王红阳院士Journal of Hepatology发表肝癌神经调控新成果
第二军医大学 · 2016/05/14
近日国际著名肝脏疾病杂志Journal of Hepatology(最新影响因子11.665)在线发表了第二军医大学附属东方肝胆外科医院研究论文,证实了β2肾上腺素能受体信号通路在肝癌进展和索拉菲尼耐药中发挥重要作用。


近日国际著名肝脏疾病杂志Journal of Hepatology(最新影响因子11.665)在线发表了第二军医大学附属东方肝胆外科医院题为“ADRB2 Signaling Promotes HCC Progression and Sorafenib Resistance by Inhibiting Autophagic Degradation of HIF1α”的研究论文,证实了β2肾上腺素能受体信号通路在肝癌进展和索拉菲尼耐药中发挥重要作用。中国工程院院士王红阳(Hong-yang Wang)教授和第二军医大学的杨文(Wen Yang) 博士是这篇论文的共同通讯作者。

微环境与肿瘤发生、发展、转移和对治疗的反应密切相关。近年来,神经系统和神经递质在肿瘤微环境中的作用逐渐受到关注。β2肾上腺素能受体(the beta-2 adrenergic receptor (ADRB2))信号通路在机体应激反应、细胞增殖、能量代谢以及肿瘤发生、发展中发挥着重要作用,但其调控肝细胞癌发生、发展的具体分子机制尚未阐明。

在这项研究中,研究人员发现肾上腺素能促进小鼠DEN诱导的肝癌发生,这一作用可被β2肾上腺素能受体的特异性抑制剂ICI118,551阻断,提示β2肾上腺素能受体信号通路在肝癌发生、发展中具有重要作用。进一步研究发现,β2肾上腺素能受体(ADRB2)信号通路通过激活AKT干预了Beclin1/Vps34/Atg14复合体的形成,从而抑制肝癌细胞自噬的发生,并导致重要转录因子HIF1α的自噬性降解减少,导致肝癌细胞代谢重编程,促进其体内成瘤能力的增强。相反,干扰ADRB2或使用ADRB2特异性抑制剂ICI118,551可增强肝癌细胞自噬水平,促进HIF1α的自噬性降解,导致肝癌细胞体内成瘤能力下降。

更为重要的是,研究人员还发现ADRB2信号通路在索拉菲尼耐药中发挥着至关重要的作用。ADRB2信号通路的激活导致肝癌细胞对索拉菲尼的耐受性增强。常用的口服降压药普萘洛尔(非选择性β肾上腺素能受体阻滞剂)不仅能通过抑制ADRB2信号通路活性抑制肝癌细胞在裸鼠皮下的生长,而且可以增强肝癌细胞对索拉菲尼的敏感性。

因此,这项研究不仅进一步阐明了ADRB2信号通路促进肝癌发生、发展的具体机制,而且提示靶向ADRB2信号通路,尤其是常用的口服降压药普萘洛尔在肝癌的预防、治疗和改善索拉菲尼耐药中可能具有重要的应用价值。

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  • ADRB2 Signaling Promotes HCC Progression and Sorafenib Resistance by Inhibiting Autophagic Degradation of HIF1α

    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 HIF1a 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 hypoxia-inducible factor-1α (HIF1α) 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, HIF1a destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. Consistently, ADRB2 expression correlated positively with HIF1a 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 HCC cell proliferation and survival. ADRB2 signaling negatively regulated autophagy, leading to hypoxia-inducible factor-1α (HIF1α) stabilization, reprogramming of HCC cells glucose metabolism, and the acquisition of resistance to sorafenib. Adrenoceptor antagonist appears to be a putative novel treatment for HCC and chemoresistance

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