Mirra Serena, Gavaldà-Navarro Aleix, Manso Yasmina, Higuera Mónica, Serrat Román, Salcedo María Teresa, Burgaya Ferran, Balibrea José Maria, Santamaría Eva, Uriarte Iker, Berasain Carmen, Avila Matias A, Mínguez Beatriz, Soriano Eduardo, Villarroya Francesc
Department of Cell Biology, Physiology and Immunology, University of Barcelona, 08007 Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Cancers (Basel). 2021 Mar 5;13(5):1110. doi: 10.3390/cancers13051110.
ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
ARMCX3由Armcx基因家族的一个成员编码，已知其参与神经系统的发育和功能。我们发现，在高脂饮食条件下，小鼠肝脏中的ARMCX3显著上调，并且在非酒精性脂肪性肝病（NAFLD）和肝细胞癌（HCC）患者的肝脏中，ARMCX3也上调。对小鼠进行ARMCX3无效化处理（诱导性ARMCX3基因敲除），然后使其接受高脂饮食和二乙基亚硝胺诱导的肝癌发生过程。我们还分析了在肝癌细胞系中进行实验性ARMCX3基因敲低或过表达的效果。ARMCX3无效化可保护小鼠免受高脂饮食诱导的NAFLD和化学诱导的肝癌发生。ARMCX3无效化促进了在高脂饮食下接受二乙基亚硝胺处理的小鼠肝脏中的凋亡细胞死亡和巨噬细胞浸润。ARMCX3下调降低了肝癌细胞系的活力、克隆性和迁移能力，而ARMCX3过表达则产生相反的效果。研究发现，SOX9介导ARMCX3在肝细胞中的作用，ARMCX3对肝细胞增殖的作用需要SOX9的相互作用。总之，ARMCX3被确定为肝脏生理病理学和致癌过程中的一个新的分子参与者。ARMCX3下调似乎可以预防肝癌发生，尤其是在高膳食脂质介导的肝脏损伤情况下。
