Sphingomyelin synthase 1 regulates the epithelial‑to‑mesenchymal transition mediated by the TGF‑β/Smad pathway in MDA‑MB‑231 cells

Liu,Shuang; Hou,Huan; Zhang,Panpan; Wu,Yifan; He,Xuanhong; Li,Hua; Yan,Nianlong

doi:10.3892/mmr.2018.9722

Sphingomyelin synthase 1 regulates the epithelial‑to‑mesenchymal transition mediated by the TGF‑β/Smad pathway in MDA‑MB‑231 cells

Authors:
- Shuang Liu
- Huan Hou
- Panpan Zhang
- Yifan Wu
- Xuanhong He
- Hua Li
- Nianlong Yan
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Affiliations: Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Biochemistry and Molecular Biology, Centre of Experimental Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: December 4, 2018 https://doi.org/10.3892/mmr.2018.9722
Pages: 1159-1167
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer is the most common cancer in women and a leading cause of cancer‑associated mortalities in the world. Epithelial‑to‑mesenchymal transition (EMT) serves an important role in the process of metastasis and invasive ability in cancer cells, and transforming growth factor β1 (TGF‑β1) have been investigated for promoting EMT. However, in the present study, the role of the sphingomyelin synthase 1 (SMS1) in TGF‑β1‑induced EMT development was investigated. Firstly, bioinformatics analysis demonstrated that the overexpression of SMS1 negatively regulated the TGFβ receptor I (TβRI) level of expression. Subsequently, the expression of SMS1 was decreased, whereas, SMS2 had no significant difference when MDA‑MB‑231 cells were treated by TGF‑β1 for 72 h. Furthermore, the present study constructed an overexpression cells model of SMS1 and these cells were treated by TGF‑β1. These results demonstrated that overexpression of SMS1 inhibited TGF‑β1‑induced EMT and the migration and invasion of MDA‑MB‑231 cells, increasing the expression of E‑cadherin while decreasing the expression of vimentin. Furthermore, the present study further confirmed that SMS1 overexpression could decrease TβRI expression levels and blocked smad family member 2 phosphorylation. Overall, the present results suggested that SMS1 could inhibit EMT and the migration and invasion of MDA‑MB‑231 cells via TGF‑β/Smad signaling pathway.

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1	Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, Allen C, Alsharif U, Alvis-Guzman N, Amini E, Anderson BO, et al: Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol. 4:1553–1568. 2018. View Article : Google Scholar : PubMed/NCBI
2	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol. 172:973–81. 2006. View Article : Google Scholar : PubMed/NCBI
3	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
4	Chen Q, Yang W, Wang X, Li X, Qi S, Zhang Y and Gao MQ: TGF-beta1 induces EMT in bovine mammary epithelial cells through the TGFbeta1/Smad signaling pathway. Cell Physiol Biochem. 43:82–93. 2017. View Article : Google Scholar : PubMed/NCBI
5	Yeh YC, Wei WC, Wang MG, Lin SC, Sung JM and Tang MJ: Transforming growth factor-β1 induces smad3-dependent β 1, integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis. Am J Pathol. 177:743–1754. 2010. View Article : Google Scholar
6	Attisano L and Wrana JL: Signal transduction by the TGF-beta superfamily. Science. 296:1646–1647. 2002. View Article : Google Scholar : PubMed/NCBI
7	Hwangbo C, Tae N, Lee S, Kim O, Park OK, Kim J, Kwon SH and Lee JH: Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization. Oncogene. 35:389–401. 2016. View Article : Google Scholar : PubMed/NCBI
8	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–42. 2006. View Article : Google Scholar : PubMed/NCBI
9	Miettinen PJ, Ebner R, Lopez AR and Derynck R: TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: Involvement of type I receptors. J Cell Biol. 127:2021–2036. 1994. View Article : Google Scholar : PubMed/NCBI
10	Derynck R and Zhang YE: Smad-dependent and smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
11	Lin XL, Liu M, Liu Y, Hu H, Pan Y, Zou W, Fan X and Hu X: Transforming growth factor beta1 promotes migration and invasion in HepG2 cells: Epithelialtomesenchymal transition via JAK/STAT3 signaling. Int J Mol Med. 41:129–136. 2017.PubMed/NCBI
12	Kim JY, An HJ, Kim WH, Gwon MG, Gu H, Park YY and Park KK: Anti-fibrotic effects of synthetic oligodeoxynucleotide for TGF-beta1 and smad in an animal model of liver cirrhosis. Mol Ther Nucleic Acids. 8:250–263. 2017. View Article : Google Scholar : PubMed/NCBI
13	Boldbaatar A, Lee S, Han S, Jeong AL, Ka HI, Buyanravjikh S, Lee JH, Lim JS, Lee MS and Yang Y: Eupatolide inhibits the TGF-beta1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5. Oncol Lett. 14:6031–6039. 2017.PubMed/NCBI
14	Wang Y, Liu X, Zheng H, Wang Q, An L and Wei G: Suppression of CUL4A attenuates TGF-beta1-induced epithelial-to-mesenchymal transition in breast cancer cells. Int J Mol Med. 40:1114–1124. 2017. View Article : Google Scholar : PubMed/NCBI
15	Le Roy C and Wrana JL: Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 6:112–26. 2005. View Article : Google Scholar : PubMed/NCBI
16	Midgley AC, Rogers M, Hallett MB, Clayton A, Bowen T, Phillips AO and Steadman R: Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J Biol Chem. 288:14824–14838. 2013. View Article : Google Scholar : PubMed/NCBI
17	Chen YG: Endocytic regulation of TGF-beta signaling. Cell Res. 19:58–70. 2009. View Article : Google Scholar : PubMed/NCBI
18	Li J, Xia K, Xiong M, Wang X and Yan N: Effects of sepsis on the metabolism of sphingomyelin and cholesterol in mice with liver dysfunction. Exp Ther Med. 14:5635–5640. 2017.PubMed/NCBI
19	Taniguchi M and Okazaki T: The role of sphingomyelin and sphingomyelin synthases in cell death, proliferation and migration-from cell and animal models to human disorders. Biochim Biophys Acta. 1841:692–703. 2014. View Article : Google Scholar : PubMed/NCBI
20	Yeang C, Ding T, Chirico WJ and Jiang XC: Subcellular targeting domains of sphingomyelin synthase 1 and 2. Nutr Metab (Lond). 8:892011. View Article : Google Scholar : PubMed/NCBI
21	Torki S, Soltani A, Shirzad H, Esmaeil N and Ghatrehsamani M: Synergistic antitumor effect of NVP-BEZ235 and CAPE on MDA-MB-231 breast cancer cells. Biomed Pharmacother. 92:39–45. 2017. View Article : Google Scholar : PubMed/NCBI
22	Luo S, Pan Z, Liu S, Yuan S and Yan N: Sphingomyelin synthase 2 overexpression promotes cisplatin-induced apoptosis of HepG2 cells. Oncol Lett. 15:483–488. 2018.PubMed/NCBI
23	Yan N, Ding T, Dong J, Li Y and Wu M: Sphingomyelin synthase overexpression increases cholesterol accumulation and decreases cholesterol secretion in liver cells. Lipids Health Dis. 10:462011. View Article : Google Scholar : PubMed/NCBI
24	Hu S, Ding Y, Gong J and Yan N: Sphingomyelin synthase 2 affects CD14 associated induction of NFkappaB by lipopolysaccharides in acute lung injury in mice. Mol Med Rep. 14:3301–3306. 2016. View Article : Google Scholar : PubMed/NCBI
25	Kwiatkowska E, Wojtala M, Gajewska A, Soszynski M, Bartosz G and Sadowska-Bartosz I: Effect of 3-bromopyruvate acid on the redox equilibrium in non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells. J Bioenerg Biomembr. 48:23–32. 2016. View Article : Google Scholar : PubMed/NCBI
26	Xu Y, Xia J, Liu S, Stein S, Ramon C, Xi H, Wang L, Xiong X, Zhang L, He D, et al: Endocytosis and membrane receptor internalization: Implication of F-BAR protein carom. Front Biosci (Landmark Ed). 22:1439–1457. 2017. View Article : Google Scholar : PubMed/NCBI
27	Conner SD and Schmid SL: Regulated portals of entry into the cell. Nature. 422:37–44. 2003. View Article : Google Scholar : PubMed/NCBI
28	Mitchell H, Choudhury A, Pagano RE and Leof EB: Ligand-dependent and -independent transforming growth factor-beta receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol Biol Cell. 15:4166–4178. 2004. View Article : Google Scholar : PubMed/NCBI
29	Razani B, Zhang XL, Bitzer M, von Gersdorff G, Bottinger EP and Lisanti MP: Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor. J Biol Chem. 276:6727–6738. 2001. View Article : Google Scholar : PubMed/NCBI
30	Zhang B, Paffett ML, Naik JS, Jernigan NL, Walker BR and Resta TC: Cholesterol regulation of pulmonary endothelial calcium homeostasis. Curr Top Membr. 82:53–91. 2018. View Article : Google Scholar : PubMed/NCBI
31	Huang SS, Liu IH, Chen CL, Chang JM, Johnson FE and Huang JS: 7-Dehydrocholesterol (7-DHC), but not cholesterol, causes suppression of canonical TGF-beta signaling and is likely involved in the development of Atherosclerotic Cardiovascular Disease (ASCVD). J Cell Biochem. 118:1387–1400. 2017. View Article : Google Scholar : PubMed/NCBI
32	Chen CL, Wu DC, Liu MY, Lin MW, Huang HT, Huang YB, Chen LC, Chen YY, Chen JJ, Yang PH, et al: Cholest-4-en-3-one attenuates TGF-beta responsiveness by inducing TGF-beta receptors degradation in Mv1Lu cells and colorectal adenocarcinoma cells. J Recept Signal Transduct Res. 37:189–199. 2017. View Article : Google Scholar : PubMed/NCBI
33	Huang SS, Chen CL, Huang FW, Hou WH and Huang JS: DMSO enhances TGF-beta activity by recruiting the type II TGF-beta receptor from intracellular vesicles to the plasma membrane. J Cell Biochem. 117:1568–1579. 2016. View Article : Google Scholar : PubMed/NCBI
34	Huang SS, Chen CL, Huang FW, Johnson FE and Huang JS: Ethanol enhances TGF-beta activity by recruiting TGF-beta receptors from intracellular vesicles/lipid rafts/caveolae to non-lipid raft microdomains. J Cell Biochem. 117:860–871. 2016. View Article : Google Scholar : PubMed/NCBI
35	Chen CL, Huang SS and Huang JS: Cellular heparan sulfate negatively modulates transforming growth factor-beta1 (TGF-beta1) responsiveness in epithelial cells. J Biol Chem. 281:11506–11514. 2006. View Article : Google Scholar : PubMed/NCBI