SPT6通过上调hTERT表达促进结肠癌发生发展的分子作用机制和临床意义

端粒酶重要组分hTERT的异常活化是结肠癌发生发展的风向标，发现和确定肿瘤特异性的hTERT转录活化因子意义重大。前期研究中，我们利用磁生物淘洗和蛋白质组学方法，在结肠癌细胞中垂钓并确定了新型的hTERT启动子结合蛋白SPT6，发现其在结肠癌细胞和组织中高表达，调控hTERT转录并影响结肠癌细胞生长，但SPT6在结肠癌细胞中调控hTERT继而影响肿瘤发生发展的具体分子机制和临床意义，尚不清楚。本项目拟在结肠癌细胞和动物模型中敲低或过表达SPT6，研究其对hTERT表达、端粒酶活性、端粒长度、肿瘤干细胞干性以及肿瘤生长的调控，揭示SPT6/hTERT信号通路在结肠癌发生发展中的机制和功能；并利用组织芯片，结合临床资料，分析结肠癌患者组织中二者的表达水平及其相关性，评估其与结肠癌发生、分期、复发、预后的关系，确定其临床意义。本项目将为确立SPT6/hTERT作为结肠癌治疗新靶点提供理论依据。

The elevated hTERT activity is the hallmarker of colon tumorigenesis. It is of significance to discover and identify the tumor-specific factors which regulate hTERT expression in colon cancer. In our preliminary study, we pulled down and identified SPT6 as a new hTERT promoter-binding protein in colon cancer cells by magnetic biopanning technique and proteomics methods. We also showed that SPT6 was highly expressed in colon cancer cells and tissues, regulated hTERT transcription and colon cancer cell growth. However, so far it is still unclear about the molecular mechanisms by which SPT6 regulates hTERT expression and colon tumorigenesis and development as well as its clinical implications. In this study, we will knockdown or overexpress SPT6 in human lung cancer cell lines and animal models, and then study the effects of SPT6 on hTERT expression, telomerase activity, telomere length , the stemness of cancer stem cells and tumor cell growth, thereby revealing the mechanisms of action of the SPT6/hTERT signaling pathway in colon tumorigenesis. Moreover,we will use tissue array, combined with the clinical data, to analyze the expression levels and the correlation of SPT6 and hTERT in tumor tissues from cancer patients, and to evaluate their relationship with colon tumorigenesis, pathological staging, recurrence and prognosis, thereby identifying the clinical implications of SPT6/hTERT. The results from this study will provide theoretical and experimental basis for the identification of the SPT6/hTERT signaling as a new therapeutic target for colon cancer treatment.