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Cancer Cell. 2013 Dec 9;24(6):725-37. doi: 10.1016/j.ccr.2013.11.005.

NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.

Author information

1
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
2
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
3
Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
4
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
5
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
6
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
7
Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: luorc01@163.com.
8
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: xiaoh@msu.edu.

Abstract

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.

PMID:
24332041
PMCID:
PMC3891053
DOI:
10.1016/j.ccr.2013.11.005
[Indexed for MEDLINE]
Free PMC Article

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