Hu Bin, Zhang Kundong, Li Shaobo, Li Hao, Yan Zhaowen, Huang Li, Wu Jianghong, Han Xiao, Jiang Weiliang, Mulatibieke Tunike, Zheng Lin, Wan Rong, Wang Xingpeng, Hu Guoyong
Department of Gastroenterology, Shanghai General Hospital/First People's Hospital, School of Medicine, Shanghai Jiao Tong University, 100 HaiNing Road, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of General Surgery, Shanghai General Hospital/First People's Hospital, School of Medicine, Shanghai Jiao Tong University, 100 HaiNing Road, Shanghai 200080, China.
Cancer Lett. 2016 Jul 1;376(2):387-98. doi: 10.1016/j.canlet.2016.04.013. Epub 2016 Apr 13.
Hypermethylated in cancer 1 (HIC1) is a tumour suppressor gene that is frequently deleted or epigenetically silenced in many human cancers. However, the molecular function of HIC1 in pancreatic cancer has not been fully elucidated, especially in cancer invasion and metastasis. We aimed to clarify the clinical relevance of HIC1 and human pancreatic cancer and the mechanism of its effect on invasion and metastasis .HIC1 was downregulated in pancreatic cancer patient cancer tissue and pancreatic cancer cell lines. A tissue microarray analysis demonstrated that negative HIC1 expression predicted advanced pathological stages and worse patient survival. In addition, HIC1 inhibited the invasion and metastasis of pancreatic cancer cells both in vitro and in vivo. Finally, HIC1 repressed the expression of STAT3 target genes, including c-Myc, VEGF, CyclinD1, MMP2 and MMP9, by binding and interacting with STAT3 to impede its DNA-binding ability but without affecting the protein levels of STAT3 and p-STAT3. Therefore, HIC1 appears to function as a STAT3 inhibitor and may be a promising target for cancer research and for the development of an optimal treatment approach for pancreatic cancer.
癌症高甲基化 1（HIC1）是一种肿瘤抑制基因，在许多人类癌症中经常缺失或发生表观遗传沉默。然而，HIC1 在胰腺癌中的分子功能尚未完全阐明，尤其是在癌症侵袭和转移方面。我们旨在阐明 HIC1 与人类胰腺癌的临床相关性及其影响侵袭和转移的机制。HIC1 在胰腺癌患者的癌组织和胰腺癌细胞系中表达下调。组织芯片分析表明，HIC1 阴性表达预示着病理分期较晚且患者生存率较低。此外，HIC1 在体外和体内均抑制胰腺癌细胞的侵袭和转移。最后，HIC1 通过与 STAT3 结合并相互作用，抑制 STAT3 靶基因（包括 c-Myc、VEGF、细胞周期蛋白 D1、基质金属蛋白酶 2 和基质金属蛋白酶 9）的表达，从而阻碍其 DNA 结合能力，但不影响 STAT3 和 p-STAT3 的蛋白水平。因此，HIC1 似乎作为一种 STAT3 抑制剂发挥作用，可能是癌症研究和开发胰腺癌最佳治疗方法的一个有前景的靶点。
