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| Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis | |
| 2021-12 | |
| 发表期刊 | HEPATOLOGY (IF:12.9[JCR-2023],15.5[5-Year]) |
| ISSN | 0270-9139 |
| EISSN | 1527-3350 |
| DOI | 10.1002/hep.32064 |
| 摘要 | Background and Aims Insulin receptor (IR) transduces cell surface signal through phosphoinositide 3-kinase (PI3K)-AKT pathways or translocates to the nucleus and binds to the promoters to regulate genes associated with insulin actions, including de novo lipogenesis (DNL). Chronic activation of IR signaling drives malignant transformation, but the underlying mechanisms remain poorly defined. Down-regulation of fructose-1,6-bisphosphate aldolase (ALDO) B in hepatocellular carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and how ALDOB is involved in IR signaling in HCC. Approach and Results Global or liver-specific ALDOB knockout (L-ALDOB(-/-)) mice were used in N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB expression was achieved in L-ALDOB(-/-) mice by adeno-associated virus (AAV). C-13(6)-glucose was employed in metabolic flux analysis to track the de novo fatty acid synthesis from glucose, and nontargeted lipidomics and targeted fatty acid analysis using mass spectrometry were performed. We found that ALDOB physically interacts with IR and attenuates IR signaling through down-regulating PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and tumorigenesis, which is significantly attenuated with ALDOB restoration in L-ALDOB(-/-) mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in ALDOB-R43A, whereas knockdown IR sufficiently diminishes tumor-promoting effects in both mutants. Furthermore, inhibiting phosphorylated AKT or fatty acid synthase significantly attenuates HCC in L-ALDOB(-/-) mice. Consistently, ALDOB down-regulation is correlated with up-regulation of IR signaling and DNL in human HCC tumor tissues. Conclusions Our study reports a mechanism by which loss of ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to promote DNL and HCC, highlighting a potential therapeutic strategy in HCC. |
| 收录类别 | SCIE |
| 语种 | 英语 |
| WOS研究方向 | Gastroenterology & Hepatology |
| WOS类目 | Gastroenterology & Hepatology |
| WOS记录号 | WOS:000690766600001 |
| 出版者 | WILEY |
| 原始文献类型 | Article; Early Access |
| 引用统计 | 正在获取...
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| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/128100 |
| 专题 | 生命科学与技术学院_博士生 生命科学与技术学院_特聘教授组_尹慧勇组 |
| 通讯作者 | Tao, Yongzhen; Yin, Huiyong |
| 作者单位 | 1.Univ Chinese Acad Sci UCAS, Chinese Acad Sci CAS, Shanghai Inst Nutr & Hlth SIKH, CAS Key Lab Nutr, Shanghai, Peoples R China; 2.Shanghai Eastern Hepatobiliary Surg Hosp, Dept Hepat Surg 1, Ward 1, Shanghai, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 4.Minist Hlth, Key Lab Food Safety Risk Assessment, Beijing, Peoples R China |
| 通讯作者单位 | 生命科学与技术学院 |
| 推荐引用方式 GB/T 7714 | Liu, Guijun,Wang, Ningning,Zhang, Cunzhen,et al. Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis[J]. HEPATOLOGY,2021. |
| APA | Liu, Guijun.,Wang, Ningning.,Zhang, Cunzhen.,Li, Min.,He, Xuxiao.,...&Yin, Huiyong.(2021).Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis.HEPATOLOGY. |
| MLA | Liu, Guijun,et al."Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis".HEPATOLOGY (2021). |
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