Carcinogenesis 2011 Dec;32 (12): 1840-8. [IF:5.402]
Heme oxygenase-1: a molecular brake on hepatocellular carcinoma cell migration.
Zou C , Zhang H , Li Q , Xiao H , Yu L , Ke S , Zhou L , Liu W , Wang W , Huang H , Ma N , Liu Q , Wang X , Zhao W , Zhou H , Gao X .
Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China.
哈尔滨医科大学生物化学与分子生物学系
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease with great public health impact worldwide. Heme oxygenase (HO)-1 has recently been reported as an important player in tumor angiogenesis and metastasis. However, the role of HO-1 in liver cancer metastasis is unclear. In this study, we explored genetic differences and downstream signal transduction pathways of HO-1 in liver cancer cell lines. HO-1 wild-type and mutant cell lines were generated from human liver cancer cell line HepG2. The overexpression of wild-type HO-1 decreased the migration of HepG2 cells. In contrast, the overexpression of mutant HO-1G143H increased the migration of the cancer cells. Interleukin (IL)-6 is one of the major downstream molecules that mediated this process because IL-6 expression and migration are suppressed by HO-1 and increased when HO-1 is knocked down by shRNA. In addition, we demonstrated carbon monoxide (CO) and p38MAPK are the cofactors in this signal pathway. In vivo animal model demonstrated HO-1 inhibited the tumor growth. In conclusion, in vitro and in vivo data show HO-1 inhibits the human HCC cells migration and tumor growth by suppressing the expression of IL-6. The heme degradation product CO is a cofactor in this process and inhibits p38MAPK phosphorylation.
摘要：
肝细胞肿瘤是世界范围内对公众健康造成巨大危害的一种致命性疾病。血红素氧化酶(HO)—1最近被报道在肿瘤的血管发生和转移过程中扮演重要角色。然而，HO-1在肝癌转移中的作用还不清楚。在这项研究中，我们探究了不同肝癌细胞系的遗传差异及HO-1的下游信号传导通路。野生型HO-1和变异细胞系来源于人类肝癌细胞系HepG2。野生型HO-1的过度表达减少了HepG2细胞的转移。相反，变异型HO-1G143H的过度表达则增加了癌细胞的转移。IL-6是介导这一过程的主要下游分子之一。因为IL-6的表达和迁移受HO-1抑制，所以当HO-1被shRNA敲除时其表达升高。另外，我们证实了CO和p38MAPK是这一信号通路的辅因子。同时在体内动物模型中证实了HO-1抑制肿瘤生长。总之，体外和体内数据表明HO-1通过抑制IL-6的表达可以抑制人类肝细胞肿瘤细胞转移和肿瘤生长。血红素的降解产物CO是这一过程的辅因子，并能抑制p38MAPK磷酸化。
