Elevated N-methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform
Elevated N-methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform
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肝星状细胞诱导的 N-甲基转移酶表达升高通过调节 CD44v3 亚型促进肝细胞癌的转移
DOI：
10.1002/1878-0261.12544
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发表时间：
2019-07-11
影响因子：
6.6
通讯作者：
Yin, Zhenyu
中科院分区：
文献类型：
--
作者：
Li, Jie;You, Song;Yin, Zhenyu
肝星状细胞（hepatic stellate cells，HSC）与肝癌细胞之间的相互作用是导致肝癌进展的重要因素，但其机制尚不清楚。我们在这里报告，激活的HSC诱导上调烟酰胺N-甲基转移酶（NNMT），这是已知的调节多种代谢途径在肝细胞癌细胞的肝脏。肝癌组织中高水平的NNMT与血管浸润、血清HBV-DNA水平升高和远处转移呈正相关。此外，功能分析表明，NNMT通过改变组蛋白H3甲基化27甲基化模式和转录激活分化簇44（CD 44）促进HCC细胞的侵袭和转移。NNMT介导的N6-甲基腺苷对CD 44 mRNA的修饰导致CD 44 v3剪接变体的形成，而其产物1-甲基烟酰胺通过防止遍在蛋白介导的降解来稳定CD 44蛋白。最后，NNMT也被证明是抑制肝癌细胞转移的他汀类药物的靶点。综上所述，我们的研究首次表明NNMT/CD 44 v3轴调节HCC转移，并将NNMT作为HCC有希望的预后生物标志物和治疗靶点。
The cross-talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N-methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV-DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT-mediated N6-methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1-methyl-nicotinamide stabilized CD44 protein by preventing ubiquitin-mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.