Low-dose radiation-induced epithelial-mesenchymal transition through NF-κB in cervical cancer cells

Yan,Shi; Wang,Yu; Yang,Qifeng; Li,Xiaoyan; Kong,Xiaoli; Zhang,Ning; Yuan,Cunzhong; Yang,Ning; Kong,Beihua

doi:10.3892/ijo.2013.1852

Low-dose radiation-induced epithelial-mesenchymal transition through NF-κB in cervical cancer cells

Authors:
- Shi Yan
- Yu Wang
- Qifeng Yang
- Xiaoyan Li
- Xiaoli Kong
- Ning Zhang
- Cunzhong Yuan
- Ning Yang
- Beihua Kong
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Affiliations: Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China, Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
Published online on: March 8, 2013 https://doi.org/10.3892/ijo.2013.1852
Pages: 1801-1806

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Abstract

Cervical cancer is the leading cause of death from cancer among women. Radiotherapy for cervical cancer is an effective treatment method; however, the response to radiotherapy varies among patients. Epithelial-mesenchymal transition (EMT) is a morphogenesis process involved in embryonic and organismal development. During tumour progression, EMT may enhance cancer cell invasion, promoting tumour metastasis. We hypothesised that EMT was involved in the enhanced invasiveness of cervical cancer cells after low-dose radiation and aimed to elucidate the underlying mechanism of this process in low-dose radiation of cervical cancer. The irradiated cells (FIR cells) were derived from the parental cells (N cells) with a cumulative dose of 75 Gy. After resting and reorganisation, the effect of low-dose radiation on the FIR cells was analysed. The expression of E-cadherin, N-cadherin and p65 was detected by real-time qPCR and western blotting in parental cancer cells and irradiated cancer cells. Motility was detected using the migration/invasion assay. After silencing of NF-κB p65 expression using siRNA against p65, the expression of E-cadherin and N-cadherin was examined by real‑time qPCR and western blotting. We found that low-dose radiation induced morphological changes of cells. The expression of epithelial markers was downregulated and mesenchymal markers were induced in irradiated cells, both of which are characteristics of EMT. Additionally, in irradiated cells, migration and invasion were enhanced and the expression of p65 was increased. To investigate whether p65 was involved in EMT, we silenced the expression of p65 in irradiated cells using siRNA and found that the features of EMT were suppressed. In summary, p65-regulated EMT induced by low-dose irradiation of cervical cancer cell lines promoted the invasiveness and metastasis of cervical cancer cells. The reversal of EMT may be a new therapeutic target for improving the effectiveness of radiotherapy for cervical cancer.

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1.	Lee MY and Shen MR: Epithelial-mesenchymal transition in cervical carcinoma. Am J Transl Res. 4:1–13. 2012.PubMed/NCBI
2.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
3.	Kitahara O, Katagiri T, Tsunoda T, Harima Y and Nakamura Y: Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia. 4:295–303. 2002. View Article : Google Scholar
4.	Andarawewa KL, Erickson AC, Chou WS, et al: Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo transforming growth factor beta induced epithelial to mesenchymal transition. Cancer Res. 67:8662–8670. 2007. View Article : Google Scholar
5.	Qing Y, Yang XQ, Zhong ZY, et al: Microarray analysis of DNA damage repair gene expression profiles in cervical cancer cells radioresistant to 252Cf neutron and X-rays. BMC Cancer. 10:712010. View Article : Google Scholar : PubMed/NCBI
6.	Liu SS, Leung RC, Chan KY, et al: p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy. Clin Cancer Res. 10:3309–3316. 2004. View Article : Google Scholar : PubMed/NCBI
7.	Barcellos-Hoff MH: Radiation-induced transforming growth factor beta and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res. 53:3880–3886. 1993.
8.	Ewan KB, Henshall-Powell RL, Ravani SA, et al: Transforming growth factor-beta1 mediates cellular response to DNA damage in situ. Cancer Res. 62:5627–5631. 2002.PubMed/NCBI
9.	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
10.	Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
12.	Moody SE, Perez D, Pan TC, et al: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 8:197–209. 2005. View Article : Google Scholar : PubMed/NCBI
13.	Lee MY, Chou CY, Tang MJ and Shen MR: Epithelialmesenchymal 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
14.	Hsu DS, Lan HY, Huang CH, et al: Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer. Clin Cancer Res. 16:4561–4571. 2010. View Article : Google Scholar : PubMed/NCBI
15.	Yang AD, Fan F, Camp ER, et al: Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 12:4147–4153. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD and Wang LH: Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion and resistance to paclitaxel. Cancer Res. 67:1979–1987. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Arumugam T, Ramachandran V, Fournier KF, et al: Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69:5820–5828. 2009. View Article : Google Scholar : PubMed/NCBI
18.	Li Z, Xia L, Lee LM, et al: Effector genes altered in MCF-7 human breast cancer cells after exposure to fractionated ionizing radiation. Radiat Res. 155:543–553. 2001. View Article : Google Scholar : PubMed/NCBI
19.	Min C, Eddy SF, Sherr DH and Sonenshein GE: NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem. 104:733–744. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Cho KB, Cho MK, Lee WY and Kang KW: Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett. 293:230–239. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Li X, Kong X, Huo Q, et al: Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition. Cancer Sci. 102:1151–1157. 2011. View Article : Google Scholar : PubMed/NCBI
22.	Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 15:740–746. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Schmalhofer O, Brabletz S and Brabletz T: E-cadherin, beta-catenin and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 28:151–166. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Hsu YM, Chen YF, Chou CY, et al: KCl cotransporter-3 down-regulates E-cadherin/beta-catenin complex to promote epithelial-mesenchymal transition. Cancer Res. 67:11064–11073. 2007. View Article : Google Scholar : PubMed/NCBI
25.	Huber MA, Azoitei N, Baumann B, et al: NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114:569–581. 2004. View Article : Google Scholar : PubMed/NCBI
26.	Strippoli R, Benedicto I, Foronda M, et al: p38 maintains E-cadherin expression by modulating TAK1-NF-kappa B during epithelial-to-mesenchymal transition. J Cell Sci. 123:4321–4331. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Li CW, Xia W, Huo L, et al: Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 72:1290–1300. 2012. View Article : Google Scholar : PubMed/NCBI