SOX9通过miR-203a调控mTOR信号通路促进食管癌进展的分子机制

SOX9 is highly expressed in esophageal cancer and is associated with cancer stem cell characteristics and poor prognosis. Results of the whole transcriptome and miRNA screening suggested that SOX9 might regulate the mTOR signaling pathway through miRNA at the post-transcriptional level. Bioinformatics analysis revealed that the promoter region of miR-203a could be directly bound by SOX9, and its target genes included multiple key components of PI3K/AKT/mTOR cascade. Previous studies also confirmed a negative correlation between SOX9 and miR-203a expression in esophageal cancer tissues. We hypothesize that abnormally high expression of SOX9 in esophageal cancer may down-regulate the expression of miR-203a as a transcriptional inhibitor, thereby relieving its negative regulation of PI3K/AKT/mTOR cascade, and ultimately promoting the acquisition of tumor stem cell-like characteristics. Therefore, based on the previous work, this project intends to clarify the impact of SOX9 on the characteristics of cancer stem cells and reveal the molecular mechanism of SOX9 activation of the mTOR cascade and tumor stem cell properties via miR-203a. This project will also investigate the feasibility of targeting the SOX9/miR-203a/mTOR axis in inhibiting tumor growth, providing preclinical evidence for the targeted therapy of esophageal cancer with high SOX9 expression.

SOX9在食管癌中高表达并与干细胞特性和患者的不良预后相关。我们运用全转录组芯片和miRNA芯片筛选的结果提示SOX9可能通过miRNA在转录后水平调控mTOR信号通路；生物信息学分析发现miR-203a的启动子区域能被SOX9直接结合，且其靶基因包括PI3K/AKT/mTOR级联信号的多个关键成分；前期研究也证实食管癌组织中SOX9与miR-203a的表达呈负相关。我们提出假设：食管癌中异常高表达的SOX9可能作为miR-203a的转录抑制因子下调其表达，进而解除其对PI3K/AKT/mTOR级联信号的负调控，最终促进肿瘤干细胞特性和肿瘤的发生发展。因此，本项目拟在前期工作的基础上，明确SOX9对食管癌干细胞特性的影响，揭示SOX9通过miR-203a调控mTOR级联信号以及肿瘤干细胞特性的分子机制，解析靶向该信号通路抑制肿瘤生长的可行性，为SOX9高表达食管癌的靶向治疗提供临床前证据。

SOX9在食管鳞癌组织中高表达并与肿瘤干细胞特性和患者的不良预后相关。项目组运用miRNA芯片筛选的结果提示SOX9可能通过miRNA在转录后水平调控PI3K/AKT/mTOR信号通路；生物信息学分析发现miR-203a的启动子区域能被SOX9直接结合，且miR-203a的靶基因包括PI3K/AKT/mTOR级联信号的多个关键成分；前期研究也证实食管鳞癌组织中SOX9与miR-203a的表达呈负相关。通过本项目的实施，我们发现食管鳞癌中异常高表达的SOX9通过作为转录抑制因子来下调miR-203a的表达，进而解除其对PI3K/AKT级联信号的负调控，最终促进自我更新、化疗抵抗等肿瘤干细胞样特性。本项目揭示了以SOX9基因为核心的调控肿瘤干细胞特性促进食管鳞癌浸润转移的分子机制，提示SOX9等肿瘤干细胞标志物可以作为分层筛选食管鳞癌患者进行个体化治疗的依据及潜在新型治疗靶点，为食管鳞癌早期诊断、预后评估和分子靶向治疗提供了理论依据。相关研究结果在Cancer Letters、Journal of Translational Medicine、安徽医科大学学报等国内外期刊发表学术论文6篇，均标注基金资助；指导3名硕士研究生完成学业。