LncRNA-CH1通过与PTEN蛋白结合促进脊索瘤发生发展的机制研究

Chordoma is a malignant tumor which arise from residual notochord, the pathogenesis of its formation and growth is still unclear, treatment of this tumor is difficult and patients’ prognosis is poor. After lncRNA sequence analysis of Chordoma and fetal notochord tissues, validation in Chordoma tissues and Chordoma cell lines, the applicant found that lncRNA-CH1 is important in the formation and development process of chordoma through binding with PTEN protein. In this project, the applicant plan to use chordoma and notochord tissue, chordoma cell lines, chordoma model in nude mice in the subsequent experiments to explore the mechanism of the tumor promoting effect of lncRNA-CH1, these experiments include specific gene overexpression/knockout of cell lines, function testing of cells and lncRNA/mRNA sequence et al. This project will be carried out according to the following steps: 1) explore the function of lncRNA-CH1 and its regulation mechanism clearly; 2) explain the interaction between lncRNA-CH1 and PTEN protein clearly; 3) evaluate of the lncRNA-CH1 level in tissue samples, and analyze the association of lncRNA-CH1 level and clinical characteristics. Then the functions of lncRNA-CH1 in chordoma will be elucidated, and the molecular mechanism of these functions will be clarified.

脊索瘤是起源于人体未退化脊索组织的恶性肿瘤，治疗棘手，预后差，其发生发展的病理机制尚不明确。LncRNA对恶性肿瘤具有重要调控作用，与肿瘤发生发展密切相关。申请人前期研究发现lncRNA-CH1在脊索瘤中高表达，可与PTEN蛋白结合，与脊索瘤发生发展相关。本项目拟在细胞水平，明确lncRNA-CH1对脊索瘤增殖、凋亡及侵袭具有调控作用，研究lncRNA-CH1可通过抑制PTEN磷酸酶活性，调控PTEN下游肿瘤相关因子表达的作用机制；在脊索瘤裸鼠体内，研究lncRNA-CH1对肿瘤发生发展及PTEN下游肿瘤相关因子基因表达的调控作用；在组织样本中，探讨lncRNA-CH1表达水平与脊索瘤发生、发展及患者临床特点关联性。预期研究结果将明确lncRNA-CH1生物学功能和调控机制，为脊索瘤的诊断和治疗提供分子基础。

本研究通过对实验结果进行分析表明在脊索瘤中lncRNA-CH1促进肿瘤发生发展，主要通过与PTEN蛋白结合抑制PTEN蛋白的磷酸酶活性，进而导致p-AKT，p-mTOR上调，从而促进肿瘤细胞停留于S期和G2期，而导致促进细胞增殖、抑制凋亡、促进肿瘤侵袭和迁移的作用。初步明确了lncRNA-CH1生物学功能和调控机制，为脊索瘤的诊断和治疗提供了分子基础。