Deleted in liver cancer 1 isoforms are distinctly expressed in human tissues, functionally different and under differential transcriptional regulation in hepatocellular carcinoma.
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.
Ko
Frankie Chi Fat
FC
Liver Cancer and Hepatitis Research Laboratory, Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
Yeung
Yin-Shan
YS
Wong
Chun-Ming
CM
Chan
Lo-Kong
LK
Poon
Ronnie Tung Ping
RT
Ng
Irene Oi-Lin
IO
Yam
Judy Wai Ping
JW
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
C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins