Jirtle R L, Hankins G R, Reisenbichler H, Boyer I J
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710.
Carcinogenesis. 1994 Aug;15(8):1473-8. doi: 10.1093/carcin/15.8.1473.
Chronic exposure of rats to the liver tumor promoter phenobarbital (PB) significantly reduces the ability of normal hepatocytes, but not of initiated hepatocytes, to respond to mitogenic stimuli. This reduced proliferative ability of normal hepatocytes was correlated with a marked elevation in hepatic concentration of the potent mito-inhibitory factor, transforming growth factor-beta 1 (TGF-beta 1). PB also increased the mannose 6-phosphate/insulin-like growth factor-II (M6P/IGF-II) receptor concentration in hepatocytes, with a concomitant up-regulation in gene expression. Since the M6P/IGF-II receptor facilitates the proteolytic activation of TGF-beta 1, this suggests that PB increases the capacity of normal hepatocytes to activate TGF-beta 1. In contrast, a subset of preneoplastic lesions induced with N-nitrosodiethylamine did not demonstrate elevated levels of the M6P/IGF-II receptor or TGF-beta 1 in response to PB. These findings emphasize the potential importance of TGF-beta 1 during liver tumor promotion with PB and suggest that reduction of M6P/IGF-II receptor levels in liver tumors may provide the tumor cells with an important selective growth advantage.
大鼠长期暴露于肝脏肿瘤启动剂苯巴比妥（PB）会显著降低正常肝细胞对促有丝分裂刺激的反应能力，但对已启动的肝细胞无此影响。正常肝细胞这种增殖能力的降低与强效有丝分裂抑制因子转化生长因子-β1（TGF-β1）肝脏浓度的显著升高相关。PB还增加了肝细胞中甘露糖6-磷酸/胰岛素样生长因子-II（M6P/IGF-II）受体的浓度，并伴随基因表达上调。由于M6P/IGF-II受体促进TGF-β1的蛋白水解激活，这表明PB增加了正常肝细胞激活TGF-β1的能力。相反，用N-亚硝基二乙胺诱导的一部分癌前病变对PB无反应，其M6P/IGF-II受体或TGF-β1水平未升高。这些发现强调了TGF-β1在PB促进肝脏肿瘤过程中的潜在重要性，并表明肝脏肿瘤中M6P/IGF-II受体水平的降低可能为肿瘤细胞提供重要的选择性生长优势。
