SOX4 overexpression regulates the p53-mediated apoptosis in hepatocellular carcinoma: clinical implication and functional analysis in vitro.
OBJECTIVE
The underlying molecular mechanisms of hepatocellular carcinoma (HCC) remain poorly understood due to its complex development process. The human T cell-specific transcription factor sex-determining region Y-related high-mobility group (HMG) box 4 (SOX4) has been linked to development and tumorigenesis. In this study, we characterized the roles of SOX4 in regulation of the p53 transcription activity and evaluated the expression patterns and prognostic value of the transcription factor SOX4 in HCC.


METHODS
The expression levels of human SOX4 were examined in HCC samples obtained from 58 patients having curative partial hepatectomy. The interaction and effects of SOX4 on the p53 pathway were assessed in HCC cell lines. Luciferase reporter assay to examine p53-mediated transcription of target genes was performed. The association of SOX4 expression level with tumor recurrence and overall survival was evaluated.


RESULTS
We showed that the HMG box domain of SOX4 interacted with p53, resulting in the inhibition of p53-mediated transcription by the Bax promoter. More importantly, SOX4 overexpression led to a significant repression of p53-induced Bax expression and subsequent repression of p53-mediated apoptosis induced by gamma-irradiation. In clinicopathological analysis, nuclear overexpression of SOX4 was observed in 37 out of 58 (63.8%) HCC samples, and this correlated with diminished risk of recurrence (P = 0.014) and improved overall survival time (P = 0.045) in HCC patients.


CONCLUSIONS
These results suggest that SOX4 contributes to hepatocarcinogenesis by inhibiting p53-mediated apoptosis and that its overexpression might be a useful prognostic marker for survival after surgical resection.
Hur
Wonhee
W
Department of Internal Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Rhim
Hyangshuk
H
Jung
Chan Kwon
CK
Kim
Jin Dong
JD
Bae
Si Hyun
SH
Jang
Jeong Won
JW
Yang
Jin Mo
JM
Oh
Seong-Taek
ST
Kim
Dong Goo
DG
Wang
Hee Jung
HJ
Lee
Sean Bong
SB
Yoon
Seung Kew
SK
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology / Q000532:radiotherapy; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology / Q000532:radiotherapy; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D055751:SOXC Transcription Factors / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D016159:Tumor Suppressor Protein p53