Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma. 2441 37

In the last years, an increasing number of evidences on the influence of metabolic syndrome on the occurrence of hepatocellular carcinoma (HCC) have been developed. Type 2 mellitus diabetes (T2MD) has been found to increase the occurrence of primary liver tumors and to define a more aggressive carcinogenetic process. Furthermore, several preclinical and observational studies and a recent meta-analysis have shown that anti-diabetic drugs can modify the risk of HCC development in patients with T2DM. However, despite these evidences, underlying molecular mechanisms linking both pathological conditions have to be completely cleared yet. The study published by Gao et al. has found a possible molecular link between the two conditions, describing the predisposition to T2DM and HCC given by the haploinsufficiency of nuclear receptor coactivator 5 (NCOA5) in murine models. The authors have generated Ncoa5+/- (haploinsufficient) male mice and shown that 94% of male mutant mice developed HCC within 18 months of age, this in contrast with Ncoa5+/+ and Ncoa5+/- female mice. These results suggest that NCOA5 haploinsufficiency is linked to HCC development in male mice. Moreover, mutant male mice showed significantly elevated levels of fasting blood glucose and markedly decreased glucose tolerance and insulin sensitivity compared to Ncoa5+/+ littermates. This well-constructed work sheds light on the molecular link between T2DM and HCC and opens the way to further biological and clinical studies in the field of liver tumor prevention and treatment.
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PMID:Glucose intolerance and hepatocellular carcinoma: recent findings for old diseases. 2481 1

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.
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PMID:A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation. 2813 31