染色体特异性TERRA调控肝癌细胞生长的作用机制

Telomeric repeat-containing RNA (TERRA) plays an important role in regulating telomere structure and function, and is closely related to tumor and variety of other diseases. The project group had found that TERRA expression in hepatocellular carcinoma was significantly reduced compared with paracancerous tissue， and TERRA could inhibited hepatocellular carcinoma cell growth and metastasis significantly which had been confirmed by functional studies. After more study were conducted through the total 13 of chromosome specific TERRA expression, we surprisely found among which specific TERRA of chromosome 14 were significant prominent. Which indicated specific TERRA of chromosome 14 may play an important role in the development of hepatocellular carcinoma. Based on these findings, this project aims to set up a system of studies on molecule, cellular, cancer tissue and animal model: (1) To unequivocal the high doses of specific TERRA of chromosome 14 in hepatocellular carcinoma compared with paracancerous tissue and the impact on patient prognosis; (2) To clarify the function and mechanism of specific TERRA of chromosome 14 on promotion hepatocellular carcinoma growth; (3) To confirm the possible role and molecular mechanism of specific TERRA of chromosome 14 through MDM2-P53 pathway in regulate hepatocellular carcinoma cell survival. The completion of this project will help us to lay a theoretical foundation for further understanding the molecular mechanism of cancer.

非编码端粒RNA（TERRA）在端粒结构和功能调控中发挥重要功能，且与肿瘤等多种疾病密切相关。本项目组在前期研究中发现：与癌旁组织相比，肝癌组织中总TERRA表达水平显著降低，功能研究证实可显著抑制肝癌细胞生长和转移。进一步观察13个染色体特异性TERRA表达时意外发现：与其它染色体不同，14号染色体特异性TERRA在癌组织表达显著高于癌旁组织。提示该染色体特异性TERRA在肝癌细胞生长中可能具有异于其他染色体的相反功能。基于我们的工作基础及前期发现，本项目拟在分子、细胞、组织和动物四个水平开展系统研究：（1）明确肝癌组织中14号染色体特异性TERRA表达显著高于癌旁组织，且与患者不良预后相关；（2）阐明14号染色体特异性TERRA对肝癌细胞生长具有促进作用；（3）证实14号染色体特异性TERRA通过MDM2-P53信号通路调控肝癌细胞存活。本项目为深入理解肝癌的分子病理机制奠定理论基础。

非编码端粒RNA（TERRA）在端粒结构和功能调控中发挥重要功能，且与肿瘤等多种疾病密切相关。本项目组在前期研究中发现：与癌旁组织相比，肝癌组织中总TERRA表达水平显著降低，功能研究证实可显著抑制肝癌细胞生长和转移。进一步观察13个染色体特异性TERRA表达时意外发现：与其它染色体不同，14号染色体特异性TERRA在癌组织表达显著高于癌旁组织。提示该染色体特异性TERRA在肝癌细胞生长中可能具有异于其他染色体的相反功能。基于我们的工作基础及前期发现，本项目在分子、细胞、组织和动物四个水平开展系统研究，利用肝癌患者组织样本检测TERRA表达与患者预后的关系，进一步利用肝癌细胞系进行TRF1和TRF2干涉、过表达模型构建，明确TRF1和TRF2介导的TERRA对肝癌细胞生长、侵袭和迁移的影响及其调控肝癌恶性进展的分子机制，具体如下：（1）明确肝癌组织中TERRA表达显著高于癌旁组织，且与患者不良预后相关，并阐明了肝癌中TERRA调控其恶性进展的分子机制；（2）阐明染色体特异性TERRA对在胶质瘤中的表达及其与患者预后的影响，进一步阐明在胶质瘤中染色体特异性TERRA与胶质瘤免疫微环境显著相关；本项目为深入理解肝癌的分子病理机制奠定理论基础。