Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma

Wang, Jayson; Taylor, Alexandra; Showeil, Rania; Trivedi, Pritesh; Horimoto, Yoshiya; Bagwan, Izhar; Ewington, Lauren J.; Lam, Eric W.‐F.; El‐Bahrawy, Mona

doi:10.1016/j.cyto.2014.04.005

Cited by 52 publications

(37 citation statements)

References 23 publications

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“…It has been reported that VEGF takes part in the tumorigenesis and metastasis of UEC [31]. Moreover, VEGFRs are highly expressed in UEC, among these, VEGFR-3 is remarkably correlated with tumor stage and survival [32]. Here, we found that HG and estrogen promoted the expression of VEGF and VEGFR in UECC through up-regulation of GLUT4 and triggered the process of EMT, cell viability and invasion.…”

Section: Discussionmentioning

confidence: 47%

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Gu¹,

Xie²,

Zhang³

et al. 2018

Cell Physiol Biochem

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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 α (ERα) and β (ERβ) in UECC, blocking ERα or ERβ 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

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Section: Discussionmentioning

confidence: 47%

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Gu¹,

Xie²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…Angiogenesis is fundamental for tumor growth/progression to provide nutrients and oxygen necessary for tumor cell proliferation and metastasis [27]. VEGF is a major angiogenic factor even in endometrial cancer and its expression is associated with endometrial cancer prognosis [28, 29]. Recent studies showed that ERRα was co-activated with PGC-1α in response to hypoxia, thereby inducing VEGF expression and angiogenesis in the skeletal muscle [30].…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer

et al. 2016

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Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts (p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer.

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“…VEGF, which is physiologically secreted by fibroblasts and inflammatory cells [6], has also been shown to influence *E-mail: e.maeda@eng.hokudai.ac.jp (EM) angiogenic process [7,8]. It was reported that VEGF has the ability of changing EC shape during vascular lumen formation [9].…”

Section: Introductionmentioning

confidence: 99%

Development of fibrin gel-microgroove model for microvascularization by endothelial cells

et al. 2015

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This study was performed to develop a new experimental device with a fibrin gel-microgroove structure for study of microvascularization by endothelial cells (ECs). The effects of the width of microgrooves, initial cell seeding density and a supplementation of vascular endothelial growth factor (VEGF) on in vitro microvasculaization of ECs were examined. ECs were cultured in a fibrin gel formed on a polydimethylsiloxane microgroove substrate, with the microgroove width of 50, 100, 150 and 200 μm. ECs were elongated and sprouted within the gel in all the four types of microgrooves. In addition, multicellular network by connected cell branches were frequently observed in 100-μm microgrooves. Both high initial cell density and VEGF demonstrated significant promotional effects on morphology changes. The findings indicate that microgroove structure serves as a geometrical constraint for ECs, with a promotional effect on angiogenic responses of ECs, and thus, it can be used as an experimental model in the study of in vitro vascularization.

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Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma

Cited by 52 publications

References 23 publications

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

Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer

Development of fibrin gel-microgroove model for microvascularization by endothelial cells

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