SOX4 与前列腺癌的不良预后相关，并促进体外上皮间质转化。
SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro.
机构信息
1] Department of Pathology, Shandong University Medical School, Jinan, China [2] Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan, China.
出版信息
Prostate Cancer Prostatic Dis. 2013 Dec;16(4):301-7. doi: 10.1038/pcan.2013.25. Epub 2013 Aug 6.
BACKGROUND
The SOX4 transcription factor is involved in the development and cell fate decision. Although upregulation of SOX4 has been described in human prostate cancer (PCa), the prognostic value of SOX4 and its exact role in PCa progression remain unclear.
METHODS
Three tissue microarrays were constructed from 241 Chinese PCa patients who underwent TURP. Immunohistochemistry (IHC) was used to detect the expression of SOX4. Genetic aberrations of epidermal growth factor receptor and HER2 were detected by fluorescence in situ hybridization. The effect of SOX4 on proliferation was evaluated by MTT (methyl thiazolyl tetrazelium), and cell migration and invasion were evaluated by transwell and wound-healing assays. The distribution of cell-cycle phase was analyzed by flow cytometry. Real-time PCR and western blot were used to study transcript and protein levels.
RESULTS
Using tissue microarray, we found that SOX4 was overexpressed in 33.0% (76/230) Chinese PCa patients by IHC. SOX4 overexpression was significantly associated with high Gleason scores (P=0.009) and the presence of distant metastasis (P=0.023). Additionally, SOX4 overexpression was significantly correlated with high Ki67 labeling index (P=0.005) and tended to associate with amplification of HER2 (P=0.052) in our cohort. Notably, SOX4 was correlated with cancer-specific mortality of PCa patients by Kaplan-Meier analysis (P=0.001). Multivariate Cox regression analysis indicated that SOX4 was an unfavorable independent prognostic factor in Chinese PCas (P=0.017). SOX4 overexpression enhanced proliferation of Vcap cells and siRNA knockdown of SOX4 significantly decreased Vcap cell migration and invasion, suggesting a role of SOX4 in cancer metastasis. Additionally, flow cytometry DNA analysis revealed that siRNA SOX4 leads to significant accumulation of cells in the S phase and marked decrease of cells in the G2/M phase. Further in vitro study revealed that SOX4 silencing could inhibit TGF-β (transforming growth factor-β)-induced epithelial-mesenchymal transition (EMT) in Vcap cells. Overexpression of SOX4 could promote the EMT phenotype in Vcap cells.
CONCLUSIONS
Our results define an important role for SOX4 in the progression of PCa by orchestrating EMT and may serve as a prognostic marker for PCa patients.
背景
SOX4 转录因子参与了人类前列腺癌（PCa）的发生和细胞命运决定。尽管已有研究表明 SOX4 在人前列腺癌中上调，但 SOX4 的预后价值及其在 PCa 进展中的确切作用仍不清楚。
方法
从 241 名接受 TURP 的中国 PCa 患者中构建了 3 个组织微阵列。免疫组织化学（IHC）用于检测 SOX4 的表达。通过荧光原位杂交检测表皮生长因子受体和 HER2 的遗传异常。通过 MTT（噻唑蓝）评估 SOX4 对增殖的影响，通过 Transwell 和划痕愈合实验评估细胞迁移和侵袭。通过流式细胞术分析细胞周期相分布。实时 PCR 和 Western blot 用于研究转录本和蛋白水平。
结果
使用组织微阵列，我们通过 IHC 发现 33.0%（76/230）的中国 PCa 患者中 SOX4 过表达。SOX4 过表达与高 Gleason 评分（P=0.009）和远处转移的存在显著相关（P=0.023）。此外，在我们的队列中，SOX4 过表达与高 Ki67 标记指数显著相关（P=0.005），并且倾向于与 HER2 的扩增相关（P=0.052）。值得注意的是，Kaplan-Meier 分析表明 SOX4 与 PCa 患者的癌症特异性死亡率相关（P=0.001）。多变量 Cox 回归分析表明，SOX4 是中国 PCa 中不利的独立预后因素（P=0.017）。SOX4 过表达增强了 Vcap 细胞的增殖，而 siRNA 敲低 SOX4 显著降低了 Vcap 细胞的迁移和侵袭，表明 SOX4 在癌症转移中发挥作用。此外，流式细胞术 DNA 分析显示，siRNA SOX4 导致 S 期细胞显著积累，G2/M 期细胞显著减少。进一步的体外研究表明，SOX4 沉默可抑制 TGF-β（转化生长因子-β）诱导的 Vcap 细胞上皮-间质转化（EMT）。SOX4 的过表达可促进 Vcap 细胞的 EMT 表型。
结论
我们的结果通过协调 EMT 定义了 SOX4 在 PCa 进展中的重要作用，并且可能成为 PCa 患者的预后标志物。
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