SIX1 coordinates with TGFβ signals to induce epithelial-mesenchymal transition in cervical cancer

Sun,Shu‑Hua; Liu,Dan; Deng,Yun‑Te; Zhang,Xiao‑Xue; Wan,Dong‑Yi; Xi,Bi‑Xin; Huang,Wei; Chen,Qian; Li,Meng‑Chen; Wang,Ming‑Wei; Yang,Fei; Shu,Ping; Wu,Ke‑Zhi; Gao,Qing‑Lei

doi:10.3892/ol.2016.4797

SIX1 coordinates with TGFβ signals to induce epithelial-mesenchymal transition in cervical cancer

Authors:
- Shu‑Hua Sun
- Dan Liu
- Yun‑Te Deng
- Xiao‑Xue Zhang
- Dong‑Yi Wan
- Bi‑Xin Xi
- Wei Huang
- Qian Chen
- Meng‑Chen Li
- Ming‑Wei Wang
- Fei Yang
- Ping Shu
- Ke‑Zhi Wu
- Qing‑Lei Gao
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Affiliations: Department of Gynecologic Oncology, Hubei Cancer Hospital, Wuhan, Hubei 430023, P.R. China, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China, Department of Pathology, Hubei Cancer Hospital, Wuhan, Hubei 430023, P.R. China, Department of Medical Records Room, Hubei Cancer Hospital, Wuhan, Hubei 430023, P.R. China
Published online on: June 28, 2016 https://doi.org/10.3892/ol.2016.4797
Pages: 1271-1278
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)β-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E-cadherin in two independent groups of cervical cancer specimens. SIX1 could promote the transition of mesenchymal phenotype in the presence of active TGFβ signals in vitro and in vivo. TGFβ-SMAD signals were required for the SIX1‑mediated promotion of EMT and metastatic capacity of cervical cancer cells. Together, SIX1 and TGFβ cooperated to induce more remarkable changes in the transition of phenotype than each of them alone, and coordinated to promote cell motility and tumor metastasis in cervical cancer. These results suggest that the coordination of SIX1 and TGFβ signals may be crucial in the EMT program, and that SIX1/TGFβ may be considered a valuable marker for evaluating the metastatic potential of cervical cancer cells, or a therapeutic target in the treatment of cervical cancer.

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1	Gao D, Vahdat LT, Wong S, Chang JC and Mittal V: Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 72:4883–4889. 2012. View Article : Google Scholar : PubMed/NCBI
2	Tsai JH and Yang J: Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 27:2192–2206. 2013. View Article : Google Scholar : PubMed/NCBI
3	Li Y, Wang W, Wang W, Yang R, Wang T, Su T, Weng D, Tao T, Li W, Ma D and Wang S: Correlation of TWIST2 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma. Gynecol Oncol. 124:112–118. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zhou XM, Zhang H and Han X: Role of epithelial to mesenchymal transition proteins in gynecological cancers: Pathological and therapeutic perspectives. Tumour Biol. 35:9523–9530. 2014. View Article : Google Scholar : PubMed/NCBI
5	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
6	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
7	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
8	Katsuno Y, Lamouille S and Derynck R: TGF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol. 25:76–84. 2013. View Article : Google Scholar : PubMed/NCBI
9	Brown KA, Aakre ME, Gorska AE, Price JO, Eltom SE, Pietenpol JA and Moses HL: Induction by transforming growth factor-beta1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res. 6:R215–R231. 2004. View Article : Google Scholar : PubMed/NCBI
10	Feng XX, Liu M, Yan W, Zhou ZZ, Xia YJ, Tu W, Li PY and Tian DA: β3 integrin promotes TGF-β1/H₂O₂/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-β1 signaling. PLoS One. 8:e798572013. View Article : Google Scholar : PubMed/NCBI
11	Ford HL, Landesman-Bollag E, Dacwag CS, Stukenberg PT, Pardee AB and Seldin DC: Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein. J Biol Chem. 275:22245–22254. 2000. View Article : Google Scholar : PubMed/NCBI
12	Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Barón AE, Harrell JC, Horwitz KB, Billheimer D, Heichman KA, Welm AL, et al: The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest. 119:2678–2690. 2009. View Article : Google Scholar : PubMed/NCBI
13	Ng KT, Man K, Sun CK, Lee TK, Poon RT, Lo CM and Fan ST: Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma. Br J Cancer. 95:1050–1055. 2006. View Article : Google Scholar : PubMed/NCBI
14	Behbakht K, Qamar L, Aldridge CS, Coletta RD, Davidson SA, Thorburn A and Ford HL: Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res. 67:3036–3042. 2007. View Article : Google Scholar : PubMed/NCBI
15	Liu D, Zhang XX, Xi BX, Wan DY, Li L, Zhou J, Wang W, Ma D, Wang H and Gao QL: Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer. Int J Oncol. 45:1232–1240. 2014.PubMed/NCBI
16	Liu D, Zhang XX, Wan DY, Xi BX, Ma D, Wang H and Gao QL: Sine oculis homeobox homolo 1 promotes α5β1-mediated invasive migration and metastasis of cervical cancer cells. Biochem Biophys Res Commun. 446:549–554. 2014. View Article : Google Scholar : PubMed/NCBI
17	Liu D, Li L, Zhang XX, Wan DY, Xi BX, Hu Z, Ding WC, Zhu D, Wang XL, Wang W, et al: SIX1 promotes tumor lymphangiogenesis by coordinating TGFβ signals that increase expression of VEGF-C. Cancer Res. 74:5597–5607. 2014. View Article : Google Scholar : PubMed/NCBI
18	Robinson MD, McCarthy DJ and Smyth GK: edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 26:139–140. 2010. View Article : Google Scholar : PubMed/NCBI
19	Shen Y, Li Y, Ye F, Wang F, Lu W and Xie X: Identification of suitable reference genes for measurement of gene expression in human cervical tissues. Anal Biochem. 405:224–229. 2010. View Article : Google Scholar : PubMed/NCBI
20	Wang C, Zhou L, Li S, Wei J, Wang W, Zhou T, Liao S, Weng D, Deng D, Weng Y, et al: C4orf7 contributes to ovarian cancer metastasis by promoting cancer cell migration and invasion. Oncol Rep. 24:933–939. 2010.PubMed/NCBI
21	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
22	Valcourt U, Kowanetz M, Niimi H, Heldin CH and Moustakas A: TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 16:1987–2002. 2005. View Article : Google Scholar : PubMed/NCBI
23	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
24	Lamouille S and Derynck R: Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-β-induced epithelial-mesenchymal transition. Cells Tissues Organs. 193:8–22. 2011. View Article : Google Scholar : PubMed/NCBI
25	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
26	Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, Aranda S, Palomo S, McCormick F, Izpisúa-Belmonte JC and de la Pompa JL: Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18:99–115. 2004. View Article : Google Scholar : PubMed/NCBI