Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling.
Hippocalcin-Like 1 blunts liver lipid metabolism to suppress tumorigenesis via directly targeting RUVBL1-mTOR signaling.
复制标题
Hippocalcin-Like 1 通过直接靶向 RUVBL1-mTOR 信号传导减弱肝脏脂质代谢，从而抑制肿瘤发生
DOI：
10.7150/thno.75936
复制
发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Chen T;Yuan Z;Lei Z;Duan J;Xue J;Lu T;Yan G;Zhang L;Liu Y;Li Q;Zhang Y
原理：肝细胞癌（HCC）是全球最严重的癌症之一，目前针对HCC的有效靶向治疗方法很少。脂质代谢重编程作为癌症代谢的标志出现，指导对抗肿瘤治疗的反应。癌症中的这种脂质代谢改变受到雷帕霉素mTOR的哺乳动物靶标的关键调节，其被认为是有希望的治疗靶标。尽管做出了努力，mTOR抑制剂（mTORi）在临床上产生了有限的反应，部分原因是对癌症中mTORC 1成瘾的了解不完全。方法：利用CRISPR-Cas9系统建立Hpcal 1基因敲除小鼠。使用Hpcal 1缺陷型小鼠通过水动力学尾静脉注射二乙基亚硝胺（DEN）/CCL 4或MYC/Trp 53-/-来产生小鼠肝癌模型。使用RNA测序（RNA-seq）来鉴定潜在的信号传导途径。采用定量聚合酶链反应（qPCR）、蛋白质印迹和免疫组织化学方法测定HPCAL 1和mTOR信号通路的表达。通过CCK-8测定、集落形成试验和小鼠模型评估Hpcal 1在肝肿瘤发生中的作用及其对mTORi的反应。结果如下：在这项研究中，我们确定了类钙蛋白1（HPCAL 1）作为一个重要的负调节从头脂质生物合成和mTOR信号激活，限制肝肿瘤的发生和建立一个代谢脆弱性的肝癌在小鼠。HPCAL 1的遗传缺失使HCC mTORC 1成瘾，并在体外和体内对mTORi AZD-8055敏感。重要的是，HPCAL 1表达与人类标本中mTOR磷酸化水平和几种关键脂质生物合成酶呈负相关。机制上，HPCAL 1直接结合RuvB样AAA ATP酶1（RUVBL 1），抑制TEL 2-TTI 1-TTI 2（TTT）-RUVBL复合物的组装并随后导致mTOR信号转导抑制。结论：我们发现了代谢脆弱性和mTOR成瘾性HCC与HPCAL 1损失，提供了一个选择性的治疗窗口HCC与mTORC 1超激活使用mTORi。
Rationale: Hepatocellular carcinoma (HCC) is one of the most severe cancers worldwide, with few effective targeted therapies for HCC. Lipid metabolic reprogramming is emerged as a hallmark of cancer metabolism that guides response to antitumoral therapies. Such lipid metabolic alteration in cancers is critically regulated by the mammalian target of rapamycin mTOR, which is considered as a promising therapeutic target. Despite efforts, mTOR inhibitors (mTORi) have produced limited response clinically, partly due to incomplete knowledge of mTORC1 addiction in cancers. Methods: CRISPR-Cas9 system was used to establish Hpcal1 null mice. The liver cancer model in mice was generated using Hpcal1-deficient mice with diethylnitrosamine (DEN) /CCL4 or MYC/Trp53-/- via hydrodynamic tail-vein injection. RNA-sequencing (RNA-seq) was used to identify potential signaling pathways. The expression of HPCAL1 and mTOR signaling were determined using quantitative polymerase chain reaction (qPCR), western blot and immunohistochemistry. The role of Hpcal1 in liver tumorigenesis and its response to mTORi was assessed by CCK-8 measurements, colony formation assay and in mouse model. Results: In this study, we identified hippocalcin-like protein 1 (HPCAL1) as an important negative regulator of de novo lipid biosynthesis and mTOR signaling activation, limiting liver tumorigenesis and establishing a metabolic vulnerability of HCC in mice. Genetic loss of HPCAL1 rendered HCC mTORC1-addicted and sensitive to mTORi AZD-8055 in vitro and in vivo. Importantly, HPCAL1 expression was inversely correlated with the levels of mTOR phosphorylation and several critical lipid biosynthesis enzymes in human specimens. Mechanistically, HPCAL1 directly bound to RuvB Like AAA ATPase 1 (RUVBL1), inhibiting the assembly of TEL2-TTI1-TTI2 (TTT)-RUVBL complex and subsequent leading the mTOR signaling suppression. Conclusion: We uncover a metabolic vulnerability and mTOR addiction in HCC with HPCAL1 loss that provides a selective therapeutic window for HCC with mTORC1 hyperactivation using mTORi.
登录
查看更多内容
影响因子：
14.8
作者：
Lee, Bianca J.;Boyer, Jacob A.;Burnett, G. Leslie;Thottumkara, Arun P.;Tibrewal, Nidhi;Wilson, Stacy L.;Hsieh, Tientien;Marquez, Abby;Lorenzana, Edward G.;Evans, James W.;Hulea, Laura;Kiss, Gert;Liu, Hui;Lee, Dong;Larsson, Ola;McLaughlan, Shannon;Topisirovic, Ivan;Wang, Zhengping;Wang, Zhican;Zhao, Yongyuan;Wildes, David;Aggen, James B.;Singh, Mallika;Gill, Adrian L.;Smith, Jacqueline A. M.;Rosen, Neal
通讯作者：
Rosen, Neal
DOI：
10.1002/hep.32447
发表时间：
2022-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
29
作者：
Lamming DW;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
34.7
作者：
Burgoyne, Robert D.
通讯作者：
Burgoyne, Robert D.
影响因子：
45.3
作者：
Chan, S;Scheulen, ME;Moore, L
通讯作者：
Moore, L