Multidrug resistance affects the prognosis of primary epithelial ovarian cancer

Gao,Bo; Yang,Fengmei; Chen,Wei; Li,Rui; Hu,Xiuxue; Liang,Yong; Li,Dongmin

doi:10.3892/ol.2019.10745

Multidrug resistance affects the prognosis of primary epithelial ovarian cancer

Authors:
- Bo Gao
- Fengmei Yang
- Wei Chen
- Rui Li
- Xiuxue Hu
- Yong Liang
- Dongmin Li
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Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shanxi 710061, P.R. China, Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Medical Office, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Anesthesiology, Ren‑ming Hospital of Yun‑xi, Shiyan, Hubei 442000, P.R. China
Published online on: August 14, 2019 https://doi.org/10.3892/ol.2019.10745
Pages: 4262-4269

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Abstract

Multidrug‑resistant tumor cells can tolerate different structures, functions and antidrug action mechanisms, therefore, allowing these cells to respond to various structurally unrelated mechanisms of different chemotherapy drugs and to exhibit cross‑resistance. The present study aimed to investigate the role of Multi‑drug resistance gene (MDR1), Placental glutathione S‑transferase‑P1 (GSTP1), Lung resistance protein (LRP) and Ras association domain family member 1 (RASSF1A) in primary epithelial ovarian cancer (PEOC). The mRNA (protein) expression levels of MDR1, product P glycoprotein, LRP and GSTP1 were evaluated with reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis in all tissue samples, ovarian cancer cell line A2780 and A2780/DDP. Methylation‑specific PCR (MSP) was used to detect RASSF1A gene methylation in all tissue samples. The resistance genes/proteins were either poorly or not expressed in A2780, however were highly expressed in A2780/DDP cell line. The expression of resistance genes/proteins decreased following different concentrations of zebularine‑stimulated A2780/DDP. Hypermethylation and low expression of RASSF1A gene were detected in PEOC and A2780/DDP. Subsequent to being exposed to different concentrations of zebularine‑stimulated A2780/DDP, the RASSF1A methylation level was decreased, while the unmethylation level was increased. The expression of RASSF1A gene/protein was gradually restored, and the gene/protein expression was enhanced with the increase in drug concentration. Multivariate logistic regression indicated that the expression level of gene LRP and GSTP1 was a risk factor for PEOC prognosis. Furthermore, the expression of LRP and GSTP1 in the negative‑group survival curves was higher compared with the positive group. High expression of resistance genes may serve an important role in cancer primary resistance. Low expression caused by hyper‑methylation of RASSF1A gene may serve an important role in cancer‑acquired resistance in PEOC. The present study suggested that resistant gene expression may be a potential prognostic biomarker.

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1	Lheureux S, Gourley C, Vergote I and Oza AM: Epithelial ovarian cancer. Lancet. 393:1240–1253. 2019. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Marcus CS, Maxwell GL, Darcy KM, Hamilton CA and McGuire WP: Current approaches and challenges in managing and monitoring treatment response in ovarian cancer. J Cancer. 5:25–30. 2014. View Article : Google Scholar : PubMed/NCBI
4	Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N and Sessa C; ESMO Guidelines Working Group, : Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 24:vi24–vi32. 2013. View Article : Google Scholar : PubMed/NCBI
5	Asgari Z, Rouholamin S, Hosseini R, Sepidarkish M, Hafizi L and Javaheri A: Comparing ovarian reserve after laparoscopic excision of endometriotic cysts and hemostasis achieved either by bipolar coagulation or suturing: A randomized clinical trial. Arch Gynecol Obstet. 293:1015–1022. 2016. View Article : Google Scholar : PubMed/NCBI
6	Qin L, Qiu H, Zhang M, Zhang F, Yang H, Yang L, Jia L, Qin K, Jia L, Dou X, et al: Soluble CD40 ligands sensitize the epithelial ovarian cancer cells to cisplatin treatment. Biomed Pharmacother. 79:166–175. 2016. View Article : Google Scholar : PubMed/NCBI
7	Yang F, Gao B, Chen W, Du E, Liang Y, Hu X and Yang X: Expression of resistance gene and prognosis of chemotherapy in primary epithelial ovarian cancer. Medicine (Baltimore). 97:e123642018. View Article : Google Scholar : PubMed/NCBI
8	Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T and Nephew KP: Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 72:2197–2205. 2012. View Article : Google Scholar : PubMed/NCBI
9	Yin F, Liu X, Li D, Wang Q, Zhang W and Li L: Tumor suppressor genes associated with drug resistance in ovarian cancer (review). Oncol Rep. 30:3–10. 2013. View Article : Google Scholar : PubMed/NCBI
10	Chaudhry P, Srinivasan R and Patel FD: Utility of gene promoter methylation in prediction of response to platinum-based chemotherapy in epithelial ovarian cancer (EOC). Cancer Invest. 27:877–884. 2009. View Article : Google Scholar : PubMed/NCBI
11	Yang F, Gao B, Li R, Li W, Chen W, Yu Z and Zhang J: Expression levels of resistant genes affect cervical cancer prognosis. Mol Med Rep. 15:2802–2806. 2017. View Article : Google Scholar : PubMed/NCBI
12	Koh I, Hinoi T, Sentani K, Hirata E, Nosaka S, Niitsu H, Miguchi M, Adachi T, Yasui W, Ohdan H and Kudo Y: Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma. Cancer Med. 5:1546–1555. 2016. View Article : Google Scholar : PubMed/NCBI
13	Balch C, Huang TH, Brown R and Nephew KP: The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol. 191:1552–1572. 2004. View Article : Google Scholar : PubMed/NCBI
14	Lu C, Shan Z, Li C and Yang L: MiR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp. Biomed Pharmacother. 86:450–456. 2017. View Article : Google Scholar : PubMed/NCBI
15	Javadi S, Ganeshan DM, Qayyum A, Iyer RB and Bhosale P: Ovarian cancer, the revised FIGO staging system and the role of imaging. AJR Am J Roentgenol. 206:1351–1360. 2016. View Article : Google Scholar : PubMed/NCBI
16	Kurman RJ, Carcangiu ML, Herrington CS and Young RH: WHO Classification of Tumours of Female Reproductive Organs. (4th). International Agency for Research on Cancer. 3072014.
17	Prat J; FIGO Committee on Gynecologic Oncology, : Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 124:1–5. 2014. View Article : Google Scholar : PubMed/NCBI
18	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
19	Herman JG, Graff JR, Myöhänen S, Nelkin BD and Baylin SB: Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 93:9821–9826. 1996. View Article : Google Scholar : PubMed/NCBI
20	Yuan Z, Shi X, Qiu Y, Jia T, Yuan X, Zou Y, Liu C, Yu H, Yuan Y, He X, et al: Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin. Oncol Rep. 37:1815–1825. 2017. View Article : Google Scholar : PubMed/NCBI
21	Stewart DJ: Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol. 75:173–264. 2010. View Article : Google Scholar : PubMed/NCBI
22	Zhang KG, Qin CY, Wang HQ, Wang JX and Wang QM: The effect of TRAIL on the expression of multidrug resistant genes MDR1, LRP and GST-π in drug-resistant gastric cancer cell SGC7901/VCR. Hepatogastroenterology. 59:2672–2676. 2012.PubMed/NCBI
23	Wei H, Lu W, Li M, Zhang Q and Lu S: Concomitance of P-gp/LRP expression with EGFR mutations in exons 19 and 21 in non-small cell lung cancers. Yonsei Med J. 57:50–57. 2016. View Article : Google Scholar : PubMed/NCBI
24	Jiao JW and Wen F: Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells. Oncol Rep. 25:781–788. 2011.PubMed/NCBI
25	Zhan L, Zhang B, Tan Y, Yang C, Huang C, Wu Q, Zhang Y, Chen X, Zhou M and Shu A: Quantitative assessment of the relationship between RASSF1A gene promoter methylation and bladder cancer (PRISMA). Medicine (Baltimore). 96:e60972017. View Article : Google Scholar : PubMed/NCBI
26	Shou F, Xu F, Li G, Zhao Z, Mao Y, Yang F, Wang H and Guo H: RASSF1A promoter methylation is associated with increased risk of thyroid cancer: A meta-analysis. Onco Targets Ther. 10:247–257. 2017. View Article : Google Scholar : PubMed/NCBI
27	Vos MD, Martinez A, Elam C, Dallol A, Taylor BJ, Latif F and Clark GJ: A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability. Cancer Res. 64:4244–4250. 2004. View Article : Google Scholar : PubMed/NCBI
28	Kassler S, Donninger H, Birrer MJ and Clark GJ: RASSF1A and the taxol response in ovarian cancer. Mol Biol Int. 2012:2632672012. View Article : Google Scholar : PubMed/NCBI
29	Choi YL, Kang SY, Shin YK, Choi JS, Kim SH, Lee SJ, Bae DS and Ahn G: Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas. Virchows Arch. 448:331–336. 2006. View Article : Google Scholar : PubMed/NCBI
30	Pronina IV, Loginov VI, Kholdyrev DS, Kazubskaia TP and Braga ÉA: Alterations of expression level of RASSFIA gene in primary epithelial tumors of various locations. Mol Biol (Mosk). 46:260–268. 2012.(In Russian). View Article : Google Scholar : PubMed/NCBI
31	Balch C, Yan P, Craft T, Young S, Skalnik DG, Huang TH and Nephew KP: Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer. Mol Cancer Ther. 4:1505–1514. 2005. View Article : Google Scholar : PubMed/NCBI
32	Hou XL, Takahashi K, Tanaka K, Tougou K, Qiu F, Komatsu K, Takahashi K and Azuma J: Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways. Int J Pharm. 358:224–229. 2008. View Article : Google Scholar : PubMed/NCBI
33	Cao SQ, Li P, Yin TY and Yang SL: Curcumin reverses multi-drugresistance of human hepatocellular carcinoma bel7402/5-FU cells. World Chin J Digestol. 20:135–139. 2012.
34	Wang N, Zhang H, Yao Q, Wang Y, Dai S and Yang X: TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer. J Exp Clin Cancer Res. 31:62012. View Article : Google Scholar : PubMed/NCBI
35	Chiang YC, Chang MC, Chen PJ, Wu MM, Hsieh CY, Cheng WF and Chen CA: Epigenetic silencing of BLU through interfering apoptosis results in chemoresistance and poor prognosis of ovarian serous carcinoma patients. Endocr Relat Cancer. 20:213–227. 2013. View Article : Google Scholar : PubMed/NCBI