Pabona John Mark P, Burnett Alexander F, Brown Dustin M, Quick Charles M, Simmen Frank A, Montales Maria Theresa E, Liu Shi J, Rose Tyler, Alhallak Iad, Siegel Eric R, Simmen Rosalia Cm
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
Reprod Sci. 2020 Jan;27(1):267-277. doi: 10.1007/s43032-019-00019-2. Epub 2020 Jan 1.
Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.
二甲双胍（MET）在降低糖尿病患者多种癌症类型的发病率方面的作用日益受到关注。然而，MET在非糖尿病子宫内膜癌（EC）女性中的类似作用尚不清楚。在一项试点研究中，将诊断为1型、1/2级EC且同意参与的肥胖非糖尿病女性，在诊断与子宫切除术之间的术前窗口期随机分配接受MET或不接受MET（对照组（CON））。对手术时获得的子宫内膜肿瘤（MET组，n = 4；CON组，n = 4）进行分析，检测肿瘤腺上皮（GE）和基质（ST）细胞中的增殖（Ki67）、凋亡（TUNEL）以及ERα、PGR、PTEN和KLF9蛋白的核表达。与CON组患者的肿瘤相比，MET组患者肿瘤中GE细胞中PGR和KLF9的免疫阳性细胞百分比以及ST细胞中PTEN的免疫阳性细胞百分比更高，而GE细胞中ERα的免疫阳性细胞百分比更低，但ST细胞中ERα的免疫阳性细胞百分比无差异。两组之间肿瘤GE和ST中Ki67和TUNEL阳性细胞数量无差异。在人子宫内膜癌细胞系Ishikawa中，MET处理（60 μM）可减少细胞数量，并引起ESR1、KLF9、PGR、PGR-B、KLF4、DKK1和其他肿瘤生物标志物mRNA水平的明显时间变化。在KLF9表达降低的情况下（通过靶向siRNA），MET可迅速放大PGR、PGR-B和KLF4的转录水平。我们的研究结果表明，MET直接作用于EC细胞以改变类固醇受体表达和信号网络，可能构成高危非糖尿病女性预防EC的一种策略。
