Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma

Miao,Jin-Wei; Liu,Li-Jiang; Huang,Jie

doi:10.3892/ijo.2014.2422

Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma

Authors:
- Jin-Wei Miao
- Li-Jiang Liu
- Jie Huang
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Affiliations: Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China, Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, P.R. China
Published online on: May 6, 2014 https://doi.org/10.3892/ijo.2014.2422
Pages: 165-176

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Abstract

Epithelial-mesenchymal transition (EMT) is an important process in the invasion and metastasis of human cervical carcinoma. The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown as an EMT inducer in multiple carcinomas. However, whether the EMT program can be induced by IL-6 and the mechanisms underlying the IL-6-induced EMT in human cervical carcinoma remain to be determined. In this study, we show that IL-6 receptor (IL-6R) and signal transducer and activator of transcription 3 (Stat3) were highly expressed in human cervical squamous cell carcinoma (CSCC) tissues, and the expression of EMT markers was reversed in well-differentiated and poorly-differentiated human CSCC. Additional experiments showed that IL-6 exposure in cervical carcinoma cell lines induced IL-6R and Stat3 expression, markedly promoted cell growth, and altered cell morphology. The treatment of cervical carcinoma cell lines with IL-6 resulted in downregulation of E-Cadherin and upregulation of Vimentin. Importantly, knockdown of Stat3 significantly reversed the IL-6-induced EMT program, suggesting that Stat3 is necessary for IL-6-induced EMT in the progression of human cervical carcinoma. Moreover, Slug, a member of the Snail family of EMT regulators, was observed to be associated with the expression of Stat3. We concluded that IL-6 plays an important role through Stat3 in the EMT induction and can be a potential therapeutic target and biomarker for human cervical carcinoma.

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1.	Thun MJ, Oliver DeLancey J, Center MM, Jemal A and Ward EM: The global burden of cancer: priorities for prevention. Carcinogenesis. 31:100–110. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Lee MY and Shen MR: Epithelial-mesenchymal transition in cervical carcinoma. Am J Transl Res. 4:1–13. 2012.PubMed/NCBI
3.	Castellsague X: Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol. 110:S4–S7. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Burd EM: Human papillomavirus and cervical cancer. Clin Microbiol Rev. 16:1–17. 2003. View Article : Google Scholar : PubMed/NCBI
5.	zur Hausen H: Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2:342–350. 2002.PubMed/NCBI
6.	Au WW, Abdou-Salama S, Sierra-Torres CH and Al-Hendy A: Environmental risk factors for prevention and molecular intervention of cervical cancer. Int J Hyg Environ Health. 210:671–678. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Wei LH, Kuo ML, Chen CA, Cheng WF, Cheng SP, Hsieh FJ and Hsieh CY: Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor. Gynecol Oncol. 82:49–56. 2001. View Article : Google Scholar : PubMed/NCBI
8.	Wei LH, Kuo ML, Chen CA, Chou CH, Cheng WF, Chang MC, Su JL and Hsieh CY: The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI3-K/Akt pathway. Oncogene. 20:5799–5809. 2001. View Article : Google Scholar : PubMed/NCBI
9.	Rose-John S: IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 8:1237–1247. 2012. View Article : Google Scholar : PubMed/NCBI
10.	Braunstein J, Brutsaert S, Olson R and Schindler C: Stats dimerize in the absence of phosphorylation. J Biol Chem. 278:34133–34140. 2003. View Article : Google Scholar : PubMed/NCBI
11.	Shukla S, Shishodia G, Mahata S, et al: Aberrant expression and constitutive activation of Stat3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection. Mol Cancer. 9:2822010. View Article : Google Scholar
12.	Chen CL, Hsieh FC, Lieblein JC, et al: Stat3 activation in human endometrial and cervical cancers. Br J Cancer. 96:591–599. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci. 1171:59–76. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Trimboli AJ, Fukino K, Bruin A, et al: Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 68:937–945. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Vergara D, Merlot B, Lucot JP, Collinet P, Vinatier D, Fournier I and Salzet M: Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett. 291:59–66. 2009. View Article : Google Scholar
17.	Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A and Kirchner T: Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 179:56–65. 2005. View Article : Google Scholar : PubMed/NCBI
18.	Usami Y, Satake S, Nakayama F, et al: Snail-associated epithelial-mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol. 215:330–339. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Lee MY, Chou CY, Tang MJ and Shen MR: Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res. 14:4743–4750. 2008. View Article : Google Scholar
20.	Cervantes-Arias A, Pang LY and Argyle DJ: Epithelial-mesenchymal transition as a fundamental mechanism underlying the cancer phenotype. Vet Comp Oncol. 11:169–184. 2013. View Article : Google Scholar : PubMed/NCBI
21.	Chen H, Paradies NE, Fedor-Chaiken M and Brackenbury R: E-cadherin mediates adhesion and suppresses cell motility via distinct mechanisms. J Cell Sci. 110:345–356. 1997.PubMed/NCBI
22.	McInroy L and Määttä A: Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun. 360:109–114. 2007. View Article : Google Scholar : PubMed/NCBI
23.	Vuoriluoto K, Haugen H, Kiviluoto S, et al: Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 30:1436–1448. 2011. View Article : Google Scholar : PubMed/NCBI
24.	Karantza V: Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 30:127–138. 2011. View Article : Google Scholar : PubMed/NCBI
25.	Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, Pohar K, Hoos A and Cordon-Cardo C: p63 expression profiles in human normal and tumor tissues. Clin Cancer Res. 8:494–501. 2002.PubMed/NCBI
26.	Lin DL, Whitney MC, Yao Z and Keller ET: Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. Clin Cancer Res. 7:1773–17781. 2001.PubMed/NCBI
27.	Xiao D and He J: Epithelial mesenchymal transition and lung cancer. J Thorac Dis. 2:154–159. 2010.PubMed/NCBI
28.	Castrilli G, Tatone D, Diodoro MG, Rosini S, Piantelli M and Musiani P: Interleukin 1alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells. Br J Cancer. 75:855–859. 1997. View Article : Google Scholar : PubMed/NCBI
29.	Tjiong MY, van der Vange N, ten Kate FJ, Tjong-A-Hung SP, ter Schegget J, Burger MP and Out TA: Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer. Gynecol Oncol. 73:285–291. 1999. View Article : Google Scholar : PubMed/NCBI
30.	Cheng Y, Zhou Y, Jiang W, et al: Significance of E-cadherin, β-catenin, and vimentin expression as postoperative prognosis indicators in cervical squamous cell carcinoma. Human Pathol. 43:1213–1220. 2012.
31.	Scanlon CS, Van Tubergen EA, Inglehart RC and D’Silva NJ: Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res. 92:114–121. 2013. View Article : Google Scholar : PubMed/NCBI
32.	Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM and Hall BM: Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 28:2940–2947. 2009. View Article : Google Scholar
33.	Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M and Cano A: The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 116:499–511. 2003.PubMed/NCBI