miR‑378a‑3p exerts tumor suppressive function on the tumorigenesis of esophageal squamous cell carcinoma by targeting Rab10

Ding,Naixin; Sun,Xiujin; Wang,Tingting; Huang,Lei; Wen,Jing; Zhou,Yiqin

doi:10.3892/ijmm.2018.3639

miR‑378a‑3p exerts tumor suppressive function on the tumorigenesis of esophageal squamous cell carcinoma by targeting Rab10

Authors:
- Naixin Ding
- Xiujin Sun
- Tingting Wang
- Lei Huang
- Jing Wen
- Yiqin Zhou
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Affiliations: Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
Published online on: April 24, 2018 https://doi.org/10.3892/ijmm.2018.3639
Pages: 381-391
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a life‑threatening cancer with increasing incidence worldwide. MicroRNAs (miRs) have been reported to be involved in the progression of various types of cancer. In previous studies, the expression of miR‑378a‑3p was shown to be reduced in ESCC tissues. However, the mechanism underlying the effect of miR‑378a‑3p in ESCC remains to be elucidated. By employing a reverse transcription‑quantitative polymerase chain reaction, miR‑378a‑3p expression was tested in ESCC tissues and cell lines. In addition, the effects of miR‑378a‑3p on cell viability, proliferation, apoptosis, migration and invasion were studied using an MTT assay, an EdU assay, flow cytometry analysis, wound healing analysis and a Transwell assay. In the present study, the level of miR‑378a‑3p was significantly downregulated in ESCC clinical tissues and cell lines (EC109 and KYSE150). In addition, the overexpression of miR‑378a‑3p suppressed the viability, proliferation, migration and invasion of the ESCC cells. The upregulated expression of miR‑378a‑3p also increased the expression levels of B‑cell lymphoma 2‑associated X protein and caspase‑3, and decreased the expression levels of matrix metalloproteinase (MMP)‑2 and MMP‑9, which attenuated ESCC tumorigenesis. Furthermore, Rab10 was confirmed to be a direct target gene of miR‑378a‑3p, and was negatively affected by miR‑378a‑3p. The silencing of Rab10 revealed antitumor effects in ESCC cell lines, and the expression of miR‑378a‑3p was negatively correlated with that of Rab10 in ESCC. Collectively, miR‑378a‑3p may act as a tumor‑suppressor in ESCC cells through negatively regulating Rab10.

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1	Arnold M, Soerjomataram I, Ferlay J and Forman D: Global incidence of esophageal cancer by histological subtype in 2012. Gut. 64:381–387. 2015. View Article : Google Scholar
2	Lagergren J: Oesophageal cancer in 2014: Advance in curatively intended treatment. Nat Rev Gastroenterol Hepatol. 12:74–75. 2015. View Article : Google Scholar
3	Stoner GD and Gupta A: Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis. 22:1737–1746. 2001. View Article : Google Scholar : PubMed/NCBI
4	Enzinger PC and Mayer RJ: Esophageal cancer. N Engl J Med. 349:2241–2252. 2003. View Article : Google Scholar : PubMed/NCBI
5	Calin GA and Croce CM: MicroRNAs signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
6	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
7	Kloosterman WP and Plasterk RH: The diverse functions of microRNAs in animal development and diseases. Dev Cell. 11:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
8	Zhang Y, Sui J, Shen X, Li C, Yao W, Hong W, Peng H, Pu Y, Yin L and Liang G: Differential expression profiles of microRNAs as potential biomarkers for the early diagnosis of lung cancer. Oncol Rep. 37:3543–3553. 2017. View Article : Google Scholar : PubMed/NCBI
9	Li Z, Jiang J, Tian L, Li X, Chen J, Li S, Li C and Yang Z: A plasma mir-125a-5p as a novel biomarker for Kawasaki disease and induces apoptosis in HUVECs. Plos One. 12:e01754072017. View Article : Google Scholar : PubMed/NCBI
10	Chen Y, Luo D, Tian W, Li Z and Zhang X: Demethylation of miR-495 inhibits cell proliferation, migration and promotes apoptosis by targeting STAT-3 in breast cancer. Oncol Rep. 37:3581–3589. 2017. View Article : Google Scholar : PubMed/NCBI
11	Arias Sosa LA, Cuspoca Orduz AF and Bernal Gomez BM: Deregulation of microRNAs in gastric cancer: Up regulation by miR-21 and miR-106. Rev Gastroenterol Peru. 37:65–70. 2017.In Spanish. PubMed/NCBI
12	Sharma P, Saini N and Sharma R: MiR-107 functions as a tumor suppressor in human esophageal squamous cell carcinoma and targets Cdc42. Oncol Rep. 37:3116–3127. 2017. View Article : Google Scholar : PubMed/NCBI
13	Eichner LJ, Perry MC, Dufour CR, Bertos N, Park M, St-Pierre J and Giguère V: MiR-378(*) mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway. Cell Metab. 12:352–361. 2010. View Article : Google Scholar : PubMed/NCBI
14	Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato W, Shigekawa T, Osaki A, Saeki T, Berezikov E, Mano H and Inoue S: MiR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A. Sci Rep. 5:131702015. View Article : Google Scholar : PubMed/NCBI
15	Jeon TI, Park JW, Ahn J, Jung CH and Ha TY: Fisetin protects against hepatosteatosis in mice by inhibiting miR-378. Mol Nutr Food Res. 57:1931–1937. 2013. View Article : Google Scholar : PubMed/NCBI
16	Krist B, Florczyk U, Pietraszek-Gremplewicz K, Józkowicz A and Dulak J: The Role of miR-378a in metabolism, angionesis, and muscle biology. Int J Endocrinol. 2015:2817562015. View Article : Google Scholar
17	Babbey CM, Bacallao RL and Dunn KW: Dunn. Rab10 associates with primary cilia and the exocyst complex in renal epithelial cells. Am J Physiol Renal Physiol. 299:F495–F506. 2010. View Article : Google Scholar : PubMed/NCBI
18	Sano H, Peck GR, Kettenbach AN, Gerber SA and Lienhard GE: Insulin-stimulated GLUT4 protein translocation in adipocytes requires the Rab10 guanine nucleotide exchange factor Dennd4C. J Biol Chem. 286:16541–16545. 2011. View Article : Google Scholar : PubMed/NCBI
19	Barbosa MD, Johnson SA, Achey K, Gutierrez MJ, Wakeland EK, Zerial M and Kingsmore SF: The Rab protein family: Genetic mapping of six Rab genes in the mouse. Genomics. 30:439–444. 1995. View Article : Google Scholar : PubMed/NCBI
20	He H, Dai F, Yu L, She X, Zhao Y, Jiang J, Chen X and Zhao S: Identification and characterization of nine novel human small GTPases showing variable expressions in liver cancer tissues. Gene Expr. 10:231–242. 2002. View Article : Google Scholar : PubMed/NCBI
21	Hummel R, Sie C, Waston DI, Wang T, Ansar A, Michael MZ, Van der Hoek M, Haier J and Hussey DJ: MicroRNAs signatures in chemotherapy resistant esophageal cancer cell lines. World J Gastroenterol. 20:14904–14912. 2014. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^-ΔΔ^C T method. Methods. 25:402–408. 2001. View Article : Google Scholar
23	Croce CM: Causes and consequences of microRNAs dysregulation in cancer. Nat Rev Genet. 10:704–714. 2009. View Article : Google Scholar : PubMed/NCBI
24	Prieto-Garcia E, Diaz-Garcia CV, Garcia-Ruiz I and Agulló-Ortuño MT: Epithelial-to-mesenchymal transition in tumor progression. Med Oncol. 34:1222017. View Article : Google Scholar : PubMed/NCBI
25	Megiorni F, Cialfi S, McDowell HP, Felsanj A, Camero S, Guffanti A, Pizer B, Clerico A, De Grazia A, Pizzuti A, et al: Deep Sequencing the microRNA profile in rhabdomysarcoma reveals down-regulation of miR-378 family members. BMC Cancer. 14:8802014. View Article : Google Scholar
26	Nagalingam RS, Sundaresan NR, Noor M, Gupta MP, Solaro RJ and Gupta M: Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor β (TGF β1)-dependent paracrine mechanism. J Biol Chem. 289:27199–27214. 2014. View Article : Google Scholar : PubMed/NCBI
27	Hyun J, Wang S, Kim J, Rao KM, Park SY, Chung I, Ha CS, Kim SW, Yun YH and Jung Y: MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3. Nat Commun. 7:109932016. View Article : Google Scholar
28	Stenmark H: Rab GTPase as coordinates of vesicle traffic. Nat Rev Mol Cell Biol. 10:513–525. 2009. View Article : Google Scholar : PubMed/NCBI
29	Grosshans BL, Ortiz D and Novick P: Rabs and their effectors: Achieving specificity in membrane traffic. Proc Natl Acad Sci USA. 103:11821–11827. 2006. View Article : Google Scholar : PubMed/NCBI
30	Wang P, Liu H, Wang Y, Liu O, Zhang J, Gleason A, Yang Z, Wang H, Shi A and Grant BD: RAB-10 promotes EHBP-1 bridging of filamentous actin and tubular recycling endosomes. PLoS Genet. 12:e10060932016. View Article : Google Scholar : PubMed/NCBI
31	Ito G, Katsemonova K, Tonelli F, Lis P, Baptista MA, Shpiro N, Duddy G, Wilson S, Ho PW, Ho SL, et al: Phos-tag analysis of Rab10 phosphorylation by LRRK2: A powerful assay for assessing kinase function and inhibitors. Biochem J. 473:2671–2685. 2016. View Article : Google Scholar : PubMed/NCBI
32	Lee H, Shin N, Song M, Kang UB, Yeom J, Lee C, Ahn YH, Yoo JS, Paik YK and Kim H: Analysis of nuclear high mobility group box 1 (HMGB1)-binding proteins in colon cancer cells: Clustering with proteins involved in secretion and extracellular function. J Proteome Res. 9:4661–4670. 2010. View Article : Google Scholar : PubMed/NCBI