Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma
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Pei Li1, Xiang Liu2, Zi-Ming Dong1, Zhi-Qiang Ling2
1Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
2Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou 310022, China
Pei Li, e-mail: email@example.com
Zhi-Qiang Ling, e-mail: firstname.lastname@example.org
Keywords: esophageal squamous cell carcinoma (ESCC), hypermethylated in cancer 1 (HIC1), epithelial-mesenchymal transition (EMT), promoter methylation, EphA2
Received: April 06, 2015 Accepted: September 28, 2015 Published: October 17, 2015
Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis. In this study, we investigated a role of HIC1 in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. Downregulation of HIC1 occurred in approximately 70% of primary ESCCs at both mRNA and protein level where it was associated significantly with vascular invasion, advanced clinical stage, lymph node metastasis, and poor disease free survival (DFS). The promoter methylation analyses suggested that loss of HIC1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of HIC1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, tumor formation and epithelial-mesenchymal transition (EMT). Our results decipher the mechanism through which HIC1 deficiency induce ESCC cells to undergo EMT and promote tumor progression and metastasis through activation of EphA2 signaling pathway. Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression. We identify a novel pathway that linking HIC1 downregulation to EphA2-inducing EMT in ESCC cells and may shed light on the development of novel anti-tumor therapeutics.
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