Deleted in liver cancer 1 isoforms are distinctly expressed in human tissues, functionally different and under differential transcriptional regulation in hepatocellular carcinoma

Abstract

Background: Deleted in liver cancer (DLC) is a family of tumour suppressors that plays a critical role in hepatocellular carcinoma (HCC). Aims: This study aimed to document the expression profiles of the three known DLC1 isoforms (α, β and γ) in normal human tissues and human HCCs and address their functional and regulatory differences. We also aimed to determine the clinicopathological and prognostic significance of the DLC1 dominant isoform in human HCCs. Methods: Quantitative polymerase chain reaction was performed to determine the expressions of DLC1 isoforms in different normal human tissues and human HCCs. The clinicopathological and prognostic significance of DLC1 expression in HCC samples was also analysed. In addition, the functional roles of DLC1 isoforms were addressed using HCC cell lines to examine their abilities to suppress stress fibre formation and HCC cell growth. Results: DLC1α was the most predominant of the three isoforms in the normal human tissues examined, except the heart. The DLC1α promoter, but not the DLC1β and γ promoter, was hypermethylated and epigenetically silenced in HCC cells. Underexpression of DLC1α at the mRNA level was frequently (52.5%, n = 52) observed in the 99 HCCs as compared with the corresponding nontumorous liver tissues. DLC1α underexpression correlated with poorer tumour cellular differentiation (P = 0.010). Functionally, DLC1α and β, but not DLC1γ, were localized at focal adhesions of cells and able to inhibit stress fibre formation and suppress HCC cell growth. Conclusions: The results suggested that DLC1 isoforms are differentially expressed in human tissues, have different epigenetic transcriptional regulations and are functionally different. DLC1α was underexpressed and clinically relevant in human HCCs. © 2009 John Wiley & Sons A/S.