Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Gynecol Oncol. 2014 Apr;133(1):83-9. doi: 10.1016/j.ygyno.2013.12.006.
Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin- and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (cell growth regulator with ring finger domain 1) as a novel metformin-responsive gene and characterized its possible role in endometrial cancer prevention.
CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and Western blot.
CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveals that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial tumors compared to normal human endometrium (p<0.05), suggesting that loss of CGRRF1 is associated with the presence of disease.
CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer.
肥胖相关的雌激素和胰岛素血症对子宫内膜癌的发病机制有重要贡献。我们最近证明，二甲双胍是一种长期用于治疗 2 型糖尿病的药物，可以减弱肥胖大鼠子宫内膜中胰岛素和雌激素介导的增殖信号。在这项研究中，我们试图确定组织生物标志物，这些标志物可能在预防和治疗研究中具有预测组织反应的临床应用价值。我们确定了 CGRRF1（具有环指结构域的细胞生长调节剂 1）是一种新的二甲双胍反应基因，并对其在子宫内膜癌预防中的可能作用进行了特征描述。
通过 RT-qPCR 评估肥胖和瘦大鼠子宫内膜以及正常和恶性人子宫内膜中 CGRRF1 的 mRNA 表达。在子宫内膜癌细胞中遗传操作 CGRRF1 水平，并通过 MTT 和 Western blot 评估其对增殖和凋亡的影响。
CGRRF1 明显被二甲双胍在肥胖大鼠子宫内膜中的治疗所诱导。体外研究表明，CGRRF1 的过表达抑制子宫内膜癌细胞的增殖。对人子宫内膜肿瘤的分析表明，与正常人类子宫内膜相比，CGRRF1 在增生、1 级、2 级、3 级、MMMT 和 UPSC 子宫内膜肿瘤中的表达显著降低（p<0.05），这表明 CGRRF1 的缺失与疾病的存在有关。
CGRRF1 是肥胖子宫内膜中二甲双胍反应的一种新的、可重复的组织标志物。此外，我们的初步数据表明，上调 CGRRF1 的表达可能在子宫内膜癌的预防或治疗中具有临床应用价值。
