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NAD(P)H: Quinone oxidoreductase 1 overexpression in hepatocellular carcinoma potentiates apoptosis evasion through regulating stabilization of X-linked inhibitor of apoptosis protein.

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机构: [a]The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China [b]Medical Examination Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China [c]State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China [d]Department of Hepatobliliary Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China [e]Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, College of Life Sciences, Sichuan University, Chengdu, China [f]Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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关键词: NQO1 Hepatocellular carcinoma X-linked inhibitor of apoptosis protein Apoptosis

摘要:
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAPS87D significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment. Copyright © 2019 Elsevier B.V. All rights reserved.

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出版当年[2019]版:
大类 | 2 区 医学
小类 | 2 区 肿瘤学
最新[2023]版:
大类 | 1 区 医学
小类 | 2 区 肿瘤学
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Q1 ONCOLOGY
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Q1 ONCOLOGY

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第一作者机构: [a]The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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通讯机构: [a]The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China [*1]Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing, 400016, China.
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