AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/β-catenin/CBP signaling pathway
AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/β-catenin/CBP signaling pathway
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AKIP1通过激活Wnt/β-catenin/CBP信号通路促进肝细胞癌早期复发
DOI：
10.1038/s41388-019-0807-5
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发表时间：
2019-07-04
期刊：
影响因子：
8
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Cui, Yanmei;Wu, Xianqiu;Song, Libing
肝细胞癌的早期复发是影响患者长期生存的主要障碍。Wnt/ β -连环蛋白信号通路参与了HCC的发生和发展。然而，Wnt/ β -连环蛋白激活与HCC早期复发之间的分子变化仍然知之甚少。在这里，我们发现AKIP1是β -连环蛋白的结合伙伴。AKIP1通过阻断β -连环蛋白与大肠腺瘤性息肉病蛋白（APC）的相互作用，在细胞核中与β -连环蛋白相互作用并维持其活性。此外，AKIP1增强了蛋白激酶A催化亚基（PKAc）介导的β -catenin磷酸化，导致环AMP反应元件结合蛋白（CBP）的募集和β -catenin下游转录的激活。AKIP1在HCC临床样本中表达升高，与HCC早期复发及预后不良相关。AKIP1促进体外侵袭和菌落生长，并增加体内肝内和肺转移。在细胞系和患者来源的异种移植小鼠模型中，用CBP抑制剂ICG-001治疗可有效抑制AKIP1升高的HCC肿瘤的转移进展。我们的研究结果不仅确立了AKIP1作为Wnt/ β -catenin信号传导和HCC早期复发的新调节剂，而且强调了靶向AKIP1/ β -catenin/CBP轴作为对抗HCC转移性复发的有吸引力的治疗方法。
The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/beta-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/beta-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of beta-catenin. AKIP1 interacted with and sustained beta-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of beta-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of beta-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/beta-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/beta-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.