MicroRNA‑485‑5p suppresses the progression of esophageal squamous cell carcinoma by targeting flotillin‑1 and inhibits the epithelial‑mesenchymal transition

Zhao,Riyang; Shan,Yanan; Zhou,Xinliang; Zhang,Cong; Zhao,Ruinian; Zhao,Lianmei; Shan,Baoen

doi:10.3892/or.2021.8044

MicroRNA‑485‑5p suppresses the progression of esophageal squamous cell carcinoma by targeting flotillin‑1 and inhibits the epithelial‑mesenchymal transition

Authors:
- Riyang Zhao
- Yanan Shan
- Xinliang Zhou
- Cong Zhang
- Ruinian Zhao
- Lianmei Zhao
- Baoen Shan
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Affiliations: Research Centre, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
Published online on: April 8, 2021 https://doi.org/10.3892/or.2021.8044
Article Number: 93
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

As esophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in Asia, it is crucial to uncover its underlying molecular mechanisms that support its development and progression. Several articles have reported that microRNA (miR)‑485‑5p inhibits the malignant phenotype in a number of cancer types, such as lung, gastric and breast cancer, but to the best of our knowledge, its function in ESCC has not been studied in depth until the present study. It is of great significance to probe the regulatory action and underlying mechanism of miR‑485‑5p in ESCC. In brief, this study identified that miR‑485‑5p expression in ESCC tissues was significantly lower than that in normal tissues. The decrease in miR‑485‑5p expression was associated with a larger tumour size and poor histology and stage. The expression of miR‑485‑5p was relatively high in Eca 109 and TE‑1 cells, but relatively low in KYSE 30. The overexpression of miR‑485‑5p inhibited cell proliferation, migration and invasion in vitro, whereas miR‑485‑5p knockdown did the opposite. Flotillin‑1 (FLOT‑1) can facilitate the malignant phenotype in various cancer types. The present study found that in ESCC tissue, the protein expression of FLOT‑1 was negatively correlated with miR‑485‑5p expression. Further experiments showed that miR‑485‑5p directly targeted the 3'‑untranslated region of FLOT‑1. The overexpression of miR‑485‑5p significantly suppressed the mRNA and protein expression levels of FLOT‑1, whereas knockdown had the reverse effects. Furthermore, overexpression of miR‑485‑5p restrained epithelial‑mesenchymal metastasis (EMT)‑related factors at both the mRNA and protein levels. At the same time, it also inhibited the growth of ESCC and restrained the EMT in vivo. In summary, miR‑485‑5p was found to be an inhibitor of ESCC and may have potential as a novel target candidate for ESCC treatment.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Brock MV, Gou M, Akiyama Y, Muller A, Wu TT, Montgomery E, Deasel M, Germonpré P, Rubinson L, Heitmiller RF, et al: Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res. 9:2912–2919. 2003.PubMed/NCBI
4	Thrumurthy SG, Chaudry MA, Thrumurthy SSD and Mughal M: Oesophageal cancer: Risks, prevention, and diagnosis. BMJ. 366:143732019.
5	Mariette C, Markar SR, Dabakuyo-Yonli TS, Meunier B, Pezet D, Collet D, D'Journo XB, Brigand C, Perniceni T, Carrère N, et al: Hybrid minimally invasive esophagectomy for esophageal cancer. N Engl J Med. 380:152–162. 2019. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
8	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
9	Jiang M, Shi L, Yang C, Ge Y, Lin L, Fan H, He Y, Zhang D, Miao Y and Yang L: MiR-1254 inhibits cell proliferation, migration, and invasion by down-regulating Smurf1 in gastric cancer. Cell Death Dis. 10:322019. View Article : Google Scholar : PubMed/NCBI
10	Zhang Z, Zhang Y, Sun XX, Ma X and Chen ZN: MicroRNA-146a inhibits cancer metastasis by downregulating VEGF through dual pathways in hepatocellular carcinoma. Mol Cancer. 14:11862015. View Article : Google Scholar
11	Garzon R, Calin GA and Croce CM: MicroRNAs in cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
12	Troschel FM, Böhly N, Borrmann K, Braun T, Schwickert A, Kiesel L, Eich HT, Götte M and Greve B: MiR-142-3p attenuates breast cancer stem cell characteristics and decreases radioresistance in vitro. Tumour Biol. 40:10104283187918872018. View Article : Google Scholar : PubMed/NCBI
13	Wu Y, Huang J, Xu H and Gong Z: Over-Expression of miR-15a-3p enhances the radiosensitivity of cervical cancer by targeting tumor protein D52. Biomed Pharmacother. 105:1325–1334. 2018. View Article : Google Scholar : PubMed/NCBI
14	Shao Y, Zhang D, Li X, Yang J, Chen L, Ning Z, Xu Y, Deng G, Tao M, Zhu Y and Jiang J: MicroRNA-203 increases cell radiosensitivity via directly targeting Bmi-1 in hepatocellular carcinoma. Mol Pharm. 15:3205–3215. 2018. View Article : Google Scholar : PubMed/NCBI
15	Wang L, Peng X, Lu X, Wei Q, Chen M and Liu L: Inhibition of hsa_circ_0001313 (circCCDC66) induction enhances the radio-sensitivity of colon cancer cells via tumor suppressor miR-338-3p: Effects of cicr_0001313 on colon cancer radio-sensitivity. Pathol Res Pract. 215:689–696. 2019. View Article : Google Scholar : PubMed/NCBI
16	Yu J, Wu SW and Wu WP: A tumor-suppressive microRNA, miRNA-485-5p, inhibits glioma cell proliferation and invasion by down-regulating TPD52L2. Am J Transl Res. 9:3336–3344. 2017.PubMed/NCBI
17	Wang R, Zuo X, Wang K, Han Q, Zuo J, Ni H, Liu W, Bao H, Tu Y and Xie P: MicroRNA-485-5p attenuates cell proliferation in glioma by directly targeting paired box 3. Am J Cancer Res. 8:2507–2517. 2018.PubMed/NCBI
18	Chai Y, Du Y, Zhang S, Xiao J, Luo Z, He F and Huang K: MicroRNA-485-5p reduces O-GlcNAcylation of Bmi-1 and inhibits colorectal cancer proliferation. Exp Cell Res. 368:111–118. 2018. View Article : Google Scholar : PubMed/NCBI
19	Hu XX, Xu XN, He BS, Sun HL, Xu T, Liu XX, Chen XX, Zeng KX, Wang SK and Pan YQ: MicroRNA-485-5p functions as a tumor suppressor in colorectal cancer cells by targeting CD147. J Cancer. 9:2603–2611. 2018. View Article : Google Scholar : PubMed/NCBI
20	Han DL, Wang LL, Zhang GF, Yang WF, Chai J, Lin HM, Fu Z and Yu JM: MiRNA-485-5p, inhibits esophageal cancer cells proliferation and invasion by down-regulating O-linked N-acetylglucosamine transferase. Eur Rev Med Pharmacol Sci. 23:2809–2816. 2019.PubMed/NCBI
21	Dam DHM, Jelsma SA, Yu JM, Liu H, Kong B and Paller AS: Flotillin and AP2A1/2 promote IGF-1 receptor association with clathrin and internalization in primary human keratinocytes. J Invest Dermatol. 140:1743–1752. 2020. View Article : Google Scholar : PubMed/NCBI
22	Sonnino S and Prinetti A: Membrane domains and the ‘lipid raft’ concept. Curr Med Chem X20. 4–21. 2013.
23	George KS and Wu S: Lipid raft: A floating island of death or survival. Toxicol Appl Pharmacol. 259:311–319. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ficht X, Ruef N, Stolp B, Samson GPB, Moalli F, Page N, Merkler D, Nichols BJ, Diz-Muñoz A, Legler DF, et al: In vivo function of the lipid raft protein flotillin-1 during CD8(+) T cell-mediated host surveillance. J Immunol. 203:2377–2387. 2019. View Article : Google Scholar : PubMed/NCBI
25	Lu SM and Fairn GD: Mesoscale organization of domains in the plasma membrane-beyond the lipid raft. Crit Rev Biochem Mol Biol. 53:192–207. 2018. View Article : Google Scholar : PubMed/NCBI
26	Affentranger S, Martinelli S, Hahn J, Rossy J and Niggli V: Dynamic reorganization of flotillins in chemokinestimulated human T-lymphocytes. BMC Cell Biol. 12:282011. View Article : Google Scholar : PubMed/NCBI
27	Guillaume E, Comunale F, Do Khoa N, Planchon D, Bodin S and Gauthier-Rouviere C: Flotillin microdomains stabilize cadherins at cell-cell junctions. J Cell Sci. 126:5293–5304. 2013. View Article : Google Scholar : PubMed/NCBI
28	Rice T, Ishwaran H, Hofstetter W, Kelsen D, Apperson-Hansen C and Blackstone E; Worldwide Esophageal Cancer Collaboration Investigators, : Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 29:897–905. 2016. View Article : Google Scholar : PubMed/NCBI
29	Dai SL, Wei SS, Zhang C, Li XY, Liu YP, Ma M, Lv HL, Zhang Z, Zhao LM and Shan BE: MTA2 promotes the metastasis of esophageal squamous cell carcinoma via EIF4E-twist feedback loop. Cancer Sci. 19:147782020.
30	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
31	Guo AY, Liang XJ, Liu RJ, Li XX, Bi W, Zhou LY, Tang CE, Yan A, Chen ZC and Zhang PF: Flotilin-1 promotes the tumorigenicity and progression of malignant phenotype in human lung adenocarcinoma. Cancer Biol Ther. 18:715–722. 2017. View Article : Google Scholar : PubMed/NCBI
32	Huang RS, Zheng YL, Li C, Ding C, Xu C and Zhao J: MicroRNA-485-5p suppresses growth and metastasis in non-small cell lung cancer cells by targeting IGF2BP2. Life Sci. 199:104–111. 2018. View Article : Google Scholar : PubMed/NCBI
33	Lee RC, Feinbaum RL and Ambros V: The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75:843–854. 1993. View Article : Google Scholar : PubMed/NCBI
34	Di Leva G, Garofalo M and Croce CM: MicroRNAs in cancer. Annu Rev Pathol. 9:287–314. 2014. View Article : Google Scholar : PubMed/NCBI
35	Chen H, Yao X, Di X, Zhang Y, Zhu H, Liu S, Chen T, Yu D and Sun X: MiR-450a-5p inhibits autophagy and enhances radiosensitivity by targeting dual-specificity phosphatase 10 in esophageal squamous cell carcinoma. Cancer Lett. 28:114–126. 2020. View Article : Google Scholar
36	Wang F, Li L, Piontek K, Sakaguchi M and Selaru FM: Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology. 67:940–954. 2018. View Article : Google Scholar : PubMed/NCBI
37	Qiu BQ, Lin XH, Ye XD, Huang W, Pei X, Xiong D, Long X, Zhu SQ, Lu F, Lin K, et al: Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA. Aging (Albany NY). 12:1843–1856. 2020. View Article : Google Scholar : PubMed/NCBI
38	Wang Y, Sun L, Wang L, Liu Z, Li Q, Yao B, Wang C, Chen T, Tu K and Liu Q: Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate wnt/β-catenin signal pathway in hepatocellular carcinoma. Cell Death Dis. 9:8512018. View Article : Google Scholar : PubMed/NCBI
39	Duan J, Zhang H, Li S, Wang X, Yang H, Jiao S and Ba Y: The role of miR-485-5p/NUDT1 axis in gastric cancer. Cancer Cell Int. 17:922017. View Article : Google Scholar : PubMed/NCBI
40	Gao J, Dai C, Yu X, Yin XB and Zhou F: MicroRNA-485-5p inhibits the progression of hepatocellular carcinoma through blocking the WBP2/wnt signaling pathway. Cell Signal. 66:1094662020. View Article : Google Scholar : PubMed/NCBI
41	Zhang Y, Hu J, Zhou W and Gao H: LncRNA FOXD2-AS1 accelerates the papillary thyroid cancer progression through regulating the miR-485-5p/KLK7 axis. J Cell Biochem. 19:10022018.
42	Li G and Kong Q: LncRNA LINC00460 promotes the papillary thyroid cancer progression by regulating the LINC00460/miR-485-5p/raf1 axis. Biol Res. 52:612019. View Article : Google Scholar : PubMed/NCBI
43	Bao W, Cao F, Ni S, Yang J, Li H, Su Z and Zhao B: lncRNA FLVCR1-AS1 regulates cell proliferation, migration and invasion by sponging miR-485-5p in human cholangiocarcinoma. Oncol Lett. 18:2240–2247. 2019.PubMed/NCBI
44	Gao F, Wu H, Wang R, Guo Y, Zhang Z, Wang T, Zhang G, Liu C and Liu J: MicroRNA-485-5p suppresses the proliferation, migration and invasion of small cell lung cancer cells by targeting flotillin-2. Bioengineered. 10:1–12. 2019. View Article : Google Scholar : PubMed/NCBI
45	Wang FR, Xu SH, Wang BM and Wang F: MiR-485-5p inhibits metastasis and proliferation of osteosarcoma by targeting CX3CL1. Eur Rev Med Pharmacol Sci. 22:7197–7204. 2018.PubMed/NCBI
46	Wang M, Cai WR, Meng R, Chi JR, Li YR, Chen AX, Yu Y and Cao XC: MiR-485-5p suppresses breast cancer progression and chemosensitivity by targeting survivin. Biochem Biophys Res Commun. 501:48–54. 2018. View Article : Google Scholar : PubMed/NCBI
47	Lin C, Wu Z, Lin X, Yu C, Shi T, Zeng Y, Wang X, Li J and Song L: Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a. Clin Cancer Res. 17:3089–3099. 2011. View Article : Google Scholar : PubMed/NCBI
48	Li Z, Yang Y, Gao Y, Wu X, Yang X, Zhu Y, Yang H, Wu L, Yang C and Song L: Elevated expression of flotillin-1 is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer. Am J Cancer Res. 6:38–50. 2016.
49	Liu R, Xie H, Luo C, Chen Z, Zhou X, Xia K, Chen X, Zhou M, Cao P, Cao K and Zhou J: Identification of FLOT2 as a novel target for microRNA-34a in melanoma. J Cancer Res Clin Oncol. 141:993–1006. 2015. View Article : Google Scholar : PubMed/NCBI
50	Song L, Gong H, Lin C, Wang C, Liu L, Wu J, Li M and Li J: Flotillin-1 promotes tumor necrosis factor-alpha receptor signaling and activation of NF-κB in esophageal squamous cell carcinoma cells. Gastroenterology. 143:995–1005. 2012. View Article : Google Scholar : PubMed/NCBI
51	Jang D, Kwon H, Choi M, Lee J and Pak Y: Sumoylation of flotillin-1 promotes EMT in metastatic prostate cancer by suppressing snail degradation. Oncogene. 38:3248–3260. 2019. View Article : Google Scholar : PubMed/NCBI