title: 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).
  
  
  OBJECTIVE
  This study aimed to document the expression profiles of the three known DLC1 isoforms (alpha, beta and gamma) 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
  DLC1alpha was the most predominant of the three isoforms in the normal human tissues examined, except the heart. The DLC1alpha promoter, but not the DLC1beta and gamma promoter, was hypermethylated and epigenetically silenced in HCC cells. Underexpression of DLC1alpha at the mRNA level was frequently (52.5%, n=52) observed in the 99 HCCs as compared with the corresponding nontumorous liver tissues. DLC1alpha underexpression correlated with poorer tumour cellular differentiation (P=0.010). Functionally, DLC1alpha and beta, but not DLC1gamma, 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. DLC1alpha was underexpressed and clinically relevant in human HCCs.
authors.affiliation: Liver Cancer and Hepatitis Research Laboratory, Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Frankie Chi Fat
authors.initials: FC
authors.lastname: Ko
authors.forename: Yin-Shan
authors.initials: YS
authors.lastname: Yeung
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Lo-Kong
authors.initials: LK
authors.lastname: Chan
authors.forename: Ronnie Tung Ping
authors.initials: RT
authors.lastname: Poon
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.forename: Judy Wai Ping
authors.initials: JW
authors.lastname: Yam
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D020690:GTPase-Activating Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins