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World Journal of Surgical Oncology

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01-12-2021 | NSCLC | Research

MiR-194-5p enhances the sensitivity of nonsmall-cell lung cancer to doxorubicin through targeted inhibition of hypoxia-inducible factor-1

Authors: Mengning Xia, Lili Sheng, Wei Qu, Xue Xue, Hucheng Chen, Guoyan Zheng, Weigang Chen

Published in: World Journal of Surgical Oncology | Issue 1/2021

Abstract

Background

Despite chemotherapy being a common treatment, an increase in chemoresistance over time is unavoidable. We therefore investigated the role of miR-194-5p in regulating chordoma cell behavior and examined the downstream effectors of miR-194-5p.

Methods

In this study, NSCLC cell lines A549 and H460 were cultured under hypoxic conditions for 1 week to induce drug resistance to doxorubicin (DOX). The connection between miR-194-5p and HIF-1 was revealed by reverse transcription and real-time polymerase chain reaction (RT-qPCR), western blot, and dual-luciferase assays. We used TUNEL staining and the CCK-8 test to assess the sensitivity of NSCLC cells to DOX.

Results

We found that hypoxia-induced NSCLC cells enhanced resistance to DOX. MiR-194-5p was substantially reduced, and HIF-1 was increased in hypoxia-induced drug-resistant NSCLC cells. Moreover, miR-194-5p successfully induced NSCLC cell apoptosis by directly inhibiting HIF-1, thereby enhancing DOX sensitivity.

Conclusions

MiR-194-5p enhanced the sensitivity of NSCLC cells to DOX by directly inhibiting HIF-1. This work provides insights into underlying treatments for drug-resistant NSCLC.

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85. https://doi.org/10.1016/j.cell.2017.09.021.CrossRefPubMedPubMedCentral

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

Chen W, Sun K, Zheng R, Zeng H, Zhang S, Xia C, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res. 2018;30(1):1–12. https://doi.org/10.21147/j.issn.1000-9604.2018.01.01.CrossRefPubMedPubMedCentral

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. https://doi.org/10.1056/NEJMoa040938.CrossRefPubMed

Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015;16(9):e447–59. https://doi.org/10.1016/S1470-2045(15)00246-6.CrossRefPubMed

Wang J, Feng C, He Y, Ding W, Sheng J, Arshad M, et al. Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis. Oncotarget. 2015;6(29):27700–13. https://doi.org/10.18632/oncotarget.4392.CrossRefPubMedPubMedCentral

Tao L, Shu-Ling W, Jing-Bo H, Ying Z, Rong H, Xiang-Qun L, et al. MiR-451a attenuates doxorubicin resistance in lung cancer via suppressing epithelialmesenchymal transition (EMT) through targeting c-Myc. Biomed Pharmacother. 2020;125:109962. https://doi.org/10.1016/j.biopha.2020.109962.CrossRefPubMed

Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer. 2016;138(5):1058–66. https://doi.org/10.1002/ijc.29519.CrossRefPubMed

Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, et al. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol. 2011;162(5):1096–108. https://doi.org/10.1111/j.1476-5381.2010.01101.x.CrossRefPubMedPubMedCentral

10.

Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65(2):613–21.PubMed

11.

Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol. 2004;24(7):2875–89. https://doi.org/10.1128/MCB.24.7.2875-2889.2004.CrossRefPubMedPubMedCentral

12.

Kim HS, Wannatung T, Lee S, Yang WK, Chung SH, Lim JS, et al. Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer. Apoptosis. 2012;17(9):938–49. https://doi.org/10.1007/s10495-012-0719-0.CrossRefPubMed

13.

Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genom. 2010;11(7):537–61. https://doi.org/10.2174/138920210793175895.CrossRef

14.

Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009;4(1):199–227. https://doi.org/10.1146/annurev.pathol.4.110807.092222.CrossRefPubMedPubMedCentral

15.

Nijhuis A, Thompson H, Adam J, Parker A, Gammon L, Lewis A, et al. Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance. Hum Mol Genet. 2017;26(8):1552–64. https://doi.org/10.1093/hmg/ddx059.CrossRefPubMedPubMedCentral

16.

Kim SW. The role of microRNAs in colorectal cancer. Korean J Gastroenterol. 2017;69(4):206–11. https://doi.org/10.4166/kjg.2017.69.4.206.CrossRefPubMed

17.

Muller S, Janke F, Dietz S, Sultmann H. Circulating microRNAs as potential biomarkers for lung cancer. Recent Results Cancer Res. 2020;215:299–318. https://doi.org/10.1007/978-3-030-26439-0_16.CrossRefPubMed

18.

Yu G, Zhou H, Yao W, Meng L, Lang B. lncRNA TUG1 promotes cisplatin resistance by regulating CCND2 via epigenetically silencing miR-194-5p in bladder cancer. Mol Ther Nucleic Acids. 2019;16:257–71. https://doi.org/10.1016/j.omtn.2019.02.017.CrossRefPubMedPubMedCentral

19.

Zhu X, Li D, Yu F, Jia C, Xie J, Ma Y, et al. miR-194 inhibits the proliferation, invasion, migration, and enhances the chemosensitivity of non-small cell lung cancer cells by targeting forkhead box A1 protein. Oncotarget. 2016;7(11):13139–52. https://doi.org/10.18632/oncotarget.7545.CrossRefPubMedPubMedCentral

20.

Wald P, Liu XS, Pettit C, Dillhoff M, Manilchuk A, Schmidt C, et al. Prognostic value of microRNA expression levels in pancreatic adenocarcinoma: a review of the literature. Oncotarget. 2017;8(42):73345–61. https://doi.org/10.18632/oncotarget.20277.CrossRefPubMedPubMedCentral

21.

Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, et al. Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene. 2017;36(5):639–51. https://doi.org/10.1038/onc.2016.229.CrossRefPubMed

22.

Genovese I, Fiorillo A, Ilari A, Masciarelli S, Fazi F, Colotti G. Binding of doxorubicin to Sorcin impairs cell death and increases drug resistance in cancer cells. Cell Death Dis. 2017;8(7):e2950. https://doi.org/10.1038/cddis.2017.342.CrossRefPubMedPubMedCentral

23.

Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. Non-small cell lung cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2017;15(4):504–35. https://doi.org/10.6004/jnccn.2017.0050.CrossRef

24.

Daniel C, Mato AR. BCL-2 as a therapeutic target in chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2017;15(3):210–8.PubMed

25.

Li Z, Ying X, Chen H, Ye P, Shen Y, Pan W, et al. MicroRNA-194 inhibits the epithelial-mesenchymal transition in gastric cancer cells by targeting FoxM1. Dig Dis Sci. 2014;59(9):2145–52. https://doi.org/10.1007/s10620-014-3159-6.CrossRefPubMed

26.

Miao J, Wang W, Wu S, Zang X, Li Y, Wang J, et al. miR-194 suppresses proliferation and migration and promotes apoptosis of osteosarcoma cells by targeting CDH2. Cell Physiol Biochem. 2018;45(5):1966–74. https://doi.org/10.1159/000487973.CrossRefPubMed

27.

Wang ZH, Ren LL, Zheng P, Zheng HM, Yu YN, Wang JL, et al. miR-194 as a predictor for adenoma recurrence in patients with advanced colorectal adenoma after polypectomy. Cancer Prev Res. 2014;7:607–16.CrossRef

28.

Wu J, Zhang L, Wu S, Yi X, Liu Z. miR-194-5p inhibits SLC40A1 expression to induce cisplatin resistance in ovarian cancer. Pathol Res Pract. 2020;216:152979.CrossRefPubMed

29.

Nakamura K, Sawada K, Miyamoto M, Kinose Y, Yoshimura A, Ishida K, et al. Downregulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression. Oncotarget. 2019;10(6):673–83. https://doi.org/10.18632/oncotarget.26586.CrossRefPubMedPubMedCentral

Title: MiR-194-5p enhances the sensitivity of nonsmall-cell lung cancer to doxorubicin through targeted inhibition of hypoxia-inducible factor-1
Authors: Mengning Xia
Lili Sheng
Wei Qu
Xue Xue
Hucheng Chen
Guoyan Zheng
Weigang Chen
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
Lung Cancer
Published in: World Journal of Surgical Oncology / Issue 1/2021
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/s12957-021-02278-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

MiR-194-5p enhances the sensitivity of nonsmall-cell lung cancer to doxorubicin through targeted inhibition of hypoxia-inducible factor-1

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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