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.

中文翻译：

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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亚型而促进肝细胞癌的转移。

肝星状细胞（HSC）与肝癌细胞之间的相互影响有助于肝细胞癌（HCC）的进展，但是其潜在机制在很大程度上尚不清楚。我们在这里报告激活的HSCs诱导烟酰胺N-甲基转移酶（NNMT）的上调，已知它可以调节肝脏肝癌细胞中的多种代谢途径。HCC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27个甲基化模式上的组蛋白H3甲基化和转录激活分化分化簇44（CD44）来促进HCC细胞侵袭和转移。NNMT介导的CD44 mRNA的N6-甲基腺苷修饰导致CD44v3剪接变体的形成，而其产品1-甲基烟酰胺则通过阻止泛素介导的降解作用来稳定CD44蛋白。最后，NNMT还被证明是抑制肝癌细胞转移的他汀类药物的靶标。综上所述，我们的研究首次显示NNMT / CD44v3轴调节HCC转移，并将NNMT提出为有希望的HCC预后生物标志物和治疗靶标。