| Hepatocellular carcinoma (HCC) is the fifth common tumors in the world, whichranks third in the mortality of malignant tumor. HCC incidence and death rates remain highworldwide, particular in China.Although during the past decade, clinical diagnosis andtreatment for HCC has made a great deal of development, the molecular mechanismscontributing to HCC are still largely unknown. High malignancy of hepatocellularcarcinoma, poor prognosis and low survival rates greatly threat the life of patients withHCC. So solely relying on treatment can not eliminate the threats from HCC, and we mustprevent the occurrence of HCC.Recent years, studies have shown that DNAmethylation, histone methylation, histoneacetylation and other epigenetic modification play important roles in gene expressionregulation. People pay more attention to the effects of epigenetic modification on thedevelopment and progression of cancer. Folic acid, as a necessary nutrient in the diet, hascomplicate interactions with epigenetic modification, and can modulate epigeneticmodification to control gene expression, and thus have an important impact on thedevelopment and progression of cancer. Recent years epidemiological and animal modelstudies show that folate deficiency is associated with multiple tumors, such as esophagealcancer, colorectal cancer, prostate cancer, breast cancer, gastric cancer, pancreatic cancer,and so on. Clinical epidemiological studies showed that low level of folic acid in the bloodis closely associated with the development and progression of HCC, but the supporttingexperimental data is lack and the follow-up mechanism is unclear. Therefore furtherdiscussion on whether there is a protective effect of folic acid supplementation on HCCand the specific molecular mechanisms is necessary and should provide solid theoreticaland experimental basis for whether it can be used as an important candidate molecules ofchemical prevention and treatment of hepatocellular carcinoma.In order to examine whether there is a protective effect of folic acid supplementationon hepatocellular carcinoma and its specific molecular mechanisms, we built a rat model ofHCC induced by DEN. The rates were fed different concentrations of folic acid from beingweaned, and were observed regularly. Results indicated that folic acid supplementationreduced liver damage and liver cirrhosis induced by DEN, and slowed the occurrence and progress of hepatocellular carcinoma. Recently a large number of research report that EMTis closely related with the development and progression of liver damage, cirrhosis andhepatocellular carcinoma, so we speculated that folic acid may control the developmentand progression of liver damage, liver cirrhosis and liver cancer through regulating EMT.On this basis, we explored the effects of folic acid on EMT through in vitro and in vivoexperiments. First we detected the expression of EMT related markers in mouse hepatictissue, and found that folic acid inhibit EMT of the mouse liver. Then in vitro experiments,we use different concentrations folic acid medium to continuously culture humanhepatocytes for1year and confirmed that folic acid could inhibit EMT of human liver cells,indicating that the folic acid inhibits the development of liver cancer through inhibitingEMT.At the same time we found that as the changes of chromatin modification during thedevelopment and progression of hepatocellular carcinoma, the changes of chromatinmodification also occurred during EMT. Lysine specific histone methyltransferase1(LSD1), plays an important role in the change of chromatin modification. It also reportsthat LSD1is a folic acid-binding protein. To study whether folic acid regulates EMTthrough regulating LSD1, we first verify the effects of folic acid on LSD1. In vitroexperiments confirmed that folic acid decreased LSD1. Then we conducted chromatinimmunoprecipitation experiments using LSD1specific antibody and histone H3K4Me2specific antibody. The results confirmed that through reducing LSD1, folic acid decreasedthe binding of LSD1on the promoter region of epithelial gene (CDH1), and increasedhistone H3K4Me2levels on the promoter region of epithelial gene, thereby raising theexpression of epithelial gene. Finally, using interference and overexpression experimentswe confirmed that the effect of folic acid on epithelial gene expression depended on LSD1.In summary, this study has confirmed that folic acid reduced LSD1, decreased the bindingof LSD1on the promoter region of epithelial gene, and increased the levels of histoneH3K4Me2on the promoter region of epithelial gene. Thereby folic acid increased theexpression of epithelial gene, inhibited EMT, and inhibited the development andprogression of hepatocellular carcinoma. Folic acid could be used as an importantcandidate molecule for chemical prevention of hepatocellular carcinoma. |
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