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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

HOXC6 gene silencing inhibits epithelial-mesenchymal transition and cell viability through the TGF-β/smad signaling pathway in cervical carcinoma cells

Authors: Feng Zhang, Chen-Chen Ren, Ling Liu, Yan-Nan Chen, Li Yang, Xiao-An Zhang

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Homeobox C6 (HOXC6) plays a part in malignant progression of some tumors. However, the expression of HOXC6 and its clinical significance remains unclear in cervical carcinoma (CC). The purpose of this study is to verify the effects of HOXC6 gene silencing on CC through the TGF-β/smad signaling pathway.

Methods

CC tissues and corresponding paracancerous tissues were collected from CC patients with involvement of a series of HOXC6-siRNA, HA-HOXC6 and the TGF-β/smad pathway antagonist. HOXC6 expression was analyzed in six CC cell lines (C-33A, HeLa, CaSki, SiHa, ME-180, and HCC-94) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The mRNA and protein expression of HOXC6, TGF-β1, TGF-β RII, smad4, smad7, E-cadherin, N-cadherin, Vimentin, ki-67, proliferating cell nuclear antigen (PCNA), p27, and Cyclin D1 were determined by RT-qPCR and western blot analysis. Cell proliferation, apoptosis and cell cycle were detected by MTT assay and flow cytometry, respectively.

Results

Higher positive expression rate of HOXC6 protein was observed in CC tissues and HOXC6 was related to TNM stage, lymphatic metastasis, cancer types, primary lesion diameter, and histological grade of CC. Silencing HOXC6 inhibited epithelial-mesenchymal transition (EMT) (shown as decreased N-cadherin and Vimentin, and increased E-cadherin) through the inactivation of the TGF-β/smad signaling pathway. HOXC6 gene silencing hindered cell proliferation and accelerated cell apoptosis of CC cells. Furthermore, the effect of HOXC6 silencing was enhanced when the TGF-β/smad signaling pathway was suppressed.

Conclusion

The results reveal that HOXC6 gene silencing may inhibit EMT event and cell viability in CC through the inhibition of the activation of TGF-β/smad signaling pathway.
Literature
1.
Arbyn M, Castellsague X, de Sanjose S, Bruni L, Saraiya M, Bray F, Ferlay J. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011;22(12):2675–86.CrossRef
2.
Ondrusova M, Zubor P, Ondrus D. Time trends in cervical cancer epidemiology in the Slovak Republic: reflection on the non-implementation of screening with international comparisons. Neoplasma. 2012;59(2):121–8.CrossRef
3.
Mwaka AD, Orach CG, Were EM, Lyratzopoulos G, Wabinga H, Roland M. Awareness of cervical cancer risk factors and symptoms: cross-sectional community survey in post-conflict northern Uganda. Health Expect. 2016;19(4):854–67.CrossRef
4.
Masch R, Ditzian LR, April AK, Maza M, Peralta E, Cremer ML. Cervical cancer screening and treatment training course in El Salvador: experience and lessons learned. J Womens Health (Larchmt). 2011;20(9):1357–61.CrossRef
5.
Ma SR, Mao L, Deng WW, Li YC, Bu LL, Yu GT, Zhang WF, Sun ZJ. AGR2 promotes the proliferation, migration and regulates epithelial-mesenchymal transition in salivary adenoid cystic carcinoma. Am J Transl Res. 2017;9(2):507–19.PubMedPubMedCentral
6.
Lopez R, Garrido E, Pina P, Hidalgo A, Lazos M, Ochoa R, Salcedo M. HOXB homeobox gene expression in cervical carcinoma. Int J Gynecol Cancer. 2006;16(1):329–35.CrossRef
7.
Agnelli L, Storti P, Todoerti K, Sammarelli G, Dalla Palma B, Bolzoni M, Rocci A, Piazza F, Semenzato G, Palumbo A, Neri A, Giuliani N. Overexpression of HOXB7 and homeobox genes characterizes multiple myeloma patients lacking the major primary immunoglobulin heavy chain locus translocations. Am J Hematol. 2011;86(12):E64–6.CrossRef
8.
Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. Immunocytochemical detection of the homeobox B3, B4, and C6 gene products in childhood medulloblastomas/primitive neuroectodermal tumors. Anticancer Res. 2000;20(3A):1769–80.PubMed
9.
Bodey B, Bodey B Jr, Siegel SE, Luck JV, Kaiser HE. Homeobox B3, B4, and C6 gene product expression in osteosarcomas as detected by immunocytochemistry. Anticancer Res. 2000;20(4):2717–21.PubMed
10.
Hussain I, Bhan A, Ansari KI, Deb P, Bobzean SA, Perrotti LI, Mandal SS. Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer. Biochim Biophys Acta. 2015;1849(6):697–708.CrossRef
11.
Bodey B, Bodey B Jr, Groger AM, Siegel SE, Kaiser HE. Immunocytochemical detection of homeobox B3, B4, and C6 gene product expression in lung carcinomas. Anticancer Res. 2000;20(4):2711–6.PubMed
12.
Moreno CS. The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. Am J Pathol. 2010;176(2):518–27.CrossRef
13.
Hamid AR, Hoogland AM, Smit F, Jannink S, van Rijt-van de Westerlo C, Jansen CF, van Leenders GJ, Verhaegh GW, Schalken JA. The role of HOXC6 in prostate cancer development. Prostate. 2015;75(16):1868–76.CrossRef
14.
Zhou B, Chen L, Wu X, Wang J, Yin Y, Zhu G. MH1 domain of SMAD4 binds N-terminal residues of the homeodomain of Hoxc9. Biochim Biophys Acta. 2008;1784(5):747–52.CrossRef
15.
Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell. 2010;39(3):373–84.CrossRef
16.
Pang K, Ryan JF, Baxevanis AD, Martindale MQ. Evolution of the TGF-beta signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PLoS ONE. 2011;6(9):e24152.CrossRef
17.
Slattery ML, Herrick JS, Lundgreen A, Wolff RK. Genetic variation in the TGF-beta signaling pathway and colon and rectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2011;20(1):57–69.CrossRef
18.
Wu T, Chen X, Peng R, Liu H, Yin P, Peng H, Zhou Y, Sun Y, Wen L, Yi H, Li A, Zhang Z. Let7a suppresses cell proliferation via the TGFbeta/SMAD signaling pathway in cervical cancer. Oncol Rep. 2016;36(6):3275–82.CrossRef
19.
Shparyk IaV. New classification of malignant tumors TNM (5th edition). Klin Khir. 1998;6:36–8.
20.
Tuo YL, Li XM, Luo J. Long noncoding RNA UCA1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive miR-143. Eur Rev Med Pharmacol Sci. 2015;19(18):3403–11.PubMed
21.
Nanthamongkolkul K, Hanprasertpong J. Longer waiting times for early stage cervical cancer patients undergoing radical hysterectomy are associated with diminished long-term overall survival. J Gynecol Oncol. 2015;26(4):262–9.CrossRef
22.
Ge TT, Yang M, Chen Z, Lou G, Gu T. UHRF1 gene silencing inhibits cell proliferation and promotes cell apoptosis in human cervical squamous cell carcinoma CaSki cells. J Ovarian Res. 2016;9(1):42.CrossRef
23.
Tucci R, Campos MS, Matizonkas-Antonio LF, Durazzo M, Junior P, dos Santos D, Nunes FD. HOXB5 expression in oral squamous cell carcinoma. J Appl Oral Sci. 2011;19(2):125–9.CrossRef
24.
Vinarskaja A, Yamanaka M, Ingenwerth M, Schulz WA. DNA methylation and the HOXC6 paradox in prostate cancer. Cancers (Basel). 2011;3(4):3714–25.CrossRef
25.
Zhang Q, Jin XS, Yang ZY, Wei M, Liu BY, Gu QL. Upregulated Hoxc6 expression is associated with poor survival in gastric cancer patients. Neoplasma. 2013;60(4):439–45.CrossRef
26.
Ji M, Feng Q, He G, Yang L, Tang W, Lao X, Zhu D, Lin Q, Xu P, Wei Y, Xu J. Silencing homeobox C6 inhibits colorectal cancer cell proliferation. Oncotarget. 2016;7(20):29216–27.CrossRef
27.
Chang SL, Chan TC, Chen TJ, Lee SW, Lin LC, Win KT. HOXC6 overexpression is associated with Ki-67 expression and poor survival in NPC patients. J Cancer. 2017;8(9):1647–54.CrossRef
28.
Pang L, Li Q, Wei C, Zou H, Li S, Cao W, He J, Zhou Y, Ju X, Lan J, Wei Y, Wang C, Zhao W, Hu J, Jia W, Qi Y, Liu F, Jiang J, Li L, Zhao J, Liang W, Xie J, Li F. TGF-beta1/Smad signaling pathway regulates epithelial-to-mesenchymal transition in esophageal squamous cell carcinoma: in vitro and clinical analyses of cell lines and nomadic Kazakh patients from northwest Xinjiang, China. PLoS ONE. 2014;9(12):e112300.CrossRef
29.
Lu B, Zhou YN, Li Q, Wu ZQ, Zhang ZY, Ji R, Guo QH, Liu W. Correlations of TGF-betaRII, Smad4 and Smad7 expression to clinicopathologic characteristics and prognosis of gastric cancer. Ai Zheng. 2009;28(5):538–42.PubMed
30.
Nunes FDAFCSD, Tucci R. Genes homeobox: uma relação molecular entre o desenvolvimento e o câncer[J]. Pesquisa Odontológica Brasileira. 2003;17(1):94–8.CrossRef
31.
Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, Tulachan SS, Ito D, Kami K, Mori T, Kawaguchi Y, Fujimoto K, Hosotani R, Imamura M. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004;10(12 Pt 1):4125-33.PubMed
32.
Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010;24(6):1838–51.CrossRef
33.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.CrossRef
34.
Devine DJ, Rostas JW, Metge BJ, Das S, Mulekar MS, Tucker JA, Grizzle WE, Buchsbaum DJ, Shevde LA, Samant RS. Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-beta/SMAD signaling. Oncogene. 2014;33(20):2620–8.CrossRef
35.
Xiao W, Zhou S, Xu H, Li H, He G, Liu Y, Qi Y. Nogo-B promotes the epithelial-mesenchymal transition in HeLa cervical cancer cells via Fibulin-5. Oncol Rep. 2013;29(1):109–16.CrossRef
36.
Derynck R, Muthusamy BP, Saeteurn KY. Signaling pathway cooperation in TGF-beta-induced epithelial-mesenchymal transition. Curr Opin Cell Biol. 2014;31:56–66.CrossRef
37.
Chen SW, Zhang Q, Xu ZF, Wang HP, Shi Y, Xu F, Zhang WJ, Wang P, Li Y. HOXC6 promotes gastric cancer cell invasion by upregulating the expression of MMP9. Mol Med Rep. 2016;14(4):3261–8.CrossRef
38.
Moon SM, Kim SA, Yoon JH, Ahn SG. HOXC6 is deregulated in human head and neck squamous cell carcinoma and modulates Bcl-2 expression. J Biol Chem. 2012;287(42):35678–88.CrossRef
39.
Sui CJ, Xu F, Shen WF, Dai BH, Lu JJ, Zhang MF, Yang JM. MicroRNA-147 suppresses human hepatocellular carcinoma proliferation migration and chemosensitivity by inhibiting HOXC6. Am J Cancer Res. 2016;6(12):2787–98.PubMedPubMedCentral
40.
Ramachandran S, Liu P, Young AN, Yin-Goen Q, Lim SD, Laycock N, Amin MB, Carney JK, Marshall FF, Petros JA, Moreno CS. Loss of HOXC6 expression induces apoptosis in prostate cancer cells. Oncogene. 2005;24(1):188–98.CrossRef
41.
Gulubova M, Manolova I, Ananiev J, Julianov A, Yovchev Y, Peeva K. Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer. Int J Colorectal Dis. 2010;25(5):591–9.CrossRef
42.
Zhao HW, Li YW, Feng R, Yu JB, Li J, Zhang Y, Li JC, Wang YX. TGF-beta/Smad2/3 signal pathway involves in U251 cell proliferation and apoptosis. Gene. 2015;562(1):76–82.CrossRef
43.
Li Y, Liu H, Liang Y, Peng P, Ma X, Zhang X. DKK3 regulates cell proliferation, apoptosis and collagen synthesis in keloid fibroblasts via TGF-beta1/Smad signaling pathway. Biomed Pharmacother. 2017;91:174–80.CrossRef
Metadata
Title
HOXC6 gene silencing inhibits epithelial-mesenchymal transition and cell viability through the TGF-β/smad signaling pathway in cervical carcinoma cells
Authors
Feng Zhang
Chen-Chen Ren
Ling Liu
Yan-Nan Chen
Li Yang
Xiao-An Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0680-2

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