Bhat H, Hacker H, Thompson E, Liehr J
UNIV TEXAS,MED BRANCH,DEPT PHARMACOL & TOXICOL,GALVESTON,TX 77555. UNIV TEXAS,MED BRANCH,DEPT HUMAN BIOL CHEM & GENET,GALVESTON,TX 77555. DEUTSCH KREBSFORSCHUNGSZENTRUM,CYTOPATHOL ABT,W-6620 HEIDELBERG,GERMANY.
Int J Oncol. 1995 Sep;7(3):527-34. doi: 10.3892/ijo.7.3.527.
Chronic administration of 17 beta-estradiol to male Syrian hamsters for at least six months induces estrogen-dependent kidney tumors, which express high levels of c-fos mRNA compared to surrounding renal or control tissues. We have investigated the cellular localization of c-Fos oncoprotein in these tissues and studied the estrogenic regulation of c-fos mRNA in kidney and in H-301 cells, a cell line derived from primary hamster kidney tumors. Immunocytochemical analyses showed that levels of c-Fos protein were high in estrogen-dependent tumors. To study the early events in this model, hamsters were treated with 17 beta-estradiol for only 15 days. At this time, well before the appearance of tumors, c-Fos protein was concentrated in interstitial capillaries, arteries, and podocytes of the glomerulus, but not in renal tubular epithelium, and this pattern was not appreciably changed from controls. To study the regulation of c-fos that led to the altered expression in tumor vs. kidney, total RNA was isolated from kidneys of Syrian hamsters 3-48 h after treatment with single injections of either 17 beta- or 17 alpha-estradiol, 17 alpha-ethinylestradiol, the steroidal antiestrogen ICI 182,780, or 17 beta-estradiol plus ICI 182,780. Similar studies were carried out on H-301 cells grown in D-MEM/F-12 medium and charcoal-stripped serum. The increases in c-fos mRNA levels in H-301 cells but not kidney were elicited by classical estrogen receptor-mediated processes. In H-301 cells, c-fos levels were increased four-fold over controls after 3 h of 17 beta-estradiol treatment and this induction was suppressed by antiestrogen treatment. In hamster kidneys, c-fos levels were increased about two-fold by 17 beta-estradiol, but this induction was not affected by antiestrogen treatment. In H-301 cells but not in hamster kidneys, 17 alpha-ethinylestradiol induced c-fos. 17 alpha-estradiol was more potent than 17 beta-estradiol in the induction of c-fos in hamster kidney but was a poor inducer in H-301 cells. These studies are consistent with regulation of c-fos expression in H-301 tumor cells by an estrogen receptor-mediated mechanism. But in hamster kidney, c-fos expression does not appear to be regulated by receptor-mediated pathways. We propose that it may be induced by estrogen metabolites.
对雄性叙利亚仓鼠长期给予17β-雌二醇至少六个月会诱发雌激素依赖性肾肿瘤，与周围肾组织或对照组织相比，这些肿瘤中c-fos mRNA表达水平较高。我们研究了c-Fos癌蛋白在这些组织中的细胞定位，并研究了肾组织和H-301细胞（一种源自原发性仓鼠肾肿瘤的细胞系）中c-fos mRNA的雌激素调节作用。免疫细胞化学分析表明，雌激素依赖性肿瘤中c-Fos蛋白水平较高。为了研究该模型中的早期事件，仅用17β-雌二醇处理仓鼠15天。此时，远在肿瘤出现之前，c-Fos蛋白集中在肾小球的间质毛细血管、动脉和足细胞中，而不在肾小管上皮中，并且这种模式与对照相比没有明显变化。为了研究导致肿瘤与肾中表达改变的c-fos的调节，在用单次注射17β-或17α-雌二醇、17α-炔雌醇、甾体抗雌激素ICI 182,780或17β-雌二醇加ICI 182,780处理3-48小时后，从叙利亚仓鼠的肾脏中分离总RNA。对在D-MEM/F-12培养基和经活性炭处理的血清中生长的H-301细胞进行了类似研究。H-301细胞而非肾组织中c-fos mRNA水平的升高是由经典雌激素受体介导的过程引起的。在H-301细胞中，17β-雌二醇处理3小时后，c-fos水平比对照增加了四倍，并且这种诱导被抗雌激素处理所抑制。在仓鼠肾脏中，17β-雌二醇使c-fos水平增加约两倍，但这种诱导不受抗雌激素处理的影响。在H-301细胞而非仓鼠肾脏中，17α-炔雌醇诱导了c-fos。17α-雌二醇在诱导仓鼠肾脏中的c-fos方面比17β-雌二醇更有效，但在H-301细胞中诱导作用较差。这些研究与雌激素受体介导的机制对H-301肿瘤细胞中c-fos表达的调节一致。但在仓鼠肾脏中，c-fos表达似乎不受受体介导途径的调节。我们推测它可能是由雌激素代谢产物诱导的。
