High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion
High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion
复制标题
高葡萄糖通过增加 ER/GLUT4 介导的 VEGF 分泌来促进子宫内膜癌细胞的上皮-间质转化。
DOI：
10.1159/000494237
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Li, Ming-Qing
中科院分区：
文献类型：
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作者：
Gu, Chun-Jie;Xie, Feng;Li, Ming-Qing
背景/目的：子宫内膜癌（UEC）是妇科肿瘤中常见的恶性肿瘤，以雌激素依赖型UEC居多。众所周知，糖尿病是UEC发生的危险因素。然而，UEC中高糖（HG）与雌激素受体之间的潜在联系尚不清楚。上皮-间质转化（EMT）也被证明发生在癌症进展中转移的起始阶段。本研究旨在探讨HG、雌激素受体和EMT在UEC生长和迁移中的关系和作用。方法：采用免疫组化（IHC）法检测对照子宫内膜和UEC组织中葡萄糖转运蛋白4 （GLUT4）的表达；通过CCK-8和Matrigel侵袭试验分析细胞活力和侵袭性；实时荧光定量PCR检测emt相关基因的转录水平；分别通过western blotting、ELISA和流式细胞术（FCM）分析HG和/或GLUT4对雌激素受体、血管内皮生长因子（VEGF）及其受体VEGFR的影响。构建ishikawa异种移植裸鼠，在体内分析雌激素和GLUT4对UEC生长的影响。结果：在这里，我们发现暴露于汞会导致UEC细胞系（UECC， Ishikawa和RL95-2细胞）的高水平活力和侵袭。与正常子宫内膜相比，UEC组织中GLUT4水平较高。短句来源沉默GLUT4可明显抑制HG促进的UECC存活、侵袭及emt相关基因TWIST、SNAIL、CTNNB1的表达，进一步分析发现HG和GLUT4促进了UECC中VEGF的分泌和VEGFR的表达。HG处理导致UECC中雌激素受体（ER）和（ER）升高，阻断ER或ER导致UECC中GLUT4表达、TWIST、SNAIL和CTNNB1转录以及VEGF和VEGFR表达降低。抗人VEGF中和抗体抑制HG和雌激素诱导的UECC的存活和侵袭。暴露于雌激素可加速ishikawa异种移植裸鼠UEC中的生长、VEGF产生以及TWIST和CTNNB1的表达，而沉默GLUT4则限制了这些作用。结论：这些数据表明HG增加GLUT4和VEGF/VEGFR的表达，通过上调ER进一步促进EMT进程，加速UEC的发展(c) 2018
Background/Aims: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. Methods: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. Results: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor (ER) and (ER) in UECC, blocking ER or ER resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. Conclusion: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER (c) 2018 The Author(s) Published by S. Karger AG, Basel