San Cecilio University Hospital, Granada, Spain.
Hepatology. 2010 Jan;51(1):255-66. doi: 10.1002/hep.23249.
Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to a lack of effective treatment options. In HCC a significant role is played by DNA damage and the inflammatory response. Poly (ADP-ribose) polymerase-1 (PARP-1) is an important protein that regulates both these mechanisms. The objective of this study was to examine the effect of pharmacology PARP-1 inhibition on the reduction of tumor volume of HCC xenograft and on the hepatocarcinogenesis induced by diethyl-nitrosamine (DEN). Pharmacologic PARP-1 inhibition with DPQ greatly reduces tumor xenograft volume with regard to a nontreated xenograft (394 mm(3) versus 2,942 mm(3), P < 0.05). This observation was paralleled by reductions in xenograft mitosis (P = 0.02) and tumor vasculogenesis (P = 0.007, confirmed by in vitro angiogenesis study), as well as by an increase in the number of apoptotic cells in DPQ-treated mice (P = 0.04). A substantial difference in key tumor-related gene expression (transformed 3T3 cell double minute 2 [MDM2], FLT1 [vascular endothelial growth factor receptor-1, VEGFR1], epidermal growth factor receptor [EPAS1]/hypoxia-inducible factor 2 [HIF2A], EGLN1 [PHD2], epidermal growth factor receptor [EGFR], MYC, JUND, SPP1 [OPN], hepatocyte growth factor [HGF]) was found between the control tumor xenografts and the PARP inhibitor-treated xenografts (data confirmed in HCC cell lines using PARP inhibitors and PARP-1 small interfering RNA [siRNA]). Furthermore, the results obtained in mice treated with DEN to induce hepatocarcinogenesis showed, after treatment with a PARP inhibitor (DPQ), a significant reduction both in preneoplastic foci and in the expression of preneoplastic markers and proinflammatory genes (Gstm3, Vegf, Spp1 [Opn], IL6, IL1b, and Tnf), bromodeoxyuridine incorporation, and NF-kappaB activation in the initial steps of carcinogenesis (P < 0.05).
This study shows that PARP inhibition is capable of controlling HCC growth and preventing tumor vasculogenesis by regulating the activation of different genes involved in tumor progression.
肝细胞癌（HCC）由于缺乏有效治疗方法，预后较差。在 HCC 中，DNA 损伤和炎症反应起着重要作用。多聚（ADP-核糖）聚合酶 1（PARP-1）是一种重要的蛋白质，它调节这两种机制。本研究的目的是研究药理学 PARP-1 抑制对 HCC 异种移植肿瘤体积减少和二乙基亚硝胺（DEN）诱导的肝癌发生的影响。用 DPQ 进行药理学 PARP-1 抑制可使肿瘤异种移植体积相对于未经治疗的异种移植明显减少（394mm3 与 2942mm3，P<0.05）。这种观察结果与异种移植有丝分裂减少（P=0.02）和肿瘤血管生成减少（P=0.007，体外血管生成研究证实）以及 DPQ 治疗小鼠中凋亡细胞数量增加（P=0.04）相平行。在关键肿瘤相关基因表达（转化 3T3 细胞双微体 2[MDM2]、FLT1[血管内皮生长因子受体-1，VEGFR1]、表皮生长因子受体[EPAS1]/缺氧诱导因子 2[HIF2A]、EGLN1[PHD2]、表皮生长因子受体[EGFR]、MYC、JUND、SPP1[OPN]、肝细胞生长因子[HGF]）方面，对照肿瘤异种移植与 PARP 抑制剂治疗的异种移植之间存在显著差异（使用 PARP 抑制剂和 PARP-1 小干扰 RNA[siRNA]在 HCC 细胞系中证实了这一结果）。此外，用 DEN 处理诱导肝癌发生的小鼠的结果表明，用 PARP 抑制剂（DPQ）处理后，在癌前病灶数量以及癌前标记物和促炎基因（Gstm3、Vegf、SPP1[Opn]、IL6、IL1b 和 TNF）的表达、溴脱氧尿苷掺入和 NF-kappaB 激活等方面，均有显著减少（P<0.05）。
本研究表明，PARP 抑制通过调节参与肿瘤进展的不同基因的激活，能够控制 HCC 生长并防止肿瘤血管生成。
