Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis.
Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis.
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发表时间：
1996-06
期刊：
影响因子：
11.2
通讯作者：
X. Hou;J. Li;W. Chen;S. Li
中科院分区：
文献类型：
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作者：
X. Hou;J. Li;W. Chen;S. Li
对雄性叙利亚仓鼠长期给予雌激素7 ~ 9个月可诱发雌激素依赖性肾癌的高频率。我们提出了一个顺序的多阶段方案，包括小管细胞损伤、再生细胞增殖、非整倍体、染色体失衡、遗传不稳定、基因改变和扩增，这些都是该模型中雌激素致癌的基本步骤。为了进一步支持这一方案，我们进行了一项系统的研究，通过Northern blot分析评估核原癌基因c-myc、c-fos和c-jun以及抑制基因p53和WT-1的表达。在这些研究中，每隔一个月（1.0至6.0个月）从己烯雌酚（DES）处理的阉割雄性仓鼠和相应年龄匹配的未处理对照组中提取仓鼠肾脏RNA，以及原发性雌激素诱导的肾肿瘤RNA作为参考。虽然在雌激素治疗的前4个月，与年龄匹配的对照组相比，这些原癌基因的表达没有明显变化，但在5.0个月和6.0个月时，2.1 kb c-myc的表达分别升高了2.8倍和4.1倍。2.2 kb c-fos转录本的表达量分别增加了4.6倍和4.8倍；在相同的雌激素治疗时间间隔内，3.2和2.7 kb c-jun的表达分别增加了2.8倍和5.1倍。肿瘤抑制基因p53和WT-1的表达也在类似的雌激素暴露仓鼠中进行了评估。虽然在DES治疗的前5.0个月仓鼠肾脏p53表达没有明显变化，但在雌激素治疗的6.0个月时，它上升了1.8倍，在原发性肾肿瘤中上升了2.0倍以上。相比之下，在DES治疗的前6.0个月未发现WT-1表达的可检测变化。然而，在原发性肾肿瘤中观察到WT-1表达显著增加7.0倍。很明显，两个WT-1转录本存在于仓鼠肾脏中；在正常成人肾脏中发现了一个分子量较低的转录本，在肾肿瘤中观察到一个分子量较高的3.2 kb转录本，与新生小鼠肾脏中的转录本相似。综上所述，本文报道的雌激素诱导的不适当基因表达，包括p53，与基因表达的升高有助于仓鼠雌激素驱动肿瘤形成所需的某些近端小管间质细胞的增殖优势的观点是一致的。
Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancers. We have proposed a sequential multistage scheme involving tubular cell damage, regenerative cell proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene alteration, and amplification as essential steps for estrogen carcinogenesis in this model. A systematic study was undertaken to assess the expression of nuclear proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by Northern blot analysis to further support this scheme. Hamster kidney RNA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated castrated male hamsters and corresponding age-matched untreated controls was used in these studies, as well as primary estrogen-induced renal tumor RNA, for reference. Although no significant changes in the expression of these proto-oncogenes were detected in the first 4 months of estrogen treatment relative to age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar estrogen-exposed hamsters. Although no significant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal tumor. In contrast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in WT-1 expression was observed in the primary renal tumor. It is evident that two WT-1 transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney. In summary, the estrogen-induced inappropriate gene expression, including p53, reported herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain proximal tubular interstitial cells necessary for estrogen-driven tumor formation in the hamster.