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

Department of Internal Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Carcinogenesis (Impact Factor: 5.33). 07/2010; 31(7):1298-307. DOI: 10.1093/carcin/bgq072
Source: PubMed


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.
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.
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.

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    • "In line with this, Sox4 and Sox11 have been described as survival factors during the development of the spinal cord [30] and sympathetic nervous system [22]. Repression of tp53 activity was observed by gain of Sox4 function [18]. In contrast, Sox4 was described as a DNA damage sensor in lung carcinoma cells [32] promoting cell cycle arrest and apoptosis. "
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    ABSTRACT: SoxC genes are involved in many developmental processes such as cardiac, lymphoid, and bone development. The SoxC gene family is represented by Sox4, Sox11, and Sox12. Loss of either Sox4 or Sox11 function is lethal during mouse embryogenesis. Here, we demonstrate that sox4 and sox11 are strongly expressed in the developing eye, heart as well as brain in Xenopus laevis. Morpholino oligonucleotide mediated knock-down approaches in anterior neural tissue revealed that interference with either Sox4 or Sox11 function affects eye development. A detailed analysis demonstrated strong effects on eye size and retinal lamination. Neural induction was unaffected upon Sox4 or Sox11 MO injection and early eye field differentiation and cell proliferation were only mildly affected. Depletion of both genes, however, led independently to a significant increase in cell apoptosis in the eye. In summary, Sox4 and Sox11 are required for Xenopus visual system development.
    PLoS ONE 07/2013; 8(7):e69372. DOI:10.1371/journal.pone.0069372 · 3.23 Impact Factor
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    • "Sox4 has been implicated in cell survival in a variety of cancers (Hur et al., 2010; Pramoonjago et al., 2006; Shen et al., 2010). "
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    ABSTRACT: Gene expression profiling has uncovered the transcription factor Sox4 with upregulated activity during TGF-β-induced epithelial-mesenchymal transition (EMT) in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 (H3K27me3) for gene repression. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT in Sox4-deficient cells. Ezh2-mediated H3K27me3 marks associate with key EMT genes, representing an epigenetic EMT signature that predicts patient survival. Our results identify Sox4 as a master regulator of EMT by governing the expression of the epigenetic modifier Ezh2.
    Cancer cell 06/2013; 23(6):768-83. DOI:10.1016/j.ccr.2013.04.020 · 23.52 Impact Factor
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    • "Therefore, whether SOX4 may act as a tumor suppressor or an oncogene seems to be determined by the function of its interactors and the signal transduction it is involved in. Consistent with the findings of Aaboe et al. [13] in bladder carcinoma and Hur et al. [14] in hepatocellular carcinoma, our data shown that the expression levels of SOX4 in moderately or poorly differentiated PGC was significantly lower than that in well-differentiated PGC. The decreased expression of SOX4 was also significantly associated with advanced pathologic T stage, advanced clinical stage, and positive nodal metastasis, suggesting that SOX4 expression might be of clinical relevance in the aggressiveness of PGC. "
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    ABSTRACT: SOX4, as a member of the SRY-related HMG-box (SOX) transcription factor family, has been demonstrated to be involved in tumorigenesis of many human malignancies; however, its role in primary gallbladder carcinoma (PGC) is still largely unknown. The aim of this study was to investigate SOX4 expression in PGC and its prognostic significance. From 1997 to 2006, 136 patients underwent resection for PGC. The median follow-up was 12.8 months. Immunostainings for SOX4 were performed on these archival tissues. The correlation of SOX4 expression with clinicopathological features including survival was analyzed. SOX4 was expressed in 75.0% (102/136) of PGC but not in the normal epithelium of the gallbladder. In addition, the over-expression of SOX4 was significantly associated with low histologic grade (P = 0.02), low pathologic T stage (P = 0.02), and early clinical stage (P = 0.03). The levels of SOX4 immunostainings in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Moreover, Kaplan-Meier curves showed that SOX4 over-expression was significantly related to better overall (P = 0.008) and disease-free survival (P = 0.01). Furthermore, multivariate analyses showed that SOX4 expression was an independent risk factor for both overall (P = 0.03, hazard ratio, 3.682) and disease-free survival (P = 0.04, hazard ratio, 2.215). Our data indicate for the first time that the over-expression of SOX4 in PGC was significantly correlated with favorable clinicopathologic features and was an independent prognostic factor for better overall and disease-free survival in patients. Therefore, SOX4 might be an auxiliary parameter for predicting malignant behavior for PGC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 04/2012; 7(1):41. DOI:10.1186/1746-1596-7-41 · 2.60 Impact Factor
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