miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway

Liu,Jiangang; Xing,Yingru; Rong,Ling

doi:10.3892/or.2018.6268

miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway

Authors:
- Jiangang Liu
- Yingru Xing
- Ling Rong
View Affiliations

Affiliations: Department of Medical Oncology, The People's Hospital of Bozhou, Bozhou, Anhui 236804, P.R. China, Affiliated Tumor Hospital, Huainan Eastern Hospital Group, Huainan, Anhui 232001, P.R. China, Department of Respiratory Medicine, The People's Hospital of Bozhou, Bozhou, Anhui 236804, P.R. China
Published online on: February 13, 2018 https://doi.org/10.3892/or.2018.6268
Pages: 1631-1639
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

A number of miRNAs have been found to be abnormally expressed or mutated in numerous cancers and thus, are considered to act as oncogenes or tumor suppressor genes. The aim of the present study was to investigate the effect of miR-181 on cisplatin-resistant non-small cell lung cancer (NSCLC). In patients with cisplatin-resistant NSCLC, miR-181 expression was found to be markedly decreased. In addition, in the cisplatin-resistant human lung adenocarcinoma cell line A549/DDP, miR-181 downregulation promoted cell growth and metastasis and inhibited cell apoptosis, whereas miR-181 overexpression exerted the opposite effects. Furthermore, miR-181 downregulation suppressed LC3 and ATG5 protein expression in A549/DDP cells through suppression of the PTEN/PI3K/AKT/mTOR pathway, whereas miR-181 overexpression recovered LC3 and ATG5 protein expression by promoting PTEN/PI3K/AKT/mTOR signaling. In turn, PTEN inhibitors reduced the anticancer effects of miR-181 overexpression on A549/DDP cell growth via the regulation of autophagy through the PI3K/AKT/mTOR pathway. Therefore, miR-181 may be a novel and important regulator of cisplatin-resistant NSCLC by serving a role in the regulation of apoptosis, as an established rate-limiting miRNA target.

View Figures

View References

1	Yamamoto N, Goto K, Nishio M, Chikamori K, Hida T, Maemondo M, Katakami N, Kozuki T, Yoshioka H, Seto T, et al: Final overall survival in JO22903, a phase II, open-label study of first-line erlotinib for Japanese patients with EGFR mutation-positive non-small-cell lung cancer. Int J Clin Oncol. 22:70–78. 2017. View Article : Google Scholar : PubMed/NCBI
2	Krzakowski M, Lucas C and Gridelli C: Fractionated scheme of oral vinorelbine as single-agent therapy or in combination with cisplatin concomitantly with thoracic radiotherapy in stage III non-small-cell lung cancer: Dose-escalation phase I trial. Clin Lung Cancer. 15:266–273. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kelley MJ, Jha G, Shoemaker D, Herndon JE II, Gu L, Barry WT, Crawford J and Ready N: Phase II Study of dasatinib in previously treated patients with advanced non-small cell lung cancer. Cancer Invest. 35:32–35. 2017. View Article : Google Scholar : PubMed/NCBI
4	Dingemans AM, Bootsma G, van Baardwijk A, Reymen B, Wanders R, Brans B, Das M, Hochstenbag M, van Belle A, Houben R, et al: A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer. J Thorac Oncol. 9:710–716. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kentepozidis N, Economopoulou P, Christofyllakis C, Chelis L, Polyzos A, Vardakis N, Koinis F, Vamvakas L, Katsaounis P, Kalbakis K, et al: Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: A randomized phase II study of the Hellenic Oncology Research Group (HORG). Clin Transl Oncol. 19:317–325. 2017. View Article : Google Scholar : PubMed/NCBI
6	Belani CP, Yamamoto N, Bondarenko IM, Poltoratskiy A, Novello S, Tang J, Bycott P, Niethammer AG, Ingrosso A, Kim S, et al: Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer. BMC Cancer. 14:2902014. View Article : Google Scholar : PubMed/NCBI
7	Okamoto K, Okamoto I, Takeda M, Kobayashi S, Takeda K, Nakamatsu K, Nishimura Y and Nakagawa K: A phase I study of split-dose cisplatin and etoposide with concurrent accelerated hyperfractionated thoracic radiotherapy in elderly patients with limited-disease small cell lung cancer. Jpn J Clin Oncol. 44:743–748. 2014. View Article : Google Scholar : PubMed/NCBI
8	Zhu Q, Liang X, Dai J and Guan X: Prostaglandin transporter, SLCO2A1, mediates the invasion and apoptosis of lung cancer cells via PI3K/AKT/mTOR pathway. Int J Clin Exp Pathol. 8:9175–9181. 2015.PubMed/NCBI
9	Wang R, Zhang Q, Peng X, Zhou C, Zhong Y, Chen X, Qiu Y, Jin M, Gong M and Kong D: Stellettin B induces G1 arrest, apoptosis and autophagy in human non-small cell lung cancer A549 cells via blocking PI3K/Akt/mTOR pathway. Sci Rep. 6:270712016. View Article : Google Scholar : PubMed/NCBI
10	Guo Y, Chang H, Li J, Xu XY, Shen L, Yu ZB and Liu WC: Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway. Apoptosis. 20:1109–1121. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wu N, Zhang C, Bai C, Han YP and Li Q: MiR-4782-3p inhibited non-small cell lung cancer growth via USP14. Cell Physiol Biochem. 33:457–467. 2014. View Article : Google Scholar : PubMed/NCBI
12	Voortman J, Goto A, Mendiboure J, Sohn JJ, Schetter AJ, Saito M, Dunant A, Pham TC, Petrini I, Lee A, et al: MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. Cancer Res. 70:8288–8298. 2010. View Article : Google Scholar : PubMed/NCBI
13	Feng B, Chen S, Gordon AD and Chakrabarti S: miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. J Mol Cell Cardiol. 105:70–76. 2017. View Article : Google Scholar : PubMed/NCBI
14	Matysiak M, Fortak-Michalska M, Szymanska B, Orlowski W, Jurewicz A and Selmaj K: MicroRNA-146a negatively regulates the immunoregulatory activity of bone marrow stem cells by targeting prostaglandin E2 synthase-2. J Immunol. 190:5102–5109. 2013. View Article : Google Scholar : PubMed/NCBI
15	Kwon JH, Kim JH, Lee JA, Shin HC, Kim HJ, Song HH, Jung JY, Kim HY, Choi DR, Kim HS, et al: Phase II study with fractionated schedule of docetaxel and cisplatin in patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 66:889–897. 2010. View Article : Google Scholar : PubMed/NCBI
16	Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, Bálint B, Losonczy G, et al SQUIRE Investigators, : Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol. 16:763–774. 2015. View Article : Google Scholar : PubMed/NCBI
17	Niho S, Kubota K, Nihei K, Sekine I, Sumi M, Sekiguchi R, Funai J, Enatsu S, Ohe Y and Tamura T: Dose-escalation study of thoracic radiotherapy in combination with pemetrexed plus Cisplatin followed by pemetrexed consolidation therapy in Japanese patients with locally advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 14:62–69. 2013. View Article : Google Scholar : PubMed/NCBI
18	Pichler M, Winter E, Ress AL, Bauernhofer T, Gerger A, Kiesslich T, Lax S, Samonigg H and Hoefler G: miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor. J Clin Pathol. 67:198–203. 2014. View Article : Google Scholar : PubMed/NCBI
19	Sirichanchuen B, Pengsuparp T and Chanvorachote P: Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Mol Cell Biochem. 364:11–18. 2012. View Article : Google Scholar : PubMed/NCBI
20	Yang J, Zhou Y, Cheng X, Fan Y, He S, Li S, Ye H, Xie C, Wu W, Li C, et al: Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells. Sci Rep. 5:76972015. View Article : Google Scholar : PubMed/NCBI
21	Oh BS, Shin EA, Jung JH, Jung DB, Kim B, Shim BS, Yazdi MC, Iranshahi M and Kim SH: Apoptotic effect of galbanic acid via activation of caspases and inhibition of Mcl-1 in H460 non-small lung carcinoma cells. Phytother Res. 29:844–849. 2015. View Article : Google Scholar : PubMed/NCBI
22	Li YR, Li S, Ho CT, Chang YH, Tan KT, Chung TW, Wang BY, Chen YK and Lin CC: Tangeretin derivative, 5-acetyloxy-6,7,8,4′-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. Cancer Biol Ther. 17:48–64. 2016. View Article : Google Scholar : PubMed/NCBI
23	Hwang KE, Kim YS, Jung JW, Kwon SJ, Park DS, Cha BK, Oh SH, Yoon KH, Jeong ET and Kim HR: Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells. Oncotarget. 6:29482–29496. 2015. View Article : Google Scholar : PubMed/NCBI
24	Wu XF, Zhou ZH and Zou J: MicroRNA-181 inhibits proliferation and promotes apoptosis of chondrocytes in osteoarthritis by targeting PTEN. Biochem Cell Biol. 95:437–444. 2017. View Article : Google Scholar : PubMed/NCBI
25	Song BQ, Chi Y, Li X, Du WJ, Han ZB, Tian JJ, Li JJ, Chen F, Wu HH, Han LX, et al: Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K/AKT/mTOR pathway. Cell Physiol Biochem. 36:1991–2002. 2015. View Article : Google Scholar : PubMed/NCBI
26	Strotbek M, Schmid S, Sánchez-González I, Boerries M, Busch H and Olayioye MA: miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer. Int J Cancer. 140:2310–2320. 2017. View Article : Google Scholar : PubMed/NCBI
27	Trigka EA, Levidou G, Saetta AA, Chatziandreou I, Tomos P, Thalassinos N, Anastasiou N, Spartalis E, Kavantzas N, Patsouris E, et al: A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features. Oncol Rep. 30:623–636. 2013. View Article : Google Scholar : PubMed/NCBI
28	Nicoś M, Krawczyk P, Jarosz B, Sawicki M, Trojanowski T and Milanowski J: Prevalence of NRAS, PTEN and AKT1 gene mutations in the central nervous system metastases of non-small cell lung cancer. Brain Tumor Pathol. 34:36–41. 2017. View Article : Google Scholar : PubMed/NCBI
29	He Y, Mo Q, Luo B, Qiao Y, Xu R, Zuo Z, Deng J, Nong X, Peng G, He W, et al: Induction of apoptosis and autophagy via mitochondria- and PI3K/Akt/mTOR-mediated pathways by E. adenophorum in hepatocytes of saanen goat. Oncotarget. 7:54537–54548. 2016. View Article : Google Scholar : PubMed/NCBI
30	Liu Z, Wang L, Zhang LN, Wang Y, Yue WT and Li Q: Expression and clinical significance of mTOR in surgically resected non-small cell lung cancer tissues: A case control study. Asian Pac J Cancer Prev. 13:6139–6144. 2012. View Article : Google Scholar : PubMed/NCBI