Department of General Surgery, Shandong University Qilu Hospital, Jinan, China; Department of General Surgery, Yishui Central Hospital, Linyi, China.
Department of Pharmacy, Shandong Provincial Hospital, Jinan, China.
Biochem Biophys Res Commun. 2014 Sep 26;452(3):614-21. doi: 10.1016/j.bbrc.2014.08.124. Epub 2014 Aug 30.
Overexpressions of EGFR and HER2 are thought to be prognostic factors of cholangiocarcinoma (CCA). The SOX4 transcription factor is involved in the development and cell fate decision. Although up-regulation of SOX4 has been described in multiple human malignancies, the prognostic value of SOX4 and its relationship to EGFR/HER2 in CCA remain unclear. In the current study, we showed that SOX4 and EGFR were overexpressed in 17 (29.3%), and 13 (22.4%) of the 58 intrahepatic cholangiocarcinomas (IHCCs), as well as 28 (29.8%), and 33 (35.1%) of the 94 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, with the rate being 4.4% (4/90). In all, amplification of EGFR was identified in 1.8% (1/52) of IHCC cases, and in 2% (3/82) of EHCC cases. By contrast, HER2 amplification was present only in 3.5% (3/94) of the EHCC cases. Notably, Kaplan-Meier survival analysis suggested that SOX4 expression is a significant prognostic factor for poor prognosis in IHCC patients. Importantly, our findings suggested significant association of SOX4 and EGFR expression both in IHCC (P<0.001) and EHCC (P=0.014). SOX4 may modulate expression of EGFR, and SOX4+/EGFR+ defines a subset of CCA patients with poor prognosis. Finally, in vitro data indicated that SOX4 inhibits cellular migratory capacity and promotes epithelial-mesenchymal transition (EMT) process of CCA cells. Collectively, our results define an important role for SOX4 in CCA by orchestrating EMT and modulation on EGFR expression. SOX4 expression may serve as a prognostic marker for patients with IHCC.
SOX4 转录因子与胆管癌（CCA）的发生和细胞命运决定有关。虽然已经描述了 SOX4 在多种人类恶性肿瘤中的上调，但 SOX4 的预后价值及其与 CCA 中的 EGFR/HER2 的关系仍不清楚。在本研究中，我们表明 SOX4 和 EGFR 在 58 例肝内胆管癌（IHCC）中的 17 例（29.3%）和 13 例（22.4%），以及 28 例（29.8%）和 33 例（35.1%）中过表达。外胆管癌（EHCC）。HER2 的过表达仅在 EHCC 中被鉴定，其发生率为 4.4%（4/90）。总体而言，IHCC 病例中 EGFR 的扩增率为 1.8%（1/52），EHCC 病例中为 2%（3/82）。相比之下，HER2 扩增仅存在于 3.5%（3/94）的 EHCC 病例中。值得注意的是，Kaplan-Meier 生存分析表明 SOX4 表达是 IHCC 患者预后不良的显著预后因素。重要的是，我们的研究结果表明 SOX4 和 EGFR 表达在 IHCC（P<0.001）和 EHCC（P=0.014）中均存在显著相关性。SOX4 可能调节 EGFR 的表达，SOX4+/EGFR+定义了一组预后不良的 CCA 患者。最后，体外数据表明 SOX4 抑制 CCA 细胞的迁移能力并促进上皮-间充质转化（EMT）过程。总之，我们的研究结果通过协调 EMT 和对 EGFR 表达的调节，定义了 SOX4 在 CCA 中的重要作用。SOX4 表达可作为 IHCC 患者的预后标志物。
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