Li Pei, Liu Xiang, Dong Zi-Ming, Ling Zhi-Qiang
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou 310022, China.
Oncotarget. 2015 Nov 10;6(35):38151-65. doi: 10.18632/oncotarget.5832.
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.
新型肿瘤抑制基因HIC1（癌症中高甲基化1）的下调在各种肿瘤中频繁发生，它会导致肿瘤进展和转移。在本研究中，我们调查了HIC1在食管鳞状细胞癌（ESCC）中的作用及其潜在机制。HIC1在大约70%的原发性ESCC中在mRNA和蛋白质水平均发生下调，这与血管侵犯、临床晚期、淋巴结转移以及无病生存期（DFS）差显著相关。启动子甲基化分析表明，HIC1表达缺失是由表观遗传机制介导的。功能研究证实，ESCC细胞中HIC1的异位重新表达抑制细胞增殖、克隆形成能力、细胞运动性、肿瘤形成以及上皮-间质转化（EMT）。我们的结果揭示了HIC1缺陷通过激活EphA2信号通路诱导ESCC细胞发生EMT并促进肿瘤进展和转移的机制。总之，通过HIC1表观遗传沉默导致EphA2通路调控缺失可能是ESCC进展中的一个重要机制。我们确定了一条将ESCC细胞中HIC1下调与EphA2诱导的EMT联系起来的新途径，这可能为新型抗肿瘤治疗的开发提供线索。
