title: NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.
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.
authors: 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.
authors: Shenglan
authors: S
authors: Gao
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors: Aimin
authors: A
authors: Li
authors: Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors: Feiye
authors: F
authors: Liu
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors: Fengsheng
authors: F
authors: Chen
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
authors: Mark
authors: M
authors: Williams
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors: Chengliang
authors: C
authors: Zhang
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors: Zakiya
authors: Z
authors: Kelley
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Chin-Lee
authors: CL
authors: Wu
authors: Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: luorc01@163.com.
authors: Rongcheng
authors: R
authors: Luo
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: xiaoh@msu.edu.
authors: Hua
authors: H
authors: Xiao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D005234:Fatty Liver / Q000209:etiology; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology*; D057895:Haploinsufficiency; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D056918:Nuclear Receptor Coactivators / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011944:Receptors, Androgen / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000502:physiology
chemical_list: D015850:Interleukin-6; C418222:NCOA5 protein, human; D056918:Nuclear Receptor Coactivators; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor