MicroRNA‑181a promotes epithelial‑mesenchymal transition in esophageal squamous cell carcinoma via the TGF‑β/Smad pathway

Xu,Run; Zhou,Xue-Mei; Li,Yu-Shan; Ren,Li; He,Xin-Rong

doi:10.3892/mmr.2021.11955

MicroRNA‑181a promotes epithelial‑mesenchymal transition in esophageal squamous cell carcinoma via the TGF‑β/Smad pathway

Authors:
- Run Xu
- Xue-Mei Zhou
- Yu-Shan Li
- Li Ren
- Xin-Rong He
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Affiliations: Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Pathology, The Third People's Hospital of Mianyang, Mianyang, Sichuan 621000, P.R. China, Department of Laboratory Medicine, Nanchong Central Hospital, Nanchong, Sichuan 637000, P.R. China
Published online on: March 2, 2021 https://doi.org/10.3892/mmr.2021.11955
Article Number: 316
Copyright: © Xu 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 one of the most debilitating and invasive tumors. Although previous reports have demonstrated the critical role microRNA‑181a (miR‑181a) serves in the progression of ESCC, how miR‑181a induces epithelial‑mesenchymal transition (EMT) remains to be elucidated. In the present study, the expression profiles of TGF‑β1 and Smad4 proteins in 88 patients with ESCC and 21 adjacent non‑cancerous tissues were analyzed using immunohistochemistry. The expression of miR‑181a in ESCC cells (ECA109 and TE‑1) and HEEC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The role of miR‑181a in ESCC was analyzed using miR‑181a mimics and inhibitor in the same system. Migration, proliferation and apoptosis of cells were assessed using wound‑healing assays and cell proliferation assays and flow cytometry, respectively. The expression levels of TGF‑β1 and Smad4 in ESCC cell lines transfected with miR‑181a mimics and inhibitor were measured using RT‑qPCR and western blotting. The expression of E‑cadherin and vimentin was also assessed following transfection. The findings demonstrated that expression of TGF‑β1 was upregulated, in contrast to Smad4 expression which was downregulated. Expression levels of Smad4 affected the prognosis of patients with ESCC. Higher expression of miR‑181a promoted migration and proliferation but inhibited apoptosis of ESCC cells. miR‑181a promoted EMT by modulating Smad4 expression in ESCC cells. Overall, these findings revealed that miR‑181a induced EMT in ESCC via the TGF‑β/Smad pathway in ESCC. Consequently, miR‑181a is a potential novel target against ESCC.

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1	Chen W, Zheng R, Zuo T, Zeng H, Zhang S and He J: National cancer incidence and mortality in China, 2012. Chin J Cancer Res. 28:1–11. 2016. 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	Cui Y, Zhang L, Wang W, Ma S, Liu H, Zang X, Zhang Y and Guan F: Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway. Mol Cell Biochem. 460:93–103. 2019. View Article : Google Scholar : PubMed/NCBI
4	Zeng H, Zheng R, Zhang S, Zuo T, Xia C, Zou X and Chen W: Esophageal cancer statistics in China, 2011: Estimates based on 177 cancer registries. Thorac Cancer. 7:232–237. 2016. View Article : Google Scholar : PubMed/NCBI
5	Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, Childs T, Chen J, Li J, Weberpals J, et al: EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer. 12:912012. View Article : Google Scholar : PubMed/NCBI
6	Feng H, Liu Q, Zhang N, Zheng L, Sang M, Feng J, Zhang J, Wu X and Shan B: Leptin promotes metastasis by inducing an epithelial-mesenchymal transition in A549 lung cancer cells. Oncol Res. 21:165–171. 2013. View Article : Google Scholar : PubMed/NCBI
7	Inui M, Martello G and Piccolo S: MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 11:252–263. 2010. View Article : Google Scholar : PubMed/NCBI
8	Li YH, Li YS, Zhang RJ, Zhou XM and He XR: Expression of miR-181a-5p, miR-320a and TGF-β1 in esophageal squamous cell carcinoma. J Cancer Control Treat. 32:395–401. 2019.
9	Shukla SK, Khatoon J, Prasad KN, Rai RP, Singh AK, Kumar S, Ghoshal UC and Krishnani N: Transforming growth factor beta 1 (TGF-β1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer. Cytokine. 77:176–179. 2016. View Article : Google Scholar : PubMed/NCBI
10	Sun NF, Xue Y, Dai T and Li X: D. and Zheng NX: Tripartite motif containing 25 promotes proliferation and invasion of colorectal cancer cells through TGF-β signaling. Biosci Rep. Jul 12–2017.(Epub ahead of print). doi: 10.1042/BSR20170805. View Article : Google Scholar
11	Chang H, Kim N, Park JH, Nam RH, Choi YJ, Park SM, Choi YJ, Yoon H, Shin CM and Lee DH: Helicobacter pylori might induce TGF-β1-mediated EMT by means of cagE. Helicobacter. 20:438–448. 2015. View Article : Google Scholar : PubMed/NCBI
12	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
13	Serrano-Gomez SJ, Maziveyi M and Alahari SK: Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 15:182016. View Article : Google Scholar : PubMed/NCBI
14	Xu J, Lamouille S and Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19:156–172. 2009. View Article : Google Scholar : PubMed/NCBI
15	Zhu D, Yu Y, Qi Y, Wu K, Liu D, Yang Y, Zhang C and Zhao S: Long non-coding RNA CASC2 enhances the antitumor activity of cisplatin through suppressing the Akt pathway by inhibition of miR-181a in esophageal squamous cell carcinoma cells. Front Oncol. 9:3502019. View Article : Google Scholar : PubMed/NCBI
16	Yang L, Pang Y and Moses HL: TGF-beta and immune cells: An important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31:220–227. 2010. View Article : Google Scholar : PubMed/NCBI
17	Morikawa M, Derynck R and Miyazono K: TGF-β and the TGF-β family: Context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 8:82016. View Article : Google Scholar
18	Kang H, Ma D, Zhang J, Zhao J and Yang M: MicroRNA-18a induces epithelial-mesenchymal transition like cancer stem cell phenotype via regulating RKIP pathway in pancreatic cancer. Ann Transl Med. 8:4332020. View Article : Google Scholar : PubMed/NCBI
19	Mi Y, Zhang D, Jiang W, Weng J, Zhou C, Huang K, Tang H, Yu Y, Liu X, Cui W, et al: miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation. Cancer Lett. 389:11–22. 2017. View Article : Google Scholar : PubMed/NCBI
20	Zhiping C, Shijun T, Linhui W, Yapei W, Lianxi Q and Qiang D: MiR-181a promotes epithelial to mesenchymal transition of prostate cancer cells by targeting TGIF2. Eur Rev Med Pharmacol Sci. 21:4835–4843. 2017.PubMed/NCBI
21	Li L, Xu QH, Dong YH, Li GX, Yang L, Wang LW and Li HY: MiR-181a upregulation is associated with epithelial-to-mesenchymal transition (EMT) and multidrug resistance (MDR) of ovarian cancer cells. Eur Rev Med Pharmacol Sci. 20:2004–2010. 2016.PubMed/NCBI
22	Li H, Zhang P, Sun X, Sun Y, Shi C, Liu H and Liu X: MicroRNA-181a regulates epithelial-mesenchymal transition by targeting PTEN in drug-resistant lung adenocarcinoma cells. Int J Oncol. 47:1379–1392. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang JJ and Yu JP: miR-181a down-regulates MAP2K1 to enhance adriamycin sensitivity in leukemia HL-60 cells. Eur Rev Med Pharmacol Sci. 23:2497–2504. 2019.PubMed/NCBI