Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide in men and the seventh in women and the second most frequent cause of cancer deaths; about half of these cases and deaths occur in China [1]
Elevated intracellular Hcy level is associated with CYP2J2 upregulation and epoxyeicosatrienoic acid (EET) metabolism in hepatocellular carcinoma (HCC)
The abundance of metabolites in the CYP450 pathway but not COX or LOX pathways was higher in tumor than adjacent non-tumor tissue: 5,6-EET, 8,9-EET, 11,12-EET, 14,15EET and their corresponding dihydroxyeicosatrienoic acids (DHETs)
Summary
Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide in men and the seventh in women and the second most frequent cause of cancer deaths; about half of these cases and deaths occur in China [1]. Increasing evidence suggests that rapidly proliferating tumor cells show elevated level of circulating Hcy [4], including in HCC [5]. In HCC, the Hcy level gradually increases from healthy tissue to liver cirrhosis and carcinoma tissue [6]. This finding might be related to depleted folate and inactivated methionine synthase in cells as well as www.impactjournals.com/oncotarget mutation of methylenetetrahydrofolate reductase, which would induce lack of conversion of Hcy to methionine and its accumulation [5, 7]. The elevated Hcy level could convert S-adenosyl homocysteine (SAH), a competitive inhibitor of most methyltransferases, further inducing DNA hypomethylation [8], which represents an epigenetic mechanism in carcinogenesis. Previous studies indicated that Hcy could promote the expression of cyclin A [9], platelet-derived growth factors [10], fibroblast growth factor 2 [11] and P66shc [12] via DNA hypomethylation in vascular endothelial cells [13]
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