TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer

Abstract

Background: Metastasis is the leading cause of death in colorectal cancer (CRC) patients. It is regulated mainly by tumor cell angiogenesis, and angiogenesis is caused by the binding of vascular endothelial growth factor (VEGF) to vascular endothelial growth factor receptor 2 (VEGFR2). Tumor necrosis factor--induced protein 8 (TNFAIP8, hereto after TIPE) plays an important role in tumorigenesis, development, and prognosis. However, the relationship between TIPE and VEGFR2 in CRC angiogenesis and the mechanism of action remain unknown. Method: In this study, we used quantitative real-time PCR, Western blotting and immunohistochemistry to detect TIPE and VEGFR2 expression in 55 specimens from CRC patients. We also used HCT116 CRC cells and human umbilical vein endothelial cells (HUVECs) for in vitro experiments by stably transducing shTIPE and shRNA control lentivirus into HCT116 cells, detecting VEGFR2 expression after TIPE knockdown and repurposing the culture supernatant as conditioned medium to stimulate angiogenesis of HUVECs. In vivo experiments with chicken chorioallantoic membranes (CAMs) and a nude mouse matrix subcutaneous tumor model were performed to validate the effects of TIPE on angiogenesis. Additionally, we analyzed the expression and phosphorylation levels of PDK1 and blocked PDK1 expression using inhibitors to determine whether TIPE-induced changes in VEGFR2-mediated angiogenesis acted via the PI3K-Akt pathway. Results: We found that TIPE and VEGFR2 are highly expressed in CRC and act as oncogenes. TIPE knockdown also downregulated VEGFR2 expression, which resulted in simultaneous inhibition of cell proliferation, cell migration and angiogenesis. Then, in vivo experiments further demonstrated that TIPE promotes angiogenesis in CRC. Finally, we found that TIPE promotes VEGFR2-mediated angiogenesis by upregulating PDK1 expression and phosphorylation and that blocking PDK1 expression can inhibit this process. Conclusion: TIPE promotes angiogenesis in CRC by regulating the expression of VEGFR2, which may be a target for antiangiogenic cancer therapy.

Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

“…VEGFR-2 mediates the main physiological functions of VEGF. VEGF, the vascular permeability factor (VPF), is an essential and crucial growth factor for vascular endothelial cells, and plays various roles in cardiovascular system ( Wang et al, 2019 ), central nervous system ( Bellon et al, 2010 ; Luck et al, 2019 ), hematopoiesis ( Hooper et al, 2009 ), development ( Karaman et al, 2018 ), and tumorigenesis ( Volz et al, 2020 ; Zhong et al, 2020 ). Despite having so many physiological functions, the main physiological functions of VEGF on endothelial cells are almost all achieved by activating VEGFR-2, including stimulating endothelial cell proliferation, increasing vascular permeability, and chemotaxis to endothelial cells, etc.…”

Inflammation-Mediated Angiogenesis in Ischemic Stroke

“…PlGF, VEGF-A, and VEGF-B are required for angiogenesis (Takahashi and Shibuya, 2005). VEGF-A (also known as VEGF) is the major member of the VEGF family and promotes angiogenesis via binding to VEGF receptor-2 (VEGFR-2) (Zhong et al, 2020). VEGF-B, functionally and structurally related to VEGF-A and PlGF, regulates the bioavailability of VEGF-A (Olofsson et al, 1996).…”

Overexpression of Tumour Necrosis Factor-α-Induced Protein 8 is Associated with Prognosis in Colon Cancer

“…Studies have found that TIPE is highly expressed in pancreatic cancer, gastric cancer, endometrial cancer and other tumour cells, regulating the growth, proliferation, migration and invasion of tumour cells. [29][30][31] The TIPE protein was found to be significantly overexpressed in colon cancer tissues compared with tumour-adjacent tissues and was associated with the degree of malignancy of the tumour. 32 Zhong et al detected the relative mRNA expression levels of TIPE family members in tumour and adjacent tissue samples of patients with colorectal cancer.…”