Zhang Donghong, Lou Jinli, Zhang Xu, Zhang Lin, Wang Fei, Xu Danfei, Niu Na, Wang Yidong, Wu Yue, Cui Wei
Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, 100021, China.
Department of Clinical Laboratory, Peking Union Medical College Hospital and Peking Union Medical College, Beijing, 100730, China.
Oncotarget. 2017 Feb 28;8(9):15377-15392. doi: 10.18632/oncotarget.14165.
Hyperhomocysteinemia (HHcy) can result from liver disease or dysfunction and further alters intracellular lipid metabolism. Cytochrome P450 (CYP) arachidonic acid epoxygenases are expressed in human cancers and promote cancer metastasis. This study explored the interaction of Hcy and CYP450 metabolism in hepatocellular carcinoma (HCC). The levels of 4-epoxyeicosatrienoic acid (EET) isomers and their generative enzyme CYP2J2 level as well as intracellular Hcy level were higher in 42 cases of HCC than in paired non-tumor tissue. Elevated Hcy-decreased DNA methylation on SP1/AP1 binding motifs and enhancement on the CYP2J2 promoter via ERK1/2 signaling was essential for CYP2J2 upregulation and EET metabolism. Increased Hcy level enhanced the neoplastic cellular phenotype, which was reversed by CYP2J2 knockdown in vitro. Furthermore, tumor growth and size as well as patterns of CYP2J2 expression and DNA demethylation were increased with HHcy in mice induced orthotopically by 2% (wt/wt) L-methionine with or without folate deficiency. Moreover, the effect was attenuated by shRNA knockdown of CYP2J2. Thus, HHcy results from but can also promote hepatocarcingenesis via CYP450-EET metabolism by crosstalk of DNA demethylation of CYP2J2 and ERK1/2 signaling.
高同型半胱氨酸血症（HHcy）可由肝脏疾病或功能障碍引起，并进一步改变细胞内脂质代谢。细胞色素P450（CYP）花生四烯酸环氧化酶在人类癌症中表达并促进癌症转移。本研究探讨了同型半胱氨酸（Hcy）与CYP450代谢在肝细胞癌（HCC）中的相互作用。42例HCC患者中4-环氧二十碳三烯酸（EET）异构体水平及其生成酶CYP2J2水平以及细胞内Hcy水平均高于配对的非肿瘤组织。Hcy升高通过ERK1/2信号通路降低SP1/AP1结合基序上的DNA甲基化并增强CYP2J2启动子上的甲基化，这对于CYP2J2上调和EET代谢至关重要。Hcy水平升高增强了肿瘤细胞表型，体外实验中CYP2J2基因敲低可逆转这种表型。此外，在由2%（wt/wt）L-蛋氨酸原位诱导的伴有或不伴有叶酸缺乏的小鼠中，HHcy使肿瘤生长、大小以及CYP2J2表达和DNA去甲基化模式增加。此外，CYP2J2的短发夹RNA（shRNA）敲低减弱了这种作用。因此，HHcy源于CYP450-EET代谢，但也可通过CYP2J2的DNA去甲基化与ERK1/2信号通路的相互作用促进肝癌发生。
