Peng Xudong, Liu Guangyi, Peng Hongxia, Chen Anqi, Zha Lang, Wang Ziwei
Gastrointestinal Surgical Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
Department of General Surgery, The First People's Hospital, Yibin, Sichuan, 644000 China.
Genes Dis. 2017 Dec 26;5(1):49-61. doi: 10.1016/j.gendis.2017.12.005. eCollection 2018 Mar.
SOX4 is highly expressed in gastric cancer (GC) and is associated with tumor grade, metastasis and prognosis, however the mechanism is not clear. We report herein that SOX4 was upregulated and overexpression of SOX4 was associated with increased expression of the markers of Epithelial-mesenchymal transition (EMT) and stemness in clinic patient samples. In vitro, overexpression of SOX4 promoted the invasion as showed by Transwell assay and stemness of GC cells as assessed by sphere formation assay, which was suppressed by silencing SOX4 with shRNA. Further studies showed that SOX4 up-regulated the expression of EMT transcription factors Twist1, snail1 and zeb1 and stemness transcription factors SOX2 and OCT4, and promoted the nuclear translocation of β-catenin. Moreover, we revealed that TGF-β treatment significantly up-regulated the expression of SOX4 and silencing SOX4 reversed TGF-β induced invasion and sphere formation ability of GC cells. Finally, we showed that SOX4 promoted the lung metastasis and tumor formation ability of gastric cancer cells in nude mice. Our results suggest that SOX4 is a target TGF-β signaling and mediates TGF-β-induced EMT and stem cell characteristics of GC cells, revealing a novel role of TGF-β/SOX4 axis in the regulation of malignant behavior of GC.
SOX4在胃癌（GC）中高表达，且与肿瘤分级、转移及预后相关，但其机制尚不清楚。我们在此报告，在临床患者样本中，SOX4上调，且SOX4的过表达与上皮-间质转化（EMT）和干性标志物的表达增加相关。在体外，Transwell实验显示SOX4过表达促进了GC细胞的侵袭，成球实验评估显示其促进了GC细胞的干性，而用shRNA沉默SOX4可抑制上述作用。进一步研究表明，SOX4上调了EMT转录因子Twist1、snail1和zeb1以及干性转录因子SOX2和OCT4的表达，并促进了β-连环蛋白的核转位。此外，我们发现TGF-β处理显著上调了SOX4的表达，沉默SOX4可逆转TGF-β诱导的GC细胞侵袭和成球能力。最后，我们表明SOX4促进了裸鼠体内胃癌细胞的肺转移和肿瘤形成能力。我们的结果表明，SOX4是TGF-β信号的一个靶点，介导TGF-β诱导的GC细胞EMT和干细胞特性，揭示了TGF-β/SOX4轴在调控GC恶性行为中的新作用。
