Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Carcinogenesis. 2010 Feb;31(2):318-25. doi: 10.1093/carcin/bgp306. Epub 2009 Dec 9.
Nuclear receptor coactivator [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] is a critical component of the mediator transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using the PBP/MED1 liver conditional null (PBP/MED1(DeltaLiv)) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor alpha ligand Wy-14,643-induced receptor-mediated hepatocarcinogenesis. We now examined the role of PBP/MED1 in genotoxic chemical carcinogen diethylnitrosamine (DEN)-induced and phenobarbital-promoted hepatocarcinogenesis. The carcinogenic process was initiated by a single intraperitoneal injection of DEN at 14 days of age and initiated cells were promoted with phenobarbital (PB) (0.05%) in drinking water. PBP/MED1(DeltaLiv) mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1(DeltaLiv) mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1(fl/fl) and PBP/MED1(DeltaLiv) mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1(DeltaLiv) mice were PBP/MED1 positive. None of the tumors was PBP/MED1 negative implying that hepatocytes deficient in PBP/MED1 are not susceptible to neoplastic conversion. HCC that developed in PBP/MED1(DeltaLiv) mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1(fl/fl) genotype. PBP/MED1(fl/fl) HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1(fl/fl) allele by adeno-Cre injection into tumors caused necrosis of tumor cells. These results indicate that PBP/MED1 is essential for the development of HCC in the mouse.
核受体辅激活因子 [过氧化物酶体增殖物激活受体结合蛋白 (PBP)/中介子亚基 1 (MED1)] 是中介转录复合物的关键组成部分。该基因在小鼠中的破坏导致胚胎致死。使用 PBP/MED1 肝条件性缺失 (PBP/MED1(DeltaLiv)) 小鼠，我们报道 PBP/MED1 对于肝再生和过氧化物酶体增殖物激活受体 α 配体 Wy-14,643 诱导的受体介导的肝癌发生是必不可少的。我们现在检查了 PBP/MED1 在遗传毒性化学致癌物二乙基亚硝胺 (DEN) 诱导和苯巴比妥促进的肝癌发生中的作用。致癌过程始于 14 天大的单次腹腔注射 DEN，并通过饮用水中的苯巴比妥 (PB) (0.05%) 促进起始细胞。在 1、4 和 12 周处死的 PBP/MED1(DeltaLiv) 小鼠显示出少数逃避 Cre 介导的 PBP/MED1 基因缺失的残留 PBP/MED1 阳性肝细胞的显著增殖反应。在 PBP/MED1(DeltaLiv) 小鼠肝脏中未观察到 PBP/MED1 缺失肝细胞的增殖扩张。DEN 起始的 PBP/MED1(fl/fl) 和 PBP/MED1(DeltaLiv) 小鼠在 PB 促进后 1 年发展为多个肝细胞癌 (HCC)。有趣的是，在 PBP/MED1(DeltaLiv) 小鼠中发展的所有 HCC 均为 PBP/MED1 阳性。没有一个肿瘤是 PBP/MED1 阴性的，这意味着缺乏 PBP/MED1 的肝细胞不易发生肿瘤转化。在 PBP/MED1(DeltaLiv) 小鼠肝脏中发展的 HCC 可在无胸腺裸鼠中移植，这些小鼠保持 PBP/MED1(fl/fl) 基因型。从这些肿瘤中衍生的 PBP/MED1(fl/fl) HCC 细胞系表达 PBP/MED1，并且通过将腺病毒-Cre 注射到肿瘤中缺失 PBP/MED1(fl/fl) 等位基因导致肿瘤细胞坏死。这些结果表明 PBP/MED1 对于小鼠 HCC 的发展是必不可少的。
