State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
Liver Int. 2021 May;41(5):1131-1147. doi: 10.1111/liv.14782. Epub 2021 Jan 10.
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Tribbles homolog 2 (TRIB2) is an oncogene implicated in a variety of cancers, including liver cancer. However, the biological function and regulatory mechanism of TRIB2 in HSCs are poorly understood. In addition, little is known about its role in liver fibrosis progression to HCC. Here, we revealed the clinical significance of TRIB2 in liver fibrosis and HCC development.
We investigated TRIB2 promoting liver fibrosis in vitro and in vivo. In mouse model of liver fibrosis and HCC, we measured hepatic fibrosis and HCC level through knockdown TRIB2 with shRNA. In addition, we performed western blotting, real-time quantitative PCR, immunofluorescence and co-immunoprecipitation assay to study TRIB2 function in LX-2 cells.
TRIB2 expression was strongly upregulated in human fibrotic liver tissues and HCC tissues. TRIB2 colocalized with α-smooth muscle actin (α-SMA) in fibrotic and HCC liver tissues. Knockdown of TRIB2 inhibited HSC activation and liver fibrosis in vitro and in vivo. TRIB2 promoted Yes-associated protein (YAP) stabilization, nuclear localization, and subsequent fibrotic gene expression independent of the MST-LATS phosphorylation cascade in HSCs. TRIB2 interacted with YAP to recruit phosphatase 1A (PP1A), promoting PP1A-mediated YAP dephosphorylation. TRIB2 knockdown potently attenuated the development of fibrosis-associated liver cancer.
TRIB2 is an attractive target for hepatic fibrosis and fibrosis-associated liver cancer treatment.
肝星状细胞（HSCs）在肝纤维化和肝细胞癌（HCC）中发挥关键作用。Tribbles 同源物 2（TRIB2）是一种癌基因，涉及多种癌症，包括肝癌。然而，TRIB2 在 HSCs 中的生物学功能和调控机制尚不清楚。此外，其在肝纤维化向 HCC 进展中的作用知之甚少。在这里，我们揭示了 TRIB2 在肝纤维化和 HCC 发展中的临床意义。
我们研究了 TRIB2 在体外和体内促进肝纤维化的作用。在肝纤维化和 HCC 的小鼠模型中，我们通过 shRNA 敲低 TRIB2 来测量肝纤维化和 HCC 水平。此外，我们还进行了 Western blot、实时定量 PCR、免疫荧光和共免疫沉淀实验，以研究 LX-2 细胞中 TRIB2 的功能。
TRIB2 在人纤维化肝组织和 HCC 组织中表达强烈上调。TRIB2 在纤维化和 HCC 肝组织中与α-平滑肌肌动蛋白（α-SMA）共定位。敲低 TRIB2 抑制了体外和体内 HSC 的激活和肝纤维化。TRIB2 促进了 Yes 相关蛋白（YAP）的稳定、核定位以及随后的纤维化基因表达，而不依赖于 MST-LATS 磷酸化级联反应在 HSCs 中。TRIB2 与 YAP 相互作用，募集磷酸酶 1A（PP1A），促进 PP1A 介导的 YAP 去磷酸化。TRIB2 敲低可显著减弱纤维化相关肝癌的发展。
TRIB2 是治疗肝纤维化和纤维化相关肝癌的一个有吸引力的靶点。
