PARP抑制剂调控核糖基化介导卵巢癌CD47表达增强的机制研究

PARP inhibitors are the most important targeted drugs in the field of ovarian cancer treatment, but the clinical effect needs to be further improved. Therefore, it is the research hotspot to study the biological regulation mechanism of PARP inhibitor sensitivity in order to improve its curative effect. We have found that PARP inhibitors can significantly up-regulate the expression of CD47 in ovarian cancer cells and cause tumor immune-suppression, which may be an important reason for weakening the clinical effect of PARP inhibitors. Further studies have shown that this effect is closely related to the function of PARP1 in modifying proteins with ADP-ribose ribosylation, a large and unique post-translational modification. Based on these preliminary data, we will investigate the effect of PARP inhibitors on transcription and protein stability of CD47 and analyzed its role immune escape of ovarian cancer. Base on the ribosylation of STAT3 modified by PARP1, we will try to reveal the mechanisms that are responsible for the regulation of CD47 by PARP Inhibitors. Further, we used mouse immunization model to investigate whether CD47 or ribosylation intervention can significantly enhance the therapeutic effect of PARP inhibitor on ovarian cancer. This study will explore the key factors that may impair the therapeutic effect of PARP inhibitors from the new perspective of immune-suppression, not only bring new insight of the biological function of PARP1, find the new regulatory mechanism of CD47, but provide new ideas and strategies to improve the clinical therapy of ovarian cancer.

PARP抑制剂是目前卵巢癌治疗领域最受关注的靶向药物，但临床效果有待提高，因此深入研究影响PARP抑制剂敏感性的生物学调控机制以提高其疗效已成为该领域的研究热点。我们的研究发现PARP抑制剂可显著上调卵巢癌细胞CD47表达，从而引起肿瘤免疫逃逸，可能是削弱PARP抑制剂临床效果的重要原因，且该作用与PARP1蛋白本身的核糖基化修饰功能密切相关。本项目将以此为切入点研究PARP抑制剂对CD47的转录、蛋白稳定性以及对卵巢癌免疫逃逸的影响，揭示PARP1在此过程中的调控作用，围绕PARP1对STAT3的核糖基化修饰，深入研究PARP抑制剂调控CD47的方式及分子机制。在此基础上采用小鼠人源化免疫重构模型考察基于CD47或核糖基化的干预策略能否显著增强PARP抑制剂的治疗作用。通过本研究，不仅可完善PARP1的生物学功能，发现CD47的新调控机制，更为卵巢癌的临床治疗提供新的思路和策略。

聚二磷酸腺苷核糖聚合酶（Poly(ADP-ribose) polymerases，PARP）抑制剂作为靶向PARP1蛋白的小分子抑制剂，通过抑制肿瘤细胞的DNA修复而发挥合成致死效应，PARP抑制剂目前已经获批用于卵巢癌的临床治疗。然而，临床数据显示PARP抑制剂对卵巢癌患者的总生存时间并无显著改善作用，如何进一步提高PARP抑制剂的临床治疗效果成为该领域的焦点问题。我们研究发现PARP抑制剂能显著促进免疫检查点蛋白CD274 (PD-L1)的表达，可能是其临床效果不佳的主要原因。进一步的机制研究表明PARP1蛋白能催化转录因子STAT3发生核糖基化修饰，该修饰使得 STAT3发生去磷酸化，STAT3的转录活性受抑制，PD-L1转录减少。而PARP抑制剂则能解除这种抑制，增强STAT3的转录活性，从而促进PD-L1的转录和表达。在临床卵巢癌组织中，我们进一步确认了PARP1和PD-L1的表达水平呈显著负相关性。我们的研究提示PARP1介导的 STAT3的核糖基化是抑制PD-L1转录的关键步骤，并且这种机制广泛存在于多种癌细胞中，PARP抑制剂引起的PD-L1转录和表达增加是其临床疗效不佳的主要原因。本项目的研究结果一方面揭示了PARP1在肿瘤免疫逃逸中的新生物学功能，发现了PD-L1转录调控的新机制，并从免疫逃逸这一新的角度揭示PARP抑制剂临床疗效欠佳的原因，为PARP抑制剂在临床的进一步应用提供了新的依据和思路。