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.
|Number of pages||10|
|State||Published - Apr 10 2017|
Bibliographical noteFunding Information:
The authors thank members of the H.X. lab for helpful discussions. This work was supported by National Cancer Institute (R01 CA188305) to H. Xiao, and the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Scientists of the National Natural Science Foundation of China (Grant No. 81428017) to R. Luo. X. Liu and F. Liu were supported in part by fellowships from Southern Medical University, China. F. Chen was supported in part by Youth Fund of the National Natural Science Foundation of China (Grant No. 81502378). C. Yang was supported by National Institute of Health (1R01ES017777-01).
© 2017 The Author(s)
- Hepatocellular carcinoma
- Tumor suppressor
- Type 2 diabetes
ASJC Scopus subject areas
- Cancer Research