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β-Catenin Deficiency in Hepatocytes Aggravates Hepatocarcinogenesis Driven by Oncogenic β-Catenin and MET
Hepatology ( IF 13.5 ) Pub Date : 2018-04-06 , DOI: 10.1002/hep.29661
Yan Liang 1 , Yun Feng 1, 2 , Min Zong 1 , Xu-Fu Wei 1, 3 , Jin Lee 1 , Yukuan Feng 4, 5 , Hairi Li 4 , Guang-Shun Yang 2 , Zhong-Jun Wu 3 , Xiang-Dong Fu 4 , Gen-Sheng Feng 1
Affiliation  

Both activating and inactivating mutations in catenin β1 (ctnnb1), which encodes β‐catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein, we show that deletion of endogenous β‐catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of β‐catenin (CAT) in combination with the hepatocyte growth factor receptor MET proto‐oncogene receptor tyrosine kinase (MET). Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the β‐catenin‐deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and up‐regulation of protumorigenic cytokines, including interleukin‐6 and transforming growth factor β1. These events eventually exacerbated CAT/MET‐driven hepatocarcinogenesis in β‐catenin‐deficient livers, featured by up‐regulation of extracellular signal‐regulated kinase (Erk), protein kinase B (Akt), and Wnt/β‐catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. Conclusion: These data argue that while dominantly activating mutants of β‐catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro‐oncogenic microenvironment that may facilitate HCC recurrence following a targeted therapy of the primary tumor. An effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and suppression of the secondary tumor‐promoting stromal effects in the liver microenvironment. (Hepatology 2018;67:1807‐1822)

中文翻译:

肝细胞中的 β-Catenin 缺乏加剧了致癌性 β-Catenin 和 MET 驱动的肝癌发生

编码 β-catenin 的 catenin β1 (ctnnb1) 中的激活和失活突变都与人类和小鼠的肝脏肿瘤发生有关,尽管其潜在机制尚不完全清楚。在此,我们表明肝细胞中内源性 β-catenin 的缺失会加剧由 β-catenin (CAT) 的致癌形式与肝细胞生长因子受体 MET 原癌基因受体酪氨酸激酶 (MET) 共同驱动的肝细胞癌 (HCC) 发展. 尽管 CAT/MET 转染后促有丝分裂信号传导和细胞周期进程轻度受损,但缺乏 β-连环蛋白的肝脏显示出转录组的变化、DNA 损伤反应增加、Sox9+ 细胞扩增以及促肿瘤细胞因子(包括白细胞介素 6)的上调和转化生长因子β1。这些事件最终加剧了 β-catenin 缺陷肝脏中 CAT/MET 驱动的肝癌发生,其特征是细胞外信号调节激酶 (Erk)、蛋白激酶 B (Akt) 和 Wnt/β-catenin 信号传导和细胞周期蛋白 D1 的上调表达。由此产生的小鼠肿瘤显示出与人类 HCC 样本相似的转录组,伴随着 CTNNB1 突变和 MET 过表达。结论:这些数据表明,虽然主要激活 β-catenin 突变体是致癌的,但抑制致癌信号通路会产生促致癌微环境,这可能促进原发肿瘤靶向治疗后 HCC 的复发。有效的治疗策略必须需要破坏肿瘤细胞中的致癌信号并抑制肝脏微环境中的继发性促肿瘤基质效应。
更新日期:2018-04-06
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