Altered microRNA expression in cisplatin-resistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance

Yang,Lingyun; Li,Ningwei; Wang,Hongjing; Jia,Xibiao; Wang,Xue; Luo,Juan

doi:10.3892/or.2012.1823

Altered microRNA expression in cisplatin-resistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance

Authors:
- Lingyun Yang
- Ningwei Li
- Hongjing Wang
- Xibiao Jia
- Xue Wang
- Juan Luo
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: May 18, 2012 https://doi.org/10.3892/or.2012.1823
Pages: 592-600

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

microRNAs (miRNAs) are short non-coding RNA molecules which are involved in the regulation of various biological processes. Drug resistance has become a major obstacle to successful chemotherapy of ovarian cancer. The aim of this study was to investigate microRNA expression profiles in cisplatin-resistant ovarian cancer cells and the role of miR-130a in regulating drug resistance. Analysis of differentially expressed miRNAs between SKOV3 and SKOV3/CIS cells was assessed by miRNA microarrays. Target prediction of miRNAs was determined with the help of PicTar or TargetScan. Among these miRNAs, the expression of miR‑130a was verified using qRT-PCR. The expression of MDR1 mRNA and P-glycoprotein (P-gp) after cellular transfection was examined using qRT-PCR and western blotting, respectively. Cisplatin sensitivity was detected by the MTT assay. We indentified 35 downregulated and 54 upregulated miRNAs in SKOV3/CIS compared to those in SKOV3. We found that miR-130a was upregulated in SKOV3/CIS compared to the parental SKOV3 cells, and PTEN was predicted to be the potential target of miR-130a. Moreover, downregulation of miR-130a could inhibit MDR1 mRNA and P-gp expression and overcome the cisplatin resistance in SKOV3/CIS cells, which indicated that miR-130a may be associated with MDR1/P-gp-mediated drug resistance and plays the role of an intermediate in drug-resistance pathways of PI3K/Akt/PTEN/mTOR and ABC superfamily drug transporters in SKOV3/CIS cells. This study provides important information for the development of targeted gene therapy for reversing cisplatin resistance in ovarian cancer.

View Figures

View References

1	Legge F, Ferrandina G, Salutari V, et al: Biological characterization of ovarian cancer: prognostic and therapeutic implications. Ann Oncol. 16:95–101. 2005. View Article : Google Scholar : PubMed/NCBI
2	Heintz AP, Odicino F, Maisonneuve P, et al: Carcinoma of the ovary. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 95:S161–S192. 2006.PubMed/NCBI
3	Du Bois A and Pfisterer J: Future options for first-line therapy of advanced ovarian cancer. Int J Gynecol Cancer. 15:42–50. 2005.PubMed/NCBI
4	Foster T, Brown TM, Chang J, et al: A review of the current evidence for maintenance therapy in ovarian cancer. Gynecol Oncol. 115:290–301. 2009. View Article : Google Scholar : PubMed/NCBI
5	de Jongh FE, de Wit R, Verweij J, et al: Dose-dense cisplatin/paclitaxel: a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer. Eur J Cancer. 38:2005–2013. 2002.
6	Muggia F: Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer. Gynecol Oncol. 112:275–281. 2009.PubMed/NCBI
7	Rabik CA and Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 33:9–23. 2007. View Article : Google Scholar : PubMed/NCBI
8	Hu M, Liu Y, Deng C, Han R, et al: Enhanced invasiveness in multidrug resistant leukemic cells is associated with overexpression of P-glycoprotein and cellular inhibitor of apoptosis protein. Leuk Lymphoma. 52:1302–1311. 2011. View Article : Google Scholar : PubMed/NCBI
9	Gottesman MM and Ling V: The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 580:998–1009. 2006.PubMed/NCBI
10	Park E, Gang EJ, Hsieh YT, et al: Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood. 118:2191–2199. 2011. View Article : Google Scholar : PubMed/NCBI
11	Fraser M, Bai T and Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 122:534–546. 2008. View Article : Google Scholar : PubMed/NCBI
12	Cheung CH, Wu SY, Lee TR, et al: Cancer cells acquire mitotic drug resistance properties through beta I-tubulin mutations and alterations in the expression of beta-tubulin isotypes. PLoS One. 5:e125642010. View Article : Google Scholar : PubMed/NCBI
13	Zindy P, Bergé Y, Allal B, et al: Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 71:4068–4073. 2011. View Article : Google Scholar : PubMed/NCBI
14	Sabatino MA, Marabese M, Ganzinelli M, et al: Down-regulation of the nucleotide excision repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells. Mol Cancer. 9:2592010. View Article : Google Scholar : PubMed/NCBI
15	Kirschner K and Melton DW: Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res. 30:3223–3232. 2010.PubMed/NCBI
16	Li Z, Hu S, Wang J, Cai J, et al: MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells. Gynecol Oncol. 119:125–130. 2010. View Article : Google Scholar : PubMed/NCBI
17	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
18	Denli AM, Tops BB, Plasterk RH, et al: Processing of primary microRNAs by the Microprocessor complex. Nature. 432:231–235. 2004. View Article : Google Scholar : PubMed/NCBI
19	Berezikov E, Guryev V, van de Belt J, et al: Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 120:21–24. 2005. View Article : Google Scholar : PubMed/NCBI
20	Lund E, Güttinger S, Calado A, et al: Nuclear export of microRNA precursors. Science. 303:95–98. 2004. View Article : Google Scholar
21	He L and Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
22	Kloosterman WP and Plasterk RH: The diverse functions of microRNAs in animal development and disease. Dev Cell. 11:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
23	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar
24	Iorio MV, Visone R, Di Leva G, et al: MicroRNA signatures in human ovarian cancer. Cancer Res. 67:8699–8707. 2007. View Article : Google Scholar : PubMed/NCBI
25	Yanaihara N, Caplen N, Bowman E, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar
26	Calin GA, Dumitru CD, Shimizu M, et al: Frequent deletions and down-regulation of microRNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 99:15524–15529. 2002. View Article : Google Scholar : PubMed/NCBI
27	Gong C, Yao Y, Wang Y, et al: Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 286:19127–19137. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hwang JH, Voortman J, Giovannetti E, et al: Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One. 5:e106302010. View Article : Google Scholar : PubMed/NCBI
29	Tomimaru Y, Eguchi H, Nagano H, et al: MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 103:1617–1626. 2010.PubMed/NCBI
30	Krek A, Grün D, Poy MN, et al: Combinatorial microRNA target predictions. Nat Genet. 37:495–500. 2005. View Article : Google Scholar
31	Grün D, Wang YL, Langenberger D, et al: microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput Biol. 1:e132005.PubMed/NCBI
32	Lewis BP, Shih IH, Jones-Rhoades MW, et al: Prediction of mammalian microRNA targets. Cell. 115:787–798. 2003. View Article : Google Scholar : PubMed/NCBI
33	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
34	Kovalchuk O, Filkowski J, Meservy J, et al: Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 7:2152–2159. 2008. View Article : Google Scholar : PubMed/NCBI
35	Xia L, Zhang D, Du R, et al: MiR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 123:372–379. 2008. View Article : Google Scholar : PubMed/NCBI
36	Lu J, Getz G, Miska EA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
37	Pallante P, Visone R, Ferracin M, et al: MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 13:497–508. 2006. View Article : Google Scholar : PubMed/NCBI
38	Miller TE, Ghoshal K, Ramaswamy B, et al: MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 283:29897–29903. 2008. View Article : Google Scholar : PubMed/NCBI
39	Bhatnagar N, Li X, Padi SK, et al: Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Cell Death Dis. 1:e1052010. View Article : Google Scholar : PubMed/NCBI
40	Wang XC, Tian LL, Wu HL, et al: Expression of miRNA-130a in nonsmall cell lung cancer. Am J Med Sci. 340:385–388. 2010. View Article : Google Scholar : PubMed/NCBI
41	Chen Y and Gorski DH: Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood. 111:1217–1226. 2008. View Article : Google Scholar : PubMed/NCBI
42	Cui XY, Guo YJ and Yao HR: Analysis of microRNA in drug-resistant breast cancer cell line MCF-7/ADR. Nan Fang Yi Ke Da Xue Xue Bao. 28:1813–1815. 2008.(In Chinese).
43	Naumann RW: The role of the phosphatidylinositol 3-kinase (PI3K) pathway in the development and treatment of uterine cancer. Gynecol Oncol. 123:411–420. 2011. View Article : Google Scholar : PubMed/NCBI
44	Sherbakova EA, Stromskaia TP, Rybalkina EIu, et al: Role of PTEN protein in multidrug resistance of prostate cancer cells. Mol Biol (Mosk). 42:487–493. 2008.(In Russian).