Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage.
Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage.
复制标题
雌激素致癌过程中组织蛋白酶 D 蛋白的诱导：在雌激素介导的肾小管细胞损伤中的可能作用。
DOI：
10.1093/carcin/18.7.1375
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发表时间：
1997
期刊：
影响因子：
4.7
通讯作者：
Li,JJ
中科院分区：
文献类型：
--
作者：
Li,SA;Liao,DZ;Yazlovitskaya,EM;Pantazis,CG;Li,JJ
我们已经提出，雌激素在仓鼠肾脏癌变的早期步骤是小管损伤，随后是修复性细胞增殖。这种小管损伤是进行性的，并随着持续雌激素治疗的加重而加重；一个相关的特征是二级和三级溶酶体的数量显著增加。本文提出的数据表明，仓鼠在接受雌激素治疗后，肾脏组织蛋白酶D（一种对雌激素有反应的溶酶体蛋白水解酶）增加。在雌激素处理的肾脏中检测到组织蛋白酶D的三种异构体，分别为52、31和27 kDa，主要为52 kDa。在雌激素治疗1和3个月时，52-kDa组织蛋白酶D含量增加了1.4至1.6倍。在相同的雌激素治疗期间，这些变化与肾脏雌激素受体水平的上升相吻合。在雌激素治疗4个月和5个月后，组织蛋白酶D水平分别上升了2.7倍和3.5倍。同时还观察到雌激素受体含量增加3.0- 4.0倍。在雌二醇或DES治疗5个月时，仓鼠肾脏中除了存在52-kDa外，还存在27-和31-kDa亚型。黄体酮和DHT治疗均未影响未治疗组组织蛋白酶D水平。有趣的是，他莫昔芬或DHT和雌激素联合治疗均可阻止单独雌激素治疗后组织蛋白酶D和雌激素受体含量的升高。原发性雌激素诱导的肾肿瘤及其转移灶中组织蛋白酶D的三种亚型水平均显著升高。肾切片中组织蛋白酶D的免疫组织化学分析证实了Western blot的发现。这些数据表明雌激素诱导的组织蛋白酶D在肿瘤发生过程中在仓鼠肾脏中的新作用；也就是说，介导肾小管损伤作为修复性细胞增殖的前奏，从而启动一个多步骤的雌激素驱动过程，导致肾肿瘤的形成。
We have proposed that an early step in estrogen carcinogenesis in the hamster kidney is tubular damage followed by reparative cell proliferation. This tubular injury is progressive and increases in severity with continued estrogen treatment; one pertinent feature is a marked rise in the number of both secondary and tertiary lysosomes. Data presented herein indicate that cathepsin D, an estrogen-responsive lysosomal proteolytic enzyme, is increased in the kidney following estrogen treatment in the hamster. Three isoforms of cathepsin D were detected in estrogen-treated kidneys, 52, 31, and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen treatment, 52-kDa cathepsin D content increased 1.4- to 1.6-fold. These changes coincided with a rise in renal estrogen receptor levels during the same estrogen treatment periods. More pronounced rises in cathepsin D levels, 2.7- and 3.5-fold, were seen after 4 and 5 months of estrogen treatment, respectively. A concomitant, 3.0- to 4.0-fold rise in estrogen receptor content was also observed. At 5 months of estradiol or DES treatment, both 27- and 31-kDa isoforms were present in hamster kidneys, in addition to the 52-kDa form. Neither progesterone nor DHT treatment affected the untreated levels of cathepsin D. Interestingly, either concomitant tamoxifen or DHT and estrogen treatment prevented the rise in cathepsin D and estrogen receptor content observed after estrogen treatment alone. Primary estrogen-induced renal tumors and their metastases exhibited markedly elevated levels of all three isoforms of cathepsin D. Immunohistochemical analysis of cathepsin D in kidney sections confirmed the Western blot findings. These data suggest a novel role for estrogen-induced cathepsin D in the hamster kidney during tumorigenesis; that is, mediating renal tubular damage as a prelude to reparative cell proliferation, thus initiating a multi-step estrogen-driven process which leads to renal tumor formation.