IF 12.5 1区 医学 Q1 ONCOLOGY
Rigney E. Turnham, Adriana Pitea, Gwendolyn M. Jang, Zhong Xu, Huat Chye Lim, Alex L. Choi, John Von Dollen, Rebecca S. Levin, James T. Webber, Elizabeth McCarthy, Junjie Hu, Xiaolei Li, Li Che, Ananya Singh, Alex Yoon, Gary Chan, Robin K. Kelley, Danielle L. Swaney, Wei Zhang, Sourav Bandyopadhyay, Fabian J. Theis, Manon Eckhardt, Xin Chen, Kevan M. Shokat, Trey Ideker, Nevan J. Krogan, John D. Gordan
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引用次数: 0

摘要

乙型肝炎病毒(HBV)感染会诱发炎症和细胞应激,从而促进肝癌的发生。尽管乙型肝炎病毒对肝癌发生的影响主要是间接的,但乙型肝炎病毒与 HCC 中反复出现的基因组表型有关,这表明乙型肝炎病毒对已形成的 HCC 的生物学特性有影响。描述 HBV 与宿主蛋白的相互作用以及 HBV 对 HCC 启动和维持的机理贡献,可以让人们深入了解 HCC 的生物学特性,并发现治疗上的薄弱环节。在这里,我们使用亲和纯化质谱法全面绘制了肝细胞癌(HCC)中 HBV 与人类蛋白质之间 145 种物理相互作用的网络。在非 HBV 相关的 HCC 中,HBV 蛋白靶向的宿主因子中有一部分发生了优先突变,这表明它们与 HBV 的相互作用影响了 HCC 的生物学特性。HBV 与参与 mRNA 剪接、有丝分裂信号传导和 DNA 修复的蛋白相互作用,其中后一组蛋白与 HBV 癌蛋白 X(HBx)相互作用。HBx通过将纹蛋白调节亚基从PP2A全酶中排除,重塑了PP2A磷酸酶复合物,HBx对PP2A的影响导致了Hippo激酶的激活。同时,HBx 激活了 mTOR 复合物 2(mTORC2),而 mTORC2 可阻止 YAP 降解。在人类 HCC 标本和小鼠 HCC 模型中观察到了 mTORC2 介导的 YAP 上调,mTOR 激酶抑制剂可将其作为靶点。因此,HBV 与宿主蛋白的相互作用重构了 HCC 信号,而不是直接激活有丝分裂通路,这为肿瘤促进病毒的细胞效应提供了另一种范例。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma
Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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