miR‑200b and miR‑200c co‑contribute to the cisplatin sensitivity of ovarian cancer cells by targeting DNA methyltransferases

Liu,Jue; Zhang,Xiaobo; Huang,Yuliang; Zhang,Qunfeng; Zhou,Jianbin; Zhang,Xiaodi; Wang,Xiaoxu

doi:10.3892/ol.2018.9745

miR‑200b and miR‑200c co‑contribute to the cisplatin sensitivity of ovarian cancer cells by targeting DNA methyltransferases

Authors:
- Jue Liu
- Xiaobo Zhang
- Yuliang Huang
- Qunfeng Zhang
- Jianbin Zhou
- Xiaodi Zhang
- Xiaoxu Wang
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China, Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Joint Surgery, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: November 22, 2018 https://doi.org/10.3892/ol.2018.9745
Pages: 1453-1460
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cisplatin is a first‑line chemotherapy drug that is commonly used in the treatment of epithelial ovarian cancer (EOC). However, insensitivity to cisplatin markedly influences the outcomes of chemotherapy. MicroRNAs (miRNAs/miRs) have been demonstrated to modulate drug resistance in a number of types of cancer. The aim of the present study was to investigate the key miRNAs involved in modulating drug resistance in ovarian cancer cells. miR‑200b and miR‑200c were identified to be frequently deregulated in ovarian cancer. Upregulation of miR‑200b and miR‑200c promoted EOC cell death in the presence of cisplatin. Upregulation of miR‑125b‑5p significantly decreased tumor growth in combination with cisplatin in a mouse model. Significantly, miR‑200b and miR‑200c reversed cisplatin resistance by targeting DNA methyltransferases (DNMTs) (directly targeting DNMT3A/DNMT3B and indirectly targeting DNMT1 via specificity protein 1). These results indicate that miR‑200b‑ and miR‑200c‑mediated regulation of DNMTs serves a crucial function in the cellular response to cisplatin. miR‑200b‑ and miR‑200c‑mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells and thus may have an impact on ovarian cancer therapy.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ahmad S, Qureshi AN, Kazmi A, Rasool A, Gul M, Ashfaq M, Batool L, Rehman RA, Ahmad J and Muniba: First cancer statistics report from Hazara division. J Ayub Med Coll Abbottabad. 25:71–73. 2013.
3	Bradley A, Zheng H, Ziebarth A, Sakati W, Branham-O'Connor M, Blumer JB, Liu Y, Kistner-Griffin E, Rodriguez-Aguayo C, Lopez-Berestein G, et al: EDD enhances cell survival and cisplatin resistance and is a therapeutic target for epithelial ovarian cancer. Carcinogenesis. 35:1100–1109. 2014. View Article : Google Scholar : PubMed/NCBI
4	Cortés-Sempere M, de Miguel MP, Pernia O, Rodriguez C, de Castro Carpeño J, Nistal M, Conde E, López-Ríos F, Belda-Iniesta C, Perona R and Ibanez de Caceres I: IGFBP-3 methylation-derived deficiency mediates the resistance to cisplatin through the activation of the IGFIR/Akt pathway in non-small cell lung cancer. Oncogene. 32:1274–1283. 2013. View Article : Google Scholar : PubMed/NCBI
5	Zeller C, Dai W, Steele NL, Siddiq A, Walley AJ, Wilhelm-Benartzi CS, Rizzo S, van der Zee A, Plumb JA and Brown R: Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling. Oncogene. 31:4567–4576. 2012. View Article : Google Scholar : PubMed/NCBI
6	Gebhard C, Benner C, Ehrich M, Schwarzfischer L, Schilling E, Klug M, Dietmaier W, Thiede C, Holler E, Andreesen R and Rehli M: General transcription factor binding at CpG islands in normal cells correlates with resistance to de novo DNA methylation in cancer cells. Cancer Res. 70:1398–1407. 2010. View Article : Google Scholar : PubMed/NCBI
7	Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y, Tarasawa I, Sasaki Y, Asaoku H, Sakai H, Hayashi T, et al: Genomic screening for genes silenced by DNA methylation revealed an association between RASD1 inactivation and dexamethasone resistance in multiple myeloma. Clin Cancer Res. 15:4356–4364. 2009. View Article : Google Scholar : PubMed/NCBI
8	Du J and Zhang L: Integrated analysis of DNA methylation and microRNA regulation of the lung adenocarcinoma transcriptome. Oncol Rep. 34:585–594. 2015. View Article : Google Scholar : PubMed/NCBI
9	Kwon MJ and Shin YK: Epigenetic regulation of cancer-associated genes in ovarian cancer. Int J Mol Sci. 12:983–1008. 2011. View Article : Google Scholar : PubMed/NCBI
10	Sui C, Meng F, Li Y and Jiang Y: miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression. J Transl Med. 13:1322015. View Article : Google Scholar : PubMed/NCBI
11	Fumagalli C, Della Pasqua S, Bagnardi V, Cardillo A, Sporchia A, Colleoni M, Viale G, Barberis M and Pruneri G: Prevalence and clinicopathologic correlates of O′-methylguanine-DNA methyltransferase methylation status in patients with triple-negative breast cancer treated preoperatively by alkylating drugs. Clin Breast Cancer. 14:285–290. 2014. View Article : Google Scholar : PubMed/NCBI
12	Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, Lu YY, Tang YA, Yang YC, Yang PC and Wang YC: Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res. 70:5807–5817. 2010. View Article : Google Scholar : PubMed/NCBI
13	Qin T, Jelinek J, Si J, Shu J and Issa JP: Mechanisms of resistance to 5-aza-2′-deoxycytidine in human cancer cell lines. Blood. 113:659–667. 2009. View Article : Google Scholar : PubMed/NCBI
14	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
15	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
16	Friedman RC, Farh KK, Burge CB and Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19:92–105. 2009. View Article : Google Scholar : PubMed/NCBI
17	Lynch SM, O'Neill KM, McKenna MM, Walsh CP and McKenna DJ: Regulation of miR-200c and miR-141 by methylation in prostate cancer. Prostate. 76:1146–1159. 2016. View Article : Google Scholar : PubMed/NCBI
18	Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E, Huynh L, Vukosavljevic T, Takeki M, Klisovic RB, et al: Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood. 111:2364–2373. 2008. View Article : Google Scholar : PubMed/NCBI
19	Yang H, Ou CC, Feldman RI, Nicosia SV, Kruk PA and Cheng JQ: Aurora-A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res. 64:463–467. 2004. View Article : Google Scholar : PubMed/NCBI
20	Tang H, Wang Z, Liu X, Liu Q, Xu G, Li G and Wu M: LRRC4 inhibits glioma cell growth and invasion through a miR-185-dependent pathway. Curr Cancer Drug Targets. 12:1032–1042. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yang L, Tang H, Kong Y and Xie X, Chen J, Song C, Liu X, Ye F, Li N, Wang N and Xie X: LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/β-catenin signaling. Stem Cells. 33:2913–2924. 2015. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Ding W, Dang H, You H, Steinway S, Takahashi Y, Wang HG, Liao J, Stiles B, Albert R and Rountree CB: miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma. Oncogenesis. 1:e152012. View Article : Google Scholar : PubMed/NCBI
24	Tang H, Deng M, Tang Y and Xie X, Guo J, Kong Y, Ye F, Su Q and Xie X: miR-200b and miR-200c as prognostic factors and mediators of gastric cancer cell progression. Clin Cancer Res. 19:5602–5612. 2013. View Article : Google Scholar : PubMed/NCBI
25	Stathopoulos GP: Cisplatin: Process and future. J BUON. 18:564–569. 2013.PubMed/NCBI
26	Roossink F, de Jong S, Wisman GB, van der Zee AG and Schuuring E: DNA hypermethylation biomarkers to predict response to cisplatin treatment, radiotherapy or chemoradiation: The present state of art. Cell Oncol (Dordr). 35:231–241. 2012. View Article : Google Scholar : PubMed/NCBI
27	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
28	Helleday T, Petermann E, Lundin C, Hodgson B and Sharma RA: DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 8:193–204. 2008. View Article : Google Scholar : PubMed/NCBI
29	O'Grady S, Finn SP, Cuffe S, Richard DJ, O'Byrne KJ and Barr MP: The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev. 40:1161–1170. 2014. View Article : Google Scholar : PubMed/NCBI
30	Weis B, Schmidt J, Maamar H, Raj A, Lin H, Tóth C, Riedmann K, Raddatz G, Seitz HK, Ho AD, et al: Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a. Oncogene. 34:1822–1830. 2015. View Article : Google Scholar : PubMed/NCBI
31	Liu B, Wang Z, Zhang L, Ghosh S, Zheng H and Zhou Z: Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun. 4:18682013. View Article : Google Scholar : PubMed/NCBI
32	Hayette S, Thomas X, Jallades L, Chabane K, Charlot C, Tigaud I, Gazzo S, Morisset S, Cornillet-Lefebvre P, Plesa A, et al: High DNA methyltransferase DNMT3B levels: A poor prognostic marker in acute myeloid leukemia. PLoS One. 7:e515272012. View Article : Google Scholar : PubMed/NCBI
33	Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, et al: MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 104:15805–15810. 2007. View Article : Google Scholar : PubMed/NCBI
34	Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, Hemmi H, Koi M, Boland CR and Goel A: MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut. 62:1315–1326. 2013. View Article : Google Scholar : PubMed/NCBI
35	Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S and Brabletz T: A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9:582–589. 2008. View Article : Google Scholar : PubMed/NCBI
36	Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
37	Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y and Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
38	Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF and Goodall GJ: A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68:7846–7854. 2008. View Article : Google Scholar : PubMed/NCBI
39	Kishikawa S, Murata T, Kimura H, Shiota K and Yokoyama KK: Regulation of transcription of the Dnmt1 gene by Sp1 and Sp3 zinc finger proteins. Eur J Biochem. 269:2961–2970. 2002. View Article : Google Scholar : PubMed/NCBI
40	Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, Brisken C, Minucci S, Di Fiore PP and Pelicci PG: The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 138:1083–1095. 2009. View Article : Google Scholar : PubMed/NCBI