Zhang Yin-Ling, Xue Geng, Miao Hui, Zhou Chuan-Chuan, Sun Shu-Han, Zhang Yi
Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433, China.
Department of Clinical Genetics Division, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
Oncotarget. 2021 Feb 16;12(4):366-378. doi: 10.18632/oncotarget.27136.
The effects and mechanisms of folic acid (FA) as a chemopreventive agent for tumorigenesis of hepatocellular carcinoma (HCC) remain unclear. In this study, the QSG-7701, a human normal liver cell line, was cultured in different FA levels (High, Normal or No) for 6 months. Then, the biological characteristics, the expression of main stem cell-like genes or epithelial-mesenchymal transition (EMT) related genes and the tumorigenicity of cells cultured in different treatment groups were detected. Our results showed that No FA improved the malignant transformation of cells but High FA depressed the malignant transformation. Meanwhile, cells in different treatment groups were mapped by transcriptome sequencing. Then the relativity of increased LCN2 and decreased FA level was identified and confirmed and vivo. We also revealed that intracellular control of LCN2 would recover the effects of FA on cell proliferation, cell cycle and tumor formation and vivo. Finally, our studies displayed that increased FA level induced the down-regulation of LCN2 not by DNA hypermethylation of LCN2 promoter but by promoting the level of histone H3 lysine 9 di-methylation (H3K9Me2) in LCN2 promoter. In conclusion, our studies disclosed the chemopreventive effect of FA supplementation on hepatocarcinogenesis, which partial attributed to the inhibition of LCN2 by regulating histone methylation in promoter. Our results provide a potential mechanism of the chemoprevention of FA supplementation on tumorigenesis of HCC and may be helpful in developing treatment target against HCC.
叶酸（FA）作为肝细胞癌（HCC）肿瘤发生化学预防剂的作用及机制尚不清楚。在本研究中，将人正常肝细胞系QSG-7701在不同叶酸水平（高、正常或无）下培养6个月。然后，检测不同处理组培养细胞的生物学特性、主要干细胞样基因或上皮-间质转化（EMT）相关基因的表达以及细胞的致瘤性。我们的结果表明，无叶酸促进了细胞的恶性转化，而高叶酸则抑制了恶性转化。同时，对不同处理组的细胞进行转录组测序定位。然后在体内外鉴定并证实了脂联素2（LCN2）升高与叶酸水平降低之间的相关性。我们还发现，在体内外，对LCN2的细胞内调控可恢复叶酸对细胞增殖、细胞周期和肿瘤形成的影响。最后，我们的研究表明，叶酸水平升高诱导LCN2下调不是通过LCN2启动子的DNA高甲基化，而是通过促进LCN2启动子中组蛋白H3赖氨酸9二甲基化（H3K9Me2）的水平。总之，我们的研究揭示了补充叶酸对肝癌发生的化学预防作用，部分归因于通过调节启动子中的组蛋白甲基化来抑制LCN2。我们的结果提供了补充叶酸对HCC肿瘤发生化学预防的潜在机制，可能有助于开发针对HCC的治疗靶点。
