RTEL1通过维持端粒长度及调控ELK1磷酸化促进胶质瘤发生发展的机制研究

Glioma is the most common type of primary central nervous system (CNS) tumors, and is characterized by high recurrence and mortality rates due to high proliferation and invasion potentials of glioma cells. There is a growing body of evidence suggesting that aberrant telomere biology may be closely associated with different types of cancer including gliomas. The previous studies have demonstrated that regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends, and plays an important role in glioma tumorigenesis. Our preliminary data showed that RTEL1 was highly expressed in a cohort of gliomas and cell lines. Moreover, knocking down RTEL1 expression in glioma cell lines dramatically inhibited cell proliferation, colony formation, invasion and migration, and induced cell cycle arrest and apoptosis. In addition, we also found that RTEL1 caused aberrant expression of a panel of cancer-related genes and regulated the levels of ELK1 phosphorylation by using gene expression and phosphorylation antibody microarray. As a result of our preliminary data, we speculate the RTEL1 promotes glioma tumorigenesis by other unknown mechanisms in addition to maintaining telomere length. Thus, the aims of this project were: 1) to explore the biological roles of RTEL1 in glioma tumorigenesis; 2) to identify its downstream target genes; 3) to clarify molecular mechanisms underlying the regulation of ELK1 phosphorylation by RTEL1.

胶质瘤是颅内最常见的恶性肿瘤，恶性度高，易复发，预后差。端粒酶的激活及端粒的延长与肿瘤细胞的永生性和恶性程度关系密切，包括胶质瘤。研究发现端粒延长解旋酶调节子1（RTEL1）参与端粒长度的维持，在肿瘤发生发展中发挥重要作用。我们的前期研究显示RTEL1在胶质瘤组织及细胞系中表达显著上调，其表达增高与胶质瘤患者的不良预后密切相关。在胶质瘤细胞中敲减RTEL1基因不但能缩短肿瘤细胞的端粒长度，且能抑制细胞增殖、侵袭等恶性行为。此外，通过基因表达谱和磷酸化抗体芯片等手段，我们证实RTEL1可导致一些基因的表达异常，并且能调控转录因子ELK1的磷酸化水平。因此，我们推测RETL1除了通过维持端粒长度外，还可以通过其它的途径促进胶质瘤的进展。本项目旨在进一步明确RTEL1在胶质瘤发生发展中的功能，绘制其基因调控网络，阐明RTEL1调控ELK1磷酸化的分子机制，为胶质瘤的治疗提供新的靶点和思路。