Weige Charles C, Allred Kimberly F, Allred Clinton D
Genetics Interdisciplinary Program, Texas A&M University, College Station, Texas 77843, USA.
Cancer Res. 2009 Dec 1;69(23):9118-24. doi: 10.1158/0008-5472.CAN-09-2348. Epub 2009 Nov 10.
Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E(2)) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E(2) in noncancerous colonocytes. E(2) treatments (0-10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E(2) in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E(2) on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectomized wild-type (WT) and ERbeta knockout (ERbetaKO) mice treated with either vehicle or E(2). WT E(2)-treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ERbetaKO animals receiving either treatment. For the first time, we showed that E(2) alters the growth of nontransformed colonocytes in vitro and that, through an ERbeta-mediated mechanism, E(2) influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E(2) occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent.
大量临床和动物研究表明，激素替代疗法可降低结肠肿瘤形成的风险。然而，大多数实验表明，雌二醇（E₂）并不能抑制恶性转化的结肠上皮细胞的生长。因此，本研究聚焦于评估E₂对非癌性结肠细胞的影响。E₂处理（0 - 10 nmol/L）以剂量反应方式降低了年轻成年小鼠结肠细胞（YAMC，一种非恶性细胞系）的细胞生长并增加了其凋亡活性。在YAMC-Ras细胞（一种具有单一恶性转化的同基因细胞系）中，这些作用消失了。与雌激素受体（ER）拮抗剂共同处理可抑制E₂在YAMC细胞中的生理作用，表明该反应是由ER介导的。为了进一步研究E₂对结肠上皮细胞的影响，我们评估了用赋形剂或E₂处理的去卵巢野生型（WT）和ERβ基因敲除（ERβKO）小鼠中癌前病变的发展。与接受任何一种处理的WT对照小鼠或ERβKO动物相比，WT E₂处理的动物结肠上皮中的异常隐窝病灶明显减少，凋亡活性增加。我们首次表明，E₂在体外改变未转化结肠细胞的生长，并且通过ERβ介导的机制，E₂影响非癌性结肠细胞的生理功能，从而减少癌前病变。总体而言，这些数据表明E₂的保护作用主要发生在疾病发展的起始/促进阶段，并确定该激素为一种重要的化学保护剂。
