Abstract
BackgroundTumor angiogenesis is an essential event for tumor growth and metastasis. It has been showed that REC8, a component of the meiotic cohesion complex, played a vital role in Epithelial-Mesenchymal Transition (EMT) in gastric cancer. However, the role of REC8 in gastric cancer angiogenesis remains to be identified.ResultsInhibition of REC8 expression in gastric cancer cells contributed to tumor angiogenesis in the gastric cancer microenvironment. The clinical analysis demonstrated that the loss of REC8 in gastric cancer with enrichment of MVD. Depletion of REC8 expression in gastric cancer cells significantly increased tube formation of human umbilical vein endothelial cells (HUVECs), which is attributed to enhancement of vascular endothelial growth factor (VEGF) secretion caused by REC8 slicing. While addition of neutralizing antibody targeted VEGF into supernatant drastically reversed the effect of REC8 loss in gastric cancer cells on tube formation. Mechanistic analyses indicated that ablation of REC8 promotes nuclear factor-κB (NF-κB) p65 activity and its downstream gene VEGF expression, leading to tube formation.ConclusionsThese results demonstrated a novel REC8 function that suppressed tumor angiogenesis and progression by attenuation of VEGF in gastric cancer microenvironment.
Highlights
Tumor angiogenesis is an essential event for tumor growth and metastasis
We are for the first time to demonstrate that REC8 played an anti-angiogenic role in the tumor angiogenesis in gastric cancer and defined a novel model in which REC8 inhibited nuclear factor-κB (NF-κB) pathway in gastric cancer cells through suppression of vascular endothelial growth factor (VEGF) expression, leading to inhibit angiogenesis
Antibodies used for immunoblotting and IP assays were as follows: the NF-KB p65 primary antibody for chromatin IP was purchased from CST; primary antibodies against VEGF were from Abclonal (Cat: A17877, Wuhan, China); Cell lines, cell cultures and transfection The gastric cancer cell lines of poor differentiation, BGC823 and AGS-1, human umbilical vein endothelial cells (HUVECs) were obtained from Cell Bank of the Chinese Academy of Sciences (Chinese Academy of Sciences, Shanghai, China) and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM, Gibco) supplemented with 10% (v/v) fetal bovine serum (FBS) at 37 ̊C in a humidified atmosphere of 5% CO2
Summary
Tumor angiogenesis is an essential event for tumor growth and metastasis. It has been showed that REC8, a component of the meiotic cohesion complex, played a vital role in Epithelial-Mesenchymal Transition (EMT) in gastric cancer. It has been reported that REC8 was hypermethylated in melanomas and malignant gastrointestinal stromal tumors [13,14,15], suggesting the low level of REC8 expression in tumor and a potential tumor suppressor. These findings suggested that the multifaceted REC8-mediated anticancer effects played a causal but unclear role in mammalian oncogenesis. The expression of REC8 level is negatively correlation with MVD in gastric cancer This finding provided further support for the tumor suppressor role of REC8, and added a novel link between abnormal cell meiosis and tumor angiogenesis
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