Molecular Mechanism Of M6A Modified Lipase MRNA Mediating Hepatocellular Carcinoma In Mice

Liver cancer is one of the most common malignant tumors in the world.About 70%to 90% primary liver cancers are hepatocellular carcinoma(HCC).HCC has a high mortality rate and a poor prognosis,and its incidence has significant gender disparity.The occurrence of HCC is related to a variety of factors,such as hepatitis virus infection,carcinogen exposure,non-alcoholic fatty liver disease(NAFLD),etc.The incidence of NAFLD in adults is about 20%-30%,and has a trend of increasing year by year.NAFLD is a manifestation of hepatic metabolic syndrome and an important driving factor of HCC.It has been proved that lipid metabolism plays a key role in the occurrence and development of HCC,and in HCC,the expression levels of enzymes related lipid synthesis,such as ACLY and SCD1,are both up-regulated,and positively correlated with the severity of HCC.However,the specific mechanism of lipid regulation on the occurrence and development of HCC remains unclear.A large number of studies have proved that m6 A methylation is involved in the regulation of the occurrence and development of HCC.However,the direction and specific mechanism of its regulation are still controversial.This study aimed to explore the molecular mechanism by which m6 a methylation regulates lipid metabolism and affects the occurrence of HCC in a glycolipid-induced HCC animal model.We found that in HCC model mice induced by glucose and lipid metabolism disorder gained weight,abnormal liver morphology and liver function damage,and increased de novo fatty acid synthesis were observed.Moreover,the level of m6 a methylation in the liver of model mice was increased,accompanied by the high expression of METTL14 and METTL3.In vitro cell experiments showed that overexpression of Mettl14 or Mettl3 could promote the expression of ACLY and SCD1,key enzymes in fat synthesis,and lipid droplet accumulation.m6 a sequencing analysis and MERIP-q PCR revealed that overexpression of METTL14 mainly increased m6 a methylation modification of ACLY and SCD1 3 ’-UTR sequences.In human HCC tissue samples,we also found high expression of METTL14 and METTL3 as well as elevated m6 a methylation levels.In addition,the high expression of ACLY and SCD1 was positively correlated with the levels of METTL14 and METTL3,thereby reducing the survival rate of HCC patients.In conclusion,this study showed that the sugar,lipid metabolism in the induction of HCC,high expression METTL14 and METTL3 raised the overall m6 A methylation level,thus through targeted 3 ’UTR sequence increased ACLY and stable expression of SCD1,promote the synthesis of lipid increased and abnormal lipid accumulation,oxidative stress activation and excessive liver cell proliferation,thus promoted the development of HCC.This study is based on a novel mouse model of HCC induced by glucose and lipid metabolism,and explores the mechanism of HCC from the regulation of m6 a methylation of lipid synthase expression,revealing that the regulation of gene expression at the epigenetic level may be a potential important factor promoting the occurrence and development of HCC,and pointing out the multifaceted role of m6 a modification in the regulation of HCC.