Lindsay MA: Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J Immunol. 180:5689–5698. 2008. View Article : Google Scholar : PubMed/NCBI
22	Contreras JR, Palanichamy JK, Tran TM, Fernando TR, Rodriguez-Malave NI, Goswami N, Arboleda VA, Casero D and Rao DS: MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1. Oncotarget. 6:11023–11037. 2015. View Article : Google Scholar : PubMed/NCBI
23	Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z and Cao X: MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 183:2150–2158. 2009. View Article : Google Scholar : PubMed/NCBI
24	Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J and Benz CC: Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 27:5643–5647. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ito-Kureha T, Koshikawa N, Yamamoto M, Semba K, Yamaguchi N, Yamamoto T, Seiki M and Inoue J: Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth. Cancer Res. 75:62–72. 2015. View Article : Google Scholar : PubMed/NCBI
26	Kastrati I, Canestrari E and Frasor J: PHLDA1 expression is controlled by an estrogen receptor-NFκB-miR-181 regulatory loop and is essential for formation of ER⁺ mammospheres. Oncogene. 34:2309–2316. 2015. View Article : Google Scholar : PubMed/NCBI
27	McManus MT: MicroRNAs and cancer. Semin Cancer Biol. 13:253–258. 2003. View Article : Google Scholar : PubMed/NCBI
28	Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C and Zheng ZM: Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 3:e25572008. View Article : Google Scholar : PubMed/NCBI
29	Sathyanarayanan A, Chandrasekaran KS and Karunagaran D: microRNA-146a inhibits proliferation, migration and invasion of human cervical and colorectal cancer cells. Biochem Biophys Res Commun. 480:528–533. 2016. View Article : Google Scholar : PubMed/NCBI
30	Duan R, Pak C and Jin P: Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 16:1124–1131. 2007. View Article : Google Scholar : PubMed/NCBI
31	Yue C, Wang M, Ding B, Wang W, Fu S, Zhou D, Zhang Z and Han S: Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. Gynecol Oncol. 122:33–37. 2011. View Article : Google Scholar : PubMed/NCBI
32	Sarkar FH, Li Y, Wang Z and Kong D: Cellular signaling perturbation by natural products. Cell Signal. 21:1541–1547. 2009. View Article : Google Scholar : PubMed/NCBI
33	Lin Y, Bai L, Chen W and Xu S: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets. 14:45–55. 2010. View Article : Google Scholar : PubMed/NCBI
34	Kim JE, Kim SY, Lim SY, Kieff E and Song YJ: Role of Ca²⁺/calmodulin-dependent kinase II-IRAK1 interaction in LMP1-induced NF-κB activation. Mol Cell Biol. 34:325–334. 2014. View Article : Google Scholar : PubMed/NCBI
35	Gao M, Wang X, Zhang X, Ha T, Ma H, Liu L, Kalbfleisch JH, Gao X, Kao RL, Williams DL, et al: Attenuation of cardiac dysfunction in polymicrobial sepsis by microRNA-146a is mediated via targeting of IRAK1 and TRAF6 expression. J Immunol. 195:672–682. 2015. View Article : Google Scholar : PubMed/NCBI