Department of Core Medical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Mol Cancer. 2021 Jan 23;20(1):20. doi: 10.1186/s12943-021-01315-9.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.
肝细胞癌 (HCC) 是全球最常见的人类恶性肿瘤之一，预后非常差。对索拉非尼等靶向治疗药物的耐药性仍然是临床治疗的主要挑战之一。本研究发现，PARP1 在人胚胎干细胞中高度表达，但在特定的肝分化过程中逐渐减少。在索拉非尼治疗异种移植小鼠模型中的 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可能具有重要作用。PARP1 的过表达在 HCC 患者中经常观察到，并且与不良的临床预后密切相关。索拉非尼治疗诱导 DNA 损伤修复信号的激活，这对于 HCC 残留肿瘤中干细胞多能性的维持是高度活跃和必需的。PARP 抑制剂奥拉帕利广泛抑制 DNA 损伤修复信号，并显著抑制全球多能转录网络。Olaparib 通过 CHD1L 介导的启动子区域染色质结构的凝聚，对关键多能转录因子和 DNA 损伤修复信号的抑制作用。Olaparib 对多能转录组的全面重塑可能增强索拉非尼对 HCC 残留肿瘤的消除作用，并提高治疗效果。
