MicroRNA-4284 inhibits colon cancer epithelial-mesenchymal transition by down-regulating Perilipin 5
Abstract
Background: MicroRNA (miR) has been suggested in the development of several types of cancer; yet, the exact function of miR-4284 in colon cancer remains elusive.
Methods: MiR-4284 expression was assessed in normal colon cell line CCD-18Co, and HT-29 and SW480 cell lines representing human colon cancer. Potential target gene of miR-4284 was predicted using TargetScanHuman, and experimentally verified using luciferase report assay. Wound-healing, cell invasion and attachment were evaluated to determine the effect of miR-4284 on the migration, invasion, and metastatic properties of colon cancer cell lines. Expression of epithelial-mesenchymal transition (EMT) phenotypic protein hallmarks, including N-cadherin, E-cadherin, as well as Vimentin, was also evaluated.
Results: MiR-4284 was significantly decreased in colon cancer cell lines, and Perilipin 5 (PLIN5) was found to be directly targeted by miR-4284. Ectopic expression of miR-4284 significantly reduced endogenous expression level of PLIN5 in colon cancer cell lines, suppressing migration, invasion, and metastatic phenotypes. In addition, re-introducing miR-4284 reversed the expression profile of EMT markers.
Conclusion: Our findings for the first time identify miR-4284 as an anti-tumor miRNA in colon cancer, which acts to reduce PLIN5 and inhibit EMT, leading to inhibited colon cancer tumorigenesis. These results highlight the potential of miR-4284 as a therapeutic target in metastatic colon cancer.
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References
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104-17.
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683-91.
Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-6.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-97.
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-54.
Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901-6.
Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86-9.
Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861-74.
Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4(3):143-59.
Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov. 2016;6(3):235-46.
Bader AG. miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet. 2012;3:120.
Li Y, Shen Z, Jiang H, Lai Z, Wang Z, Jiang K, et al. MicroRNA4284 promotes gastric cancer tumorigenicity by targeting ten-eleven translocation 1. Mol Med Rep. 2018;17(5):6569-75.
Yang F, Nam S, Brown CE, Zhao R, Starr R, Ma Y, et al. A novel berbamine derivative inhibits cell viability and induces apoptosis in cancer stem-like cells of human glioblastoma, via up-regulation of miRNA-4284 and JNK/AP-1 signaling. PLoS One. 2014;9(4):e94443.
Munari E, Marchionni L, Chitre A, Hayashi M, Martignoni G, Brunelli M, et al. Clear cell papillary renal cell carcinoma: micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma. Hum Pathol. 2014;45(6):1130-8.
McDermott N, Meunier A, Wong S, Buchete V, Marignol L. Profiling of a panel of radioresistant prostate cancer cells identifies deregulation of key miRNAs. Clin Transl Radiat Oncol. 2017;2:63-8.
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593-601.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, et al. Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist Updat. 2010;13(4-5):109-18.
Kitamura K, Seike M, Okano T, Matsuda K, Miyanaga A, Mizutani H, et al. MiR-134/487b/655 cluster regulates TGF-beta-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells. Mol Cancer Ther. 2014;13(2):444-53.
Jiang L, He D, Yang D, Chen Z, Pan Q, Mao A, et al. MiR-489 regulates chemoresistance in breast cancer via epithelial mesenchymal transition pathway. FEBS Lett. 2014;588(11):2009-15.
Wu YM, Chen ZJ, Liu H, Wei WD, Lu LL, Yang XL, et al. Inhibition of ERRalpha suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin. Oncotarget. 2015.
Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 2013;73(10):3051-61.
Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58(2):629-41.
Cursons J, Pillman KA, Scheer KG, Gregory PA, Foroutan M, Hediyeh-Zadeh S, et al. Combinatorial targeting by microRNAs co-ordinates post-transcriptional control of EMT. Cell Syst. 2018;7(1):77-91 e7.
Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C, Londos C. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J Lipid Res. 2010;51(3):468-71.
Yamaguchi T, Matsushita S, Motojima K, Hirose F, Osumi T. MLDP, a novel PAT family protein localized to lipid droplets and enriched in the heart, is regulated by peroxisome proliferator-activated receptor alpha. J Biol Chem. 2006;281(20):14232-40.
Asimakopoulou A, Vucur M, Luedde T, Schneiders S, Kalampoka S, Weiss TS, et al. Perilipin 5 and lipocalin 2 expression in hepatocellular carcinoma. Cancers (Basel). 2019;11(3).
Copyright (c) 2021 Xiaofei Miao, Zengyao Li, Ye Zhang, Tong Wang
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