ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1α
ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1α
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DOI：
10.1016/j.jhep.2016.04.019
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发表时间：
2016-08-01
影响因子：
25.7
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Wu, Fu-Quan;Fang, Tian;Wang, Hong-Yang
背景与目的：大量证据表明肾上腺素能信号在肿瘤进展中起重要作用。然而，其在肝细胞癌（HCC）中的作用和潜在的mechanisms仍然unknowed.Methods：肾上腺素在肝癌发生中的作用观察在经典的二乙基亚硝胺诱导的肝癌小鼠模型。在增殖、细胞凋亡、集落形成试验中分析了ADRB 2信号传导抑制对肝癌细胞系的影响。通过免疫印迹、免疫荧光和免疫沉淀测定评估ADRB 2的自噬调节。在裸鼠体内研究了索拉非尼的致瘤性和抗癌作用。ADRB 2和缺氧诱导因子-1 α（HIF 1 α）在150人肝癌标本的表达水平进行了评估通过免疫组化。结果：我们发现，肾上腺素促进DEN诱导的肝癌发生，这是逆转的ADRB 2拮抗剂ICI 118，551。ADRB 2信号在维持HCC细胞增殖和存活中也起着重要作用。值得注意的是，ADRB 2信号通过以Akt依赖性方式破坏Beclin 1/VPS 34/Atg 14复合物来负调节自噬，导致HIF 1a稳定，HCC细胞葡萄糖代谢的重编程，以及对索拉非尼的耐药性的获得。相反，通过ICI 118，551或敲低ADRB 2表达抑制ADRB 2信号传导，导致增强的自噬、HIF 1 α不稳定、肿瘤生长抑制和索拉非尼的抗肿瘤活性改善。一致，ADRB 2表达与HIF 1 α在HCC标本呈正相关，并与HCC outcomes.Conclusions：我们的研究结果揭示了ADRB 2信号在调节HCC进展的重要作用。鉴于ADRB 2调节HCC抑制和索拉非尼耐药的功效，肾上腺素受体拮抗剂似乎是HCC和化疗耐药的一种推定的新疗法。ADRB 2信号负调节自噬，导致缺氧诱导因子-1 α稳定化，肝细胞癌细胞葡萄糖代谢的重编程，以及对索拉非尼耐药的获得。肾上腺素能受体拮抗剂可能是治疗肝癌和耐药的一种新方法。(C)2016年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Considerable evidence suggests that adrenergic signaling played an essential role in tumor progression. However, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms remain unknown.Methods: The effect of adrenaline in hepatocarcinogenesis was observed in a classical diethylnitrosamine-induced HCC mouse model. Effects of ADRB2 signaling inhibition in HCC cell lines were analyzed in proliferation, apoptosis, colony formation assays. Autophagy regulation by ADRB2 was assessed in immunoblotting, immunofluorescence and immunoprecipitation assays. In vivo tumorigenic properties and anticancer effects of sorafenib were examined in nude mice. Expression levels of ADRB2 and hypoxia-inducible factor-1 alpha (HIF1 alpha) in 150 human HCC samples were evaluated by immunohistochemistry.Results: We uncovered that adrenaline promoted DEN-induced hepatocarcinogenesis, which was reversed by the ADRB2 antagonist ICI118,551. ADRB2 signaling also played an essential role in sustaining HCC cell proliferation and survival. Notably, ADRB2 signaling negatively regulated autophagy by disrupting Beclin1/VPS34/Atg14 complex in an Akt-dependent manner, leading to HIF1a stabilization, reprogramming of HCC cells glucose metabolism, and the acquisition of resistance to sorafenib. Conversely, inhibition of ADRB2 signaling by ICI118,551, or knockdown ADRB2 expression, led to enhanced autophagy, HIF1 alpha destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. Consistently, ADRB2 expression correlated positively with HIF1 alpha in HCC specimens and was associated with HCC outcomes.Conclusions: Our results uncover an important role of ADRB2 signaling in regulating HCC progression. Given the efficacy of ADRB2 modulation on HCC inhibition and sorafenib resistance, adrenoceptor antagonist appears to be a putative novel treatment for HCC and chemoresistance.Lay summary: ADRB2 signaling played an essential role in sustaining hepatocellular carcinoma cell proliferation and survival. ADRB2 signaling negatively regulated autophagy, leading to hypoxia-inducible factor-1 alpha stabilization, reprogramming of hepatocellular carcinoma cells glucose metabolism, and the acquisition of resistance to sorafenib. Adrenoceptor antagonist appears to be a putative novel treatment for hepatocellular carcinoma and chemoresistance. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.