机构：[1]Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA[2]Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA[3]School of Public Health, Guangxi Medical University, Nanning, Guangxi, China[4]Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, Hangzhou, Zhejiang, China[5]Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China[6]Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China[7]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ-/- mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ-/- livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
基金：
NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1R01-CA139158]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81270601, 81328016]
语种：
外文
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区医学
小类|1 区遗传学2 区生化与分子生物学2 区细胞生物学2 区肿瘤学
最新[2023]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者：
第一作者机构：[1]Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
共同第一作者：
通讯作者：
通讯机构：[1]Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA[2]Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA[4]Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, Hangzhou, Zhejiang, China[5]Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China[*1]Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
推荐引用方式(GB/T 7714)：
Z Meng,X Ma,J Du,et al.CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.[J].Oncogene.2017,36(17):2446-2456.doi:10.1038/onc.2016.400.
APA：
Z Meng,X Ma,J Du,X Wang,M He...&W Huang.(2017).CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis..Oncogene,36,(17)
MLA：
Z Meng,et al."CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.".Oncogene 36..17(2017):2446-2456
医学