SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway

• Published in: Free radical biology & medicine 2023-09, Vol.206, p.125-133
• Main Authors: Xia, Pu, Liu, Da-Hua, Wang, Dan, Wen, Gui-Min, Zhao, Zhen-Ying
• Format: Article
• Language: English
• Subjects: Liver cancer; Reactive oxygen species; SLC3A2; Sphingolipid biosynthesis pathway; Tumorigenesis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.07.002

Excessive drinking is one of the main causes of liver cancer. In the process of alcohol metabolism, aldehyde dehydrogenase 2 (ALDH2) is the key enzyme of acetaldehyde metabolism. ALDH2 gene deficiency is positively associated with the risk of hepatocellular carcinoma (HCC). However, no studies have shown a connection between ALDH2 and another metabolic regulatory gene, SLC3A2. In this study, we analyzed the expression levels of ALDH2 and SLC3A2 in liver cancer tissues based on the TCGA database. Subsequently, we constructed ALDH2 knockout and SLC3A2 knock-in transgenic mice to check the roles of ALDH2 and SLC3A2 in tumorigenesis in vivo. In addition, we examined the mechanisms of ALDH2 and SLC3A2 in HCC cells using small RNA interference technology. Consistent with previous studies, we also confirmed the functions of ALDH2 in inhibiting hepatocarcinogenesis, while SLC3A2 had the opposite effect. The main finding of this study is that ALDH2 inhibited BSG expression through the TGF-β1 pathway, which indirectly inhibited SLC3A2 expression; subsequently, the sphingolipid metabolism pathway was also inhibited in HCC cells. Therefore, SLC3A2 is a novel target for HCC treatment. [Display omitted] •ALDH2 in inhibiting hepatocarcinogenesis, while SLC3A2 had the opposite effect.•ALDH2 indirectly inhibited SLC3A2 expression through the TGF-β1 pathway.•SLC3A2 knockdown inhibited the sphingolipid metabolism pathway in liver cancer.