NCOA5 Haploinsufficiency Results in Glucose Intolerance and Subsequent Hepatocellular Carcinoma

Type 2 diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC exclusively in male mice. Tumor development is preceded by increased interleukin-6 (IL-6) expression...

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Bibliographic Details
Published in:Cancer cell 2013-12, Vol.24 (6), p.725-737
Main Authors: Gao, Shenglan, Li, Aimin, Liu, Feiye, Chen, Fengsheng, Williams, Mark, Zhang, Chengliang, Kelley, Zakiya, Wu, Chin-Lee, Luo, Rongcheng, Xiao, Hua
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Carcinoma, Hepatocellular - etiology
Fatty Liver - etiology
Female
Glucose Intolerance - etiology
Haploinsufficiency
Humans
Interleukin-6 - genetics
Interleukin-6 - physiology
Liver Neoplasms - etiology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Middle Aged
Nuclear Receptor Coactivators - genetics
Promoter Regions, Genetic
Receptors, Androgen - genetics
STAT3 Transcription Factor - physiology
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Summary:Type 2 diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC exclusively in male mice. Tumor development is preceded by increased interleukin-6 (IL-6) expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced NCOA5 expression is associated with a fraction of human HCCs and HCCs with comorbid T2D. These findings suggest that NCOA5 is a haploinsufficient tumor suppressor and that NCOA5 deficiency increases susceptibility to both glucose intolerance and HCC, partially by increasing IL-6 expression. Thus, our findings open additional avenues for developing therapeutic approaches to combat these diseases. •NCOA5 haploinsufficiency causes glucose intolerance and HCC exclusively in male mice•NCOA5 haploinsufficiency results in hepatic inflammation and steatosis in male mice•NCOA5-haploinsufficiency-induced HCC depends partially on IL-6 overexpression•Lower NCOA5 expression is associated with human HCCs and HCCs with comorbid T2D
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.11.005