The AKT-independent MET-V-ATPase-MTOR axis suppresses liver cancer vaccination
The AKT-independent MET-V-ATPase-MTOR axis suppresses liver cancer vaccination
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DOI：
10.1038/s41392-020-0179-x
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发表时间：
2020-08-07
影响因子：
39.3
通讯作者：
Liang, Tingbo
中科院分区：
文献类型：
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作者：
Huang, Xing;Xu, Xingyuan;Liang, Tingbo
尽管近年来肝炎治疗取得了进展，但近年来肝癌疫苗的开发没有取得重大进展。在这项研究中，我们研究了肝细胞生长因子受体（MET，也称为HGFR）对小鼠肝癌肿瘤疫苗的调节作用和潜在机制。在本文中，我们证明MET表达与小鼠和人类肝癌的免疫原性显著相关，并且MET耗竭显著增强了基于化疗的抗肝癌疫苗接种的保护功效。MET抑制肝癌免疫原性的机制不依赖于传统的PI 3 K-AKT级联反应，MET与空泡ATP合酶（V-ATP酶）相互作用并介导雷帕霉素靶蛋白（MTOR）的激活，从而抑制肝癌免疫原性。通过靶向MET-V-ATPase-MTOR轴，基于化疗的肝癌疫苗接种的功效显著增强，突出了用于鉴定用于癌症预防的MET相关候选药物的翻译策略。
Despite recent progress in hepatitis treatment, there have been no significant advances in the development of liver cancer vaccines in recent years. In this study, we investigated the regulatory effect and potential mechanism of hepatocyte growth factor receptor (MET, also known as HGFR) on tumor vaccinations for liver cancer in mice. Herein, we demonstrate that MET expression is significantly associated with the immunogenicity of liver cancer in mice and humans, and that MET depletion dramatically enhances the protective efficacy of chemotherapy-based anti-liver cancer vaccination. Mechanistically, MET repressed liver cancer immunogenicity independent of the traditional PI3K-AKT cascade, and MET interacted with vacuolar ATP synthase (V-ATPase) and mediated the activation of mammalian target of rapamycin (MTOR), thus suppressing liver cancer immunogenicity. The efficacy of chemotherapy-based liver cancer vaccination was markedly enhanced by targeting the MET-V-ATPase-MTOR axis, highlighting a translational strategy for identifying MET-associated drug candidates for cancer prevention.