DeCicco L A, Panzeter P L, Cashman R E, Ringer D P
Noble Center for Biomedical Research, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Biochem Biophys Res Commun. 1996 Nov 1;228(1):69-74. doi: 10.1006/bbrc.1996.1617.
To study changes in hepatic capacity for binding epidermal growth factor (EGF) during 2-acetylaminofluorene (2-AAF)-induced, multistage hepatocarcinogenesis, a 5 cycle protocol of discontinuous 2-AAF administration was used to produce hepatocarcinogenesis in rats. The hallmark of the 5 cycle protocol is that rats fed 1 to 3 cycles of 2-AAF are at low risk for cancer, while rats fed 2-AAF for 4 or 5 cycles are at high risk for cancer. EGF binding by liver membranes was found to be lowered to 20-25% of control throughout the 5 cycle regimen. When the persistence of lowered EGF binding was tested by returning rats fed 2-AAF for 1 to 3 cycles to diet without 2-AAF for 3 weeks, binding was found to recover to 80 to 90% of values for control rats. In contrast, for rats fed 2-AAF for 4 or 5 cycles, EGF binding capacity remained low, 30 to 40% of control, following placement of rats on diet without 2-AAF for 3 weeks. Immunochemical analysis indicated a close correspondence between changes in EGF receptor levels and changes in the above EGF binding levels. These studies show that during the 2-AAF protocol, the 2-AAF-mediated loss in hepatic EGF binding capacity and EGF receptor protein undergo a transition from a reversible loss to a persistent loss in binding capacity, and EGF receptor protein, as rats underwent a change from low to high risk for developing hepatocarcinomas. The persistent decrease in hepatic EGF binding level may be associated with the progression stage of hepatocarcinogenesis.
为研究在2-乙酰氨基芴（2-AAF）诱导的多阶段肝癌发生过程中肝脏结合表皮生长因子（EGF）能力的变化，采用了一种不连续给予2-AAF的5周期方案来诱导大鼠发生肝癌。5周期方案的特点是，给予1至3周期2-AAF的大鼠患癌风险较低，而给予4或5周期2-AAF的大鼠患癌风险较高。在整个5周期方案中，发现肝细胞膜的EGF结合能力降至对照组的20%至25%。当对给予1至3周期2-AAF的大鼠停喂2-AAF 3周，以测试EGF结合能力降低的持续性时，发现结合能力恢复至对照大鼠的80%至90%。相比之下，对于给予4或5周期2-AAF的大鼠，在停喂2-AAF 3周后，EGF结合能力仍较低，为对照组的30%至40%。免疫化学分析表明，EGF受体水平的变化与上述EGF结合水平的变化密切相关。这些研究表明，在2-AAF方案期间，随着大鼠从患肝癌的低风险转变为高风险，2-AAF介导的肝脏EGF结合能力和EGF受体蛋白的丧失经历了从可逆丧失到结合能力和EGF受体蛋白持续丧失的转变。肝脏EGF结合水平的持续降低可能与肝癌发生的进展阶段有关。
