SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway
SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway
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DOI：
10.1016/j.freeradbiomed.2023.07.002
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发表时间：
2023-07-05
影响因子：
7.4
通讯作者：
Zhao，Zhen-Ying
中科院分区：
文献类型：
--
作者：
Xia，Pu;Liu，Da-Hua;Zhao，Zhen-Ying
过量饮酒是肝癌的主要原因之一。在乙醇代谢过程中，乙醛脱氢酶2（ALDH 2）是乙醛代谢的关键酶。ALDH 2基因缺陷与肝细胞癌（HCC）的风险呈正相关。然而，没有研究表明ALDH 2与另一种代谢调节基因SLC 3A 2之间存在联系。在本研究中，我们分析了ALDH 2和SLC 3A 2在肝癌组织中的表达水平的基础上TCGA数据库。随后，我们构建了ALDH 2基因敲除和SLC 3A 2基因敲入的转基因小鼠，以检测ALDH 2和SLC 3A 2在体内肿瘤发生中的作用。此外，我们还利用小RNA干扰技术研究了ALDH 2和SLC 3A 2在肝癌细胞中的作用机制。与以前的研究一致，我们还证实了ALDH 2在抑制肝癌发生中的功能，而SLC 3A 2具有相反的作用。本研究的主要发现是ALDH 2通过TGF-β1途径抑制BSG表达，从而间接抑制SLC 3A 2表达;随后，HCC细胞中鞘脂代谢途径也受到抑制。因此，SLC 3A 2是HCC治疗的新靶点。
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 tumorigenesisin 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.