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SOX4 overexpression regulates the p53-mediated apoptosis in hepatocellular carcinoma: clinical implication and functional analysis in vitro.

Authors
Hur, W; Rhim, H; Jung, CK; Kim, JD; Bae, SH; Jang, JW; Yang, JM; Oh, ST; Kim, DG; Wang, HJ; Lee, SB; Yoon, SK
Citation
Carcinogenesis, 31(7):1298-1307, 2010
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
BACKGROUND AND AIMS: 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. Conclusion: 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.
MeSH terms
ApoptosisCarcinoma, Hepatocellular/etiology*Carcinoma, Hepatocellular/pathologyCarcinoma, Hepatocellular/radiotherapyHep G2 CellsHumansLiver Neoplasms/etiology*Liver Neoplasms/pathologyLiver Neoplasms/radiotherapyPromoter Regions, GeneticProtein Structure, TertiarySOXC Transcription Factors/analysisSOXC Transcription Factors/chemistrySOXC Transcription Factors/physiology*Transcriptional ActivationTumor Suppressor Protein p53/physiology*
DOI
10.1093/carcin/bgq072
PMID
20400479
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
AJOU Authors
왕, 희정
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