Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Clin Res Hepatol Gastroenterol. 2024 Aug;48(7):102421. doi: 10.1016/j.clinre.2024.102421. Epub 2024 Jul 16.
Spermine oxidase (SMOX), an inducible enzyme involved in the catabolic pathway of polyamine, was found to be upregulated in hepatocellular carcinoma and might be an important oncogene of it in our previous studies. This study attempted to further investigate its relationship with liver inflammation and fibrosis both in vitro and in vivo.
The effect of SMOX inhibition on LPS-induced inflammatory response in mouse liver cell line AML12 was validated by using small interfering RNA or SMOX inhibitor MDL72527. Western blotting and immunofluorescence were utilized to verify whether LPS could induce β-catenin to transfer into the nucleus and whether it could be reversed by interfering with the expression of SMOX or using SMOX inhibitor. Then, the SMOX inhibitor MDL72527 and SMOX knockout mice were used to verify the hypothesis above in vivo.
The expression of SMOX could be induced by LPS in AML12 cells. The inhibition of SMOX could inhibit LPS-induced inflammatory response in AML12 cells. LPS could induce β-catenin transfer from cytoplasm to nucleus, while SMOX downregulation or inhibition could partially reverse this process. In vivo intervention with SMOX inhibitor MDL72527 or SMOX knockout mice could significantly improve the damage of liver function, reduce intrahepatic inflammation, inhibit the nuclear transfer of β-catenin in liver tissue, and alleviate carbon tetrachloride-induced liver fibrosis in mice.
SMOX can promote the inflammatory response and fibrosis of hepatocytes. It provides a new therapeutic strategy for hepatitis and liver fibrosis, inhibiting early liver cancer.
精脒氧化酶（SMOX）是多胺分解代谢途径中的一种诱导酶，在肝细胞癌中发现其表达上调，在我们之前的研究中可能是其重要的癌基因。本研究试图进一步研究其与肝内炎症和纤维化的关系，包括在体外和体内。
采用小干扰 RNA 或 SMOX 抑制剂 MDL72527 验证 SMOX 抑制对 LPS 诱导的 AML12 小鼠肝细胞系炎症反应的影响。采用 Western blot 和免疫荧光法验证 LPS 是否能诱导β-catenin转移到细胞核，以及是否能通过干扰 SMOX 的表达或使用 SMOX 抑制剂来逆转这一过程。然后，使用 SMOX 抑制剂 MDL72527 和 SMOX 敲除小鼠在体内验证上述假说。
LPS 可诱导 AML12 细胞中 SMOX 的表达。SMOX 的抑制可抑制 AML12 细胞中 LPS 诱导的炎症反应。LPS 可诱导β-catenin从细胞质转移到细胞核，而 SMOX 的下调或抑制可部分逆转这一过程。体内干预 SMOX 抑制剂 MDL72527 或 SMOX 敲除小鼠可显著改善肝功能损伤，减少肝内炎症，抑制肝组织中β-catenin 的核转移，并减轻小鼠四氯化碳诱导的肝纤维化。
SMOX 可促进肝细胞的炎症反应和纤维化。为肝炎和肝纤维化的治疗提供了一种新的策略，抑制早期肝癌的发生。
