DNA解旋酶RECQL1调控宫颈癌细胞端粒稳态及放射敏感性的机制研究

Our preliminary results showed that the expression of DNA helicase RECQL1 was increased in the established radioresistant C33AR cervical cancer cells. Moreover,we demonstrated that targeting inhibition of RECQL1 expression in C33AR cells increased their radiosensitivity to radiotherapy through induction of telomere dysfunction. Our results suggested that RECQL1 is an important determinant of cellular radioresistance in cervical cancer. Firstly,the project intends to further study the relationship between RECQL1、telomere homeostasis and radiosensitivity in different radiosensitive cell lines. Then, using the radioresistant C33AR cervical cancer cell line, we aim to investigate the role and mechanisms of RECQL1 knockdown in regulating telomere homeostasis and radiosensitivity. In addition, we will investigated the synergistic radiosensitization effects and mechanisms of RECQL1 knockdown combined with telomerase inhibitor. Lastly ,we aim to use animal tumor models to further study the effects of RECQL1 knockdown on the radiotherapy in vivo. These findings will enrich the theory of radiosensitivity regulation and provide a potent radiosensitization target in clinical radiotherapy.

我们前期研究发现DNA解旋酶RECQL1在宫颈癌放射抗拒细胞模型C33AR中表达显著升高，并发现抑制RECQL1表达能降低端粒酶活性、促进端粒失稳态进而增加宫颈癌C33AR细胞放射敏感性。我们的研究提示RECQL1可能是调控肿瘤放射敏感性的重要靶点。本项目拟进一步探索RECQL1在不同放射敏感性细胞模型中的表达差异，并使用基因沉默技术，研究RECQL1对端粒稳态及放射敏感性的影响；揭示RECQL1通过端粒稳态调节肿瘤细胞放射敏感性的可能机制；阐明抑制RECQL1联合端粒酶抑制剂的协同放射增敏作用及机制；最后采用体内实验验证细胞学实验的结论。通过以上研究阐明RECQL1在放射敏感性调节机制中的作用，丰富放射敏感性调节的理论研究，探讨RECQL1作为抗肿瘤靶点的分子基础和可行性，为实施以RECQL1为靶点的肿瘤放射增敏提供理论和实验依据。