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A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation.

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机构： [a]Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA [b]Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China [c]Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China [d]Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

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Type 2 Diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). We have previously described that haploinsufficiency of nuclear receptor coactivator 5 (NCOA5) is a genetic defect linking glucose intolerance to HCC. Here we report identification and characterization of a single nucleotide variation (T445A) in NCOA5, causing an amino acid Thr to Ala substitution, in adjacent non-tumorous liver tissues derived from patients with concurrent HCC and T2D. By using Tet-On inducible expression cells, we show that ectopic expression of NCOA5wt suppressed proliferation of HCC cells via induction of G2/M arrest, while ectopic expression of NCOA5T445A had a significantly lesser effect compared to ectopic expression of NCOA5wt. Furthermore, ectopic expression of NCOA5wt increased the occurrence of DNA damage and cell senescence, whereas expression of NCOA5T445A partly lost this activity. Xenograft tumor model analysis demonstrated that ectopic NCOA5wt expression reduced HCC tumor growth and the T445A variation impairs its tumor growth inhibitory function. Collectively, our data show that the T445A variation impairs the ability of NCOA5 to inhibit growth of HCC, suggesting that this variation may have potential to increase susceptibility to HCC comorbid with T2D. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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出版当年[2016]版：

大类 | 2 区医学

小类 | 2 区肿瘤学

最新[2025]版：

大类 | 1 区

医学

小类 | 2 区肿瘤学

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第一作者机构： [a]Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA

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通讯机构： [a]Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA [b]Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China [*1]Department of Physiology, Michigan State University, 3193 Biomedical and Physical Sciences Building, East Lansing, MI, 48824-3320, USA. [*2]Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.

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