Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma
Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma
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DOI：
10.1002/hep.28773
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发表时间：
2016-11-01
期刊：
影响因子：
13.5
通讯作者：
Su, Jen-Liang
中科院分区：
文献类型：
--
作者：
Chen, Hsin-An;Kuo, Tsang-Chih;Su, Jen-Liang
血管生成素样蛋白1（ANGPTL 1）已被证明通过抑制血管生成、癌症侵袭和转移而充当肿瘤抑制因子。然而，关于ANGPTL 1对肝细胞癌（HCC）中索拉非尼耐药和癌症干细胞特性的影响以及这些影响的机制知之甚少。在这里，我们发现ANGPTL 1表达与肝癌细胞和人肝癌组织中索拉非尼敏感性呈正相关。ANGPTL 1通过抑制Slug表达显著降低上皮-间质转化（EMT）驱动的索拉非尼耐药性、癌症干细胞性和HCC细胞的肿瘤生长。ANGPTL 1直接与MET受体相互作用并使其失活，MET受体通过抑制细胞外受体激酶/蛋白激酶B（ERK/AKT）依赖性早期生长反应蛋白1（Egr-1）途径而抑制Slug。ANGPTL 1表达与肝癌患者Slug表达、索拉非尼反应性差和临床结局差呈负相关。结论：ANGPTL 1通过抑制MET受体-AKT/ERK-Egr-1-Slug信号级联抑制EMT，从而抑制HCC细胞中的索拉非尼耐药性和癌症干细胞性。ANGPTL 1可能作为一种新的MET受体抑制剂用于晚期HCC的治疗。（肝病学2016;64：1637-1651）
Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)-dependent early growth response protein 1 (Egr-1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. Conclusion: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor-AKT/ERK-Egr-1-Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637-1651)