Downregulation of MiR-222-3p Reverses Doxorubicin-Resistance in LoVo Cells Through Upregulating Forkhead Box Protein P2 (FOXP2) Protein

Overview

Journal Med Sci Monit

Specialties General Medicine
Pathology

Date 2019 Mar 25

PMID 30904920

Citations 10

Authors

Huaiming Wang

Zhenwei Deng

Xinhua Chen

Jian Cai

Tenghui Ma

Qinghua Zhong

Ruiping Li

Libo Li

Tian Li

Affiliations

Soon will be listed here.

Abstract

BACKGROUND Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat colon cancer. Despite impressive initial clinical responses, drug resistance has dramatically compromised the effectiveness of DOX. However, the underlying mechanisms of chemotherapeutic resistance in colon cancer remain poorly understood. MATERIAL AND METHODS In this study, we compared the expression of miR-222-3p in DOX-resistant colon cancer cells (LoVo/ADR) with the corresponding DOX-sensitive parental cells (LoVo/S) using quantitative real-time PCR. In addition, miR-222-3p inhibitors were infected into LoVo/ADR cell lines and the effects of this treatment were assessed. The Cell Counting Kit 8 assay was employed to verify the sensitivity of colon cancer cell lines to DOX. EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry, and in vivo subcutaneous tumorigenesis were used to assess cell proliferation and apoptosis. Transwell and wound healing assays were used to investigate cell migration after adding DOX. Additionally, the expression of forkhead box protein P2 (FOXP2), P-glycoprotein (P-gp) and caspase pathway-associated markers was assessed by western blotting. RESULTS Our results showed that miR-222-3p was upregulated in LoVo/ADR compared with the expression in LoVo/S cells. Additionally, downregulation of miR-222-3p in LoVo/ADR cells increased their sensitivity to DOX, reduced P-gp expression, and activated the caspase pathway. However, the downregulation of FOXP2 could efficiently reverse the effect of miR-222-3p inhibitors on LoVo/ADR cells. CONCLUSIONS Taken together, our results showed that miR-222-3p induced DOX resistance via suppressing FOXP2, upregulating P-gp, and inhibiting the caspase pathway.

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References

Boiocchi M, Tumiotto L, Giannini F, Viel A, Biscontin G, Sartor F . P-glycoprotein but not topoisomerase II and glutathione-S-transferase-pi accounts for enhanced intracellular drug-resistance in LoVo MDR human cell lines. Tumori. 1992; 78(3):159-66. DOI: 10.1177/030089169207800303. View

Mashima T, Tsuruo T . Defects of the apoptotic pathway as therapeutic target against cancer. Drug Resist Updat. 2005; 8(6):339-43. DOI: 10.1016/j.drup.2005.11.001. View

Weerasinghe P, Hallock S, Tang S, Trump B, Liepins A . Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells. Exp Toxicol Pathol. 2006; 58(1):21-30. DOI: 10.1016/j.etp.2006.01.008. View

Lelong-Rebel I, Brisson C, Fabre M, Bergerat J, Rebel G . Effect of pO2 on antitumor drug cytotoxicity on MDR and non-MDR variants selected from the LoVo metastatic colon carcinoma cell line. Anticancer Res. 2008; 28(1A):55-68. View

Indran I, Tufo G, Pervaiz S, Brenner C . Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta. 2011; 1807(6):735-45. DOI: 10.1016/j.bbabio.2011.03.010. View

Shah M, Calin G . MicroRNAs miR-221 and miR-222: a new level of regulation in aggressive breast cancer. Genome Med. 2011; 3(8):56. PMC: 3238182. DOI: 10.1186/gm272. View

Li N, Tang B, Zhu E, Li B, Zhuang Y, Yu S . Increased miR-222 in H. pylori-associated gastric cancer correlated with tumor progression by promoting cancer cell proliferation and targeting RECK. FEBS Lett. 2012; 586(6):722-8. DOI: 10.1016/j.febslet.2012.01.025. View

Schetter A, Okayama H, Harris C . The role of microRNAs in colorectal cancer. Cancer J. 2012; 18(3):244-52. PMC: 3397427. DOI: 10.1097/PPO.0b013e318258b78f. View

Tsui D, Vessey J, Tomita H, Kaplan D, Miller F . FoxP2 regulates neurogenesis during embryonic cortical development. J Neurosci. 2013; 33(1):244-58. PMC: 6618635. DOI: 10.1523/JNEUROSCI.1665-12.2013. View

10.

Lee C, He H, Jiang Y, Di Y, Yang F, Li J . Elevated expression of tumor miR-222 in pancreatic cancer is associated with Ki67 and poor prognosis. Med Oncol. 2013; 30(4):700. DOI: 10.1007/s12032-013-0700-y. View

11.

Kibria G, Hatakeyama H, Harashima H . Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2013; 37(1):4-15. DOI: 10.1007/s12272-013-0276-2. View

12.

Yang Y, Wang F, Xiao J, Song Y, Zhao Y, Cao Y . MiR-222 overexpression promotes proliferation of human hepatocellular carcinoma HepG2 cells by downregulating p27. Int J Clin Exp Med. 2014; 7(4):893-902. PMC: 4057838. View

13.

Zhou S, Zhang S, Wang Y, Yi S, Zhao L, Tang X . MiR-21 and miR-222 inhibit apoptosis of adult dorsal root ganglion neurons by repressing TIMP3 following sciatic nerve injury. Neurosci Lett. 2014; 586:43-9. DOI: 10.1016/j.neulet.2014.12.006. View

14.

Kathawala R, Gupta P, Ashby Jr C, Chen Z . The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Updat. 2015; 18:1-17. DOI: 10.1016/j.drup.2014.11.002. View

15.

Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll H . A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015; 14(1):1-10. DOI: 10.1016/j.clcc.2014.11.002. View

16.

Spaeth J, Hunter C, Bonatakis L, Guo M, French C, Slack I . The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia. 2015; 58(8):1836-44. PMC: 4785827. DOI: 10.1007/s00125-015-3635-3. View

17.

Gascoyne D, Spearman H, Lyne L, Puliyadi R, Perez-Alcantara M, Coulton L . The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest. PLoS One. 2015; 10(6):e0128513. PMC: 4452790. DOI: 10.1371/journal.pone.0128513. View

18.

Yan X, Zhou H, Zhang T, Xu P, Zhang S, Huang W . Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumour Biol. 2015; 36(12):9611-9. DOI: 10.1007/s13277-015-3701-y. View

19.

Zeng L, Hu Z, Li K, Xia K . miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells. J Cell Mol Med. 2016; 20(3):559-67. PMC: 4759461. DOI: 10.1111/jcmm.12760. View

20.

Wang D, Li J, Sha H, Chen X, Yang S, Shen H . miR-222 confers the resistance of breast cancer cells to Adriamycin through suppression of p27(kip1) expression. Gene. 2016; 590(1):44-50. DOI: 10.1016/j.gene.2016.06.013. View