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

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。

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.