m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m6A in RNA fate have been revealed, the potential contribution of m6A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m6A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 was correlated with poor survival of HCC patients. m6A modification level of AC026356.1 was also increased in HCC and more significantly correlated with poor survival of HCC patients. Functional assays showed that m6A-modified AC026356.1 promoted HCC cellular proliferation, migration, and liver metastasis. Gene set enrichment analysis showed that AC026356.1 activated IL11/STAT3 signaling. Mechanistic investigation showed that m6A-modified AC026356.1 bound to IGF2BP1. The interaction between m6A-modified AC026356.1 and IGF2BP1 promoted the binding of IL11 mRNA to IGF2BP1, leading to increased IL11 mRNA stability and IL11 secretion. Functional rescue assays showed that depletion of IL11 reversed the oncogenic roles of AC026356.1. These findings revealed the potential influences of m6A modification on RNA biological functions and suggested that targeting m6A modification may be a novel strategy for HCC treatment.

Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: a four year follow-up study.

BACKGROUND: Previous epidemiological and experimental studies support the concept that serum gamma-glutamyltransferase (GGT) activity within its normal range is related to oxidative stress. Since oxidative stress plays a crucial role in the pathogenesis of various liver diseases, serum GGT may predict development of liver damage. METHODS: A total of 6,523 healthy male workers with normal alanine aminotransferase (ALT, <35 U/l) in a steel manufacturing company were followed for four years. Liver damage was defined as a chronic elevation of serum ALT (both 2001 and 2002). RESULTS: After adjusting for age, body mass index, alcohol consumption, cigarette smoking, exercise, and baseline value of ALT, in comparison with the group whose GGT level was <10 U/l, the adjusted relative risks for elevated ALT level among those with GGT levels 10-19, 20-29, 30-39, and over 40 U/l was 1.0, 2.5, 4.7, 7.4, and 12.0, respectively (P for trend <0.01). More importantly, this association was similarly observed even among non-drinkers; the corresponding relative risks were 1.0, 1.8, 3.8, 5.6, and 6.2 (P for trend <0.01). However baseline ALT did not predict abnormal GGT level four years later. CONCLUSION: Serum GGT levels within normal range predict incidence of chronic elevation of ALT. Oxidative stress might explain this relationship.