miR‑30 decreases multidrug resistance in human gastric cancer cells by modulating cell autophagy

Du,Xinming; Liu,Bing; Luan,Xuerong; Cui,Qing; Li,Leping

doi:10.3892/etm.2017.5354

miR‑30 decreases multidrug resistance in human gastric cancer cells by modulating cell autophagy

Authors:
- Xinming Du
- Bing Liu
- Xuerong Luan
- Qing Cui
- Leping Li
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Affiliations: Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266071, P.R. China, Department of Gastrointestinal Surgery, Zibo Central Hospital, Zibo, Shandong 250020, P.R. China
Published online on: October 23, 2017 https://doi.org/10.3892/etm.2017.5354
Pages: 599-605

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Abstract

Chemotherapy is an important treatment modality for gastric cancer, and multidrug resistance (MDR) represents a major obstacle for successful cancer chemotherapy. There is a lack of research on whether microRNA (miR)‑30a regulation affects the chemosensitivity of resistant gastric cancer cells, and mechanisms underlying the effects of miR‑30a on drug resistance and cell autophagy require further investigation. In the present study, the expression of miR‑30a and its effects in cisplatin (CDDP)‑resistant human gastric cancer cells were investigated. A CDDP‑resistant variant of the SGC‑7901 cell line (SGC‑7901/CDDP) was established by exposing the cells to gradually increasing drug concentrations, and miR‑30a expression was detected by reverse transcription‑semi quantitative polymerase chain reaction (RT‑sqPCR). To examine the effect of miR‑30a expression in the SGC‑7901/CDDP cells, miR30a mimics or negative control miRNA were transfected into the cells, and a Cell Counting Kit‑8 assay was performed to analyze the chemosensitivity of the different cell groups. RT‑sqPCR and western blot analysis were also used to measure MDR1 mRNA and P‑glycoprotein expression, and the light chain (LC)3‑II/LC3‑I ratio. Furthermore, apoptosis induced by the chemotherapeutic CDDP in the different groups was assessed using flow cytometry. The results demonstrated that low expression of miR‑30a was associated with chemoresistance in gastric cancer cells, and in the chemoresistant cell line SGC7901/CDDP, CDDP‑induced apoptosis was weakened. Additionally, it was demonstrated that the LC3‑II/LC3‑I ratio was elevated in SGC7901/CDDP cells compared with chemosensitive SGC7901 cells (P<0.001), which could be attenuated by upregulating miR‑30a expression (P<0.001 vs. SGC7901/CDDP control cells). These results suggested that autophagy may contribute to drug resistance in gastric cancer cells, and that the reduction of LC3‑II in response to miR‑30a overexpression may inhibit chemoresistance‑associated autophagy in gastric cancer cells.

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1	Xu W, Yang Z and Lu N: Molecular targeted therapy for the treatment of gastric cancer. J Exp Clin Cancer Res. 35:12016. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	Hu Y, Ying M, Huang C, Wei H, Jiang Z, Peng X, Hu J, Du X, Wang B, Lin F, et al: Oncologic outcomes of laparoscopy-assisted gastrectomy for advanced gastric cancer: A large-scale multicenter retrospective cohort study from China. Surg Endosc. 28:2048–2056. 2014. View Article : Google Scholar : PubMed/NCBI
4	O'Connor R: The pharmacology of cancer resistance. Anticancer Res. 27:1267–1272. 2007.PubMed/NCBI
5	Choi JH, Lim HY, Joo HJ, Kim HS, Yi JW, Kim HC, Cho YK, Kim MW and Lee KB: Expression of multidrug resistance-associated protein1, P-glycoprotein and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. Br J Cancer. 86:1578–1585. 2002. View Article : Google Scholar : PubMed/NCBI
6	Morin PJ: Drug resistance and the microenvironment: Nature and nurture. Drug Resist Updat. 6:169–172. 2003. View Article : Google Scholar : PubMed/NCBI
7	Lippert TH, Ruoff HJ and Volm M: Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. Arzneimittelforschung. 58:261–264. 2008.PubMed/NCBI
8	Zhang M and Du X: Noncoding RNAs in gastric cancer: Research progress and prospects. World J Gastroenterol. 22:6610–6618. 2016. View Article : Google Scholar : PubMed/NCBI
9	Tan P and Yeoh KG: Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 149:1153–1162.e3. 2015. View Article : Google Scholar : PubMed/NCBI
10	Song JH and Meltzer SJ: MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology. 143:35–47.e2. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhang M and Du X: Noncoding RNAs in gastric cancer: Research progress and prospects. World J Gastroenterol. 22:6610–6618. 2016. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Chen L, Zhang X, Xu X, Xing H, Zhang Y, Li W, Yu H, Zeng J, Jia J, et al: RUNX3 regulates vimentin expression via miR-30a during epithelial-mesenchymal transition in gastric cancer cells. J Cell Mol Med. 18:610–623. 2014. View Article : Google Scholar : PubMed/NCBI
13	Li C, Zou J, Zheng G and Chu J: miR-30a decreases multidrug resistance (MDR) of gastric cancer cells. Med Sci Monit. 0:02016.PubMed/NCBI
14	Lai YC, Chuang YC, Chang CP and Yeh TM: Macrophage migration inhibitory factor has a permissive role in concanavalin A-induced cell death of human hepatoma cells through autophagy. Cell Death Dis. 6:e20082015. View Article : Google Scholar : PubMed/NCBI
15	Shi WJ and Gao JB: Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol. 8:673–681. 2016. View Article : Google Scholar : PubMed/NCBI
16	An Y, Zhang Z, Shang Y, Jiang X, Dong J, Yu P, Nie Y and Zhao Q: miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2. Cell Death Dis. 6:e17662015. View Article : Google Scholar : PubMed/NCBI
17	Zhao L, Wang Y, Jiang L, He M, Bai X, Yu L and Wei M: MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). J Exp Clin Cancer Res. 35:252016. View Article : Google Scholar : PubMed/NCBI
18	Abraham I, Jain S, Wu CP, Khanfar MA, Kuang Y, Dai CL, Shi Z, Chen X, Fu L, Ambudkar SV, et al: Marine sponge-derived sipholane triterpenoids reverse P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells. Biochem Pharmacol. 80:1497–1506. 2010. View Article : Google Scholar : PubMed/NCBI
19	Fayad W, Fryknäs M, Brnjic S, Olofsson MH, Larsson R and Linder S: Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters. PLoS One. 4:e72382009. View Article : Google Scholar : PubMed/NCBI
20	Liu G, Pei F, Yang F, Li L, Amin AD, Liu S, Buchan JR and Cho WC: Role of autophagy and apoptosis in non-small-cell lung cancer. Int J Mol Sci. 18:pii: E3672017. View Article : Google Scholar
21	Qian HR and Yang Y: Functional role of autophagy in gastric cancer. Oncotarget. 7:17641–17651. 2016. View Article : Google Scholar : PubMed/NCBI
22	Talaiezadeh A, Jalali F, Galehdari H and Khodadadi A: Time depended Bcl-2 inhibition might be useful for a targeted drug therapy. Cancer Cell Int. 15:1052015. View Article : Google Scholar : PubMed/NCBI
23	Cai Y, Xu P, Yang L, Xu K, Zhu J, Wu X, Jiang C, Yuan Q, Wang B, Li Y and Qiu Y: HMGB1-mediated autophagy decreases sensitivity to oxymatrine in SW982 human synovial sarcoma cells. Sci Rep. 6:378452016. View Article : Google Scholar : PubMed/NCBI
24	An X, Sarmiento C, Tan T and Zhu H: Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B. 7:38–51. 2017. View Article : Google Scholar : PubMed/NCBI
25	O'Donovan TR, O'Sullivan GC and McKenna SL: Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy. 7:509–524. 2011. View Article : Google Scholar : PubMed/NCBI
26	Kumar A, Singh UK and Chaudhary A: Targeting autophagy to overcome drug resistance in cancer therapy. Future Med Chem. 7:1535–1542. 2015. View Article : Google Scholar : PubMed/NCBI
27	Li LQ, Xie WJ, Pan D, Chen H and Zhang L: Inhibition of autophagy by bafilomycin A1 promotes chemosensitivity of gastric cancer cells. Tumor Biol. 37:653–659. 2016. View Article : Google Scholar
28	Bhattacharya B, Low SH, Soh C, Mustapa N Kamal, Beloueche-Babari M, Koh KX, Loh J and Soong R: Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. Br J Pharmacol. 171:3255–3267. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yang C and Pan Y: Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression. Tumour Biol. Jul 25–2015.(Epub ahead of print).
30	Liu J, Zhang Y, Qu J, Xu L, Hou K, Zhang J, Qu X and Liu Y: β-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis. BMC Cancer. 11:1832011. View Article : Google Scholar : PubMed/NCBI
31	Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Nat Rev Cancer. 7:961–967. 2007. View Article : Google Scholar : PubMed/NCBI
32	Lee J, Giordano S and Zhang J: Autophagy, mitochondria and oxidative stress: Cross-talk and redox signalling. Biochem J. 441:523–540. 2012. View Article : Google Scholar : PubMed/NCBI
33	Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, Liu CG and Yang JM: Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy. 5:816–823. 2009. View Article : Google Scholar : PubMed/NCBI