PARP1通过Poly(ADP-ribose)多聚化修饰CHD1L调节肝癌细胞逆向分化和干细胞特性的分子机制研究

Tumor differentiation is closely associated with the stem cell properties and prognosis of HCC patients. HCC with poor differentiation is usually characterized with embryonic stem cells or liver progenitor cell properties. However, the molecular mechanism in regulating HCC dedifferentiation and cancer stem cell properties is still not clear. Recently, we found the chromatin remodeling protein CHD1L plays important roles in regulating HCC dedifferentiation and stem cell like properties. (Hepatology. 2016). Poly(ADP-ribose) polymerase PARP1 can form complex with CHD1L. Our preliminary data found that PARP1 has similar expression pattern with CHD1L, which is highly expressed in embryonic stem cells and HCC, but have low expression in mature hepatocytes; PARP1 can regulate the expression of progenitor cell specific transcription factors and HCC cancer stem cell like properties. PARP1 might work upstream of CHD1L and be a potential driver gene in regulating HCC dedifferentiation. Based on previous study, we will further investigate the molecular mechanism of PARP1 in regulating HCC dedifferentiation and stem cell like properties through Poly(ADP-ribose) modification of CHD1L. This study might further provide novel therapeutic strategies for HCC treatment.

肝癌的分化水平跟病人预后密切相关。分化水平差的肝癌往往具有早期胚胎干细胞的特性，然而其中的分子调控机制目前仍不清楚。我们最新的研究发现，以CHD1L为代表的染色质结构重构蛋白在调节肝癌逆向分化及干细胞特性方面起重要作用（Hepatology. 2016）。PARP1作为多腺苷二磷酸多聚酶可以对CHD1L进行多聚化修饰；PARP1在胚胎干细胞和HCC中呈现高表达，但在成熟肝细胞中呈现低表达；PARP1可能调节胚胎干细胞特异性转录因子的表达进而影响HCC的干细胞特性。这些证据提示PARP1可能位于CHD1L的上游，在HCC的逆向分化过程中起重要驱动作用。本项目将在前期研究的基础上，深入探讨PARP1是否通过Poly(ADP-ribose)多聚化修饰来调控CHD1L的生物学功能，并进一步阐明PARP1/CHD1L复合物调节肝癌细胞逆向分化和干细胞特性的分子机制，进而为肝癌的临床治疗提供新策略。

肝细胞癌（HCC）是全球最常见的人类恶性肿瘤之一。对靶向治疗药物如索拉非尼的耐药性仍然是临床治疗中的主要挑战之一。本研究发现PARP1在人类胚胎干细胞中高表达，但在特定的肝分化中逐渐减少。在异种移植小鼠模型中接受索拉非尼治疗后的HCC残留肿瘤中也检测到PARP1表达的重新激活，表明PARP1在干细胞多能性和HCC索拉非尼治疗耐药性中的潜在重要作用。在肝癌患者中经常观察到PARP1的过表达，并且与不良的临床预后密切相关。索拉非尼的治疗诱导了DNA损伤修复信号的激活。该信号对于维持HCC残留肿瘤中的干细胞多能性至关重要。PARP抑制剂Olaparib广泛抑制DNA损伤修复信号传导并显著抑制全局多能转录网络。研究发现Olaparib对关键多能转录因子和DNA损伤修复信号的抑制主要是通过CHD1L介导的启动子区域染色质结构的构象改变。Olaparib对多能性转录组的整体改变可能会加强Sorafenib消除HCC残留肿瘤并提高治疗效率。PARP抑制剂Olaparib已经FDA批准用于治疗BRCA突变的晚期卵巢癌患者。由于Olaparib只能应用于BRCA突变的少数肿瘤患者群体，应用范围极其有限。本项研究成果为Olaparib临床治疗肝癌带来重要的理论依据和广阔的临床应用前景。