Epigenetic Silencing of DACH1 Induces Loss of Transforming Growth Factor-b1 Antiproliferative Response in Human Hepatocellular Carcinoma
19027
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Epigenetic Silencing of DACH1 Induces Loss of Transforming Growth Factor-b1 Antiproliferative Response in Human Hepatocellular Carcinoma

发表时间：2013-12-11 14:05

编辑于 14:05h 学术成果, 研究论文

 

Human dachshund homolog 1 (DACH1) is a major component of the Retinal Determination Gene Network (RDGN) and functions as a tumor suppressor. However, the regulation of DACH1 expression and its function in hepatocellular carcinoma (HCC) remain unclear. In this study, epigenetic changes of DACH1 were analyzed in HCC cell lines and primary cancers. We found that promoter region hypermethylation was correlated with loss or reduction of DACH1 expression, and restoration of DACH1 expression was induced by 5-aza-2 0 -deoxycytidine (5-AZA) in HCC cell lines. Promoter regionmethylation was found in 42% of primary HCC. Reduced expression of DACH1 wasassociated with poor differentiation of HCC nodules and higher serum aspartate amino transferase/alanine aminotransferase ratio. DACH1 suppressed cellular growth by reactivating transforming growth factor beta (TGF-b) signaling. Ectopic expression of DACH1 enhanced chemosensitivity to 5-fluorouracil (5-FU) by inducing p21 expression in HCC cells. Conclusion: DACH1 is frequently methylated in HCC and DACH1 expression is regulated by promoter hypermethylation. Down-regulation of DACH1 is anovel mechanism for gaining resistance to the antiproliferative signaling of TGF-b1 and 5-FU resistance. (H EPATOLOGY 2013; 00:000-000)

第一署名医院：解放军总医院