Chemokine receptor 7 targets the vascular endothelial growth factor via the AKT/ERK pathway to regulate angiogenesis in colon cancer

Abstract

Background Studies have shown that CXCR7 is expressed in many tumors. The aim of the present study was to investigate the function of CXCR7 in colon cancer. Although evidence indicates that CXCR7 promotes angiogenesis in colon cancer, the mechanism involved in this process remains unclear. Methods The expression of CXCR7 in colon cancer was evaluated by quantitative reverse‐transcription polymerase chain reaction and western blotting. After transfection, cell proliferation, migration, and lumen formation were measured in vitro. Immunohistochemistry and western blotting were used to identify the functional target of CXCR7 in vivo and in vitro. Results In this study, CXCR7 was differentially expressed in four colon cancer cell lines. The proliferation and migration experiments showed that overexpression of CXCR7 enhanced cell growth and migration. Moreover, the tube formation assays showed that co‐culture of colon cancer cells overexpressing CXCR7 with human umbilical vein endothelial cells significantly promoted tube formation in the latter cells. Conversely, the stable knockdown of CXCR7 significantly reduced this malignant activity. In addition, we found that CXCR7 activates the AKT and ERK pathways in colon cancer cells. The phosphorylation of AKT and ERK, as well as the expression of the vascular endothelial growth factor, can be inhibited using the LY294002 and U0126 inhibitors. Furthermore, the angiogenic ability of CXCR7‐induced colon cancer cells was eliminated. Conclusion Expression of CXCR7 contributes to colon cancer growth and angiogenesis, by activating the AKT and ERK pathways. CXCR7 provides a potential therapeutic target against colon cancer.

Expression and regulation effects of chemokine receptor 7 in colon cancer cells

“…These results indicate that CXCR7 simultaneously regulates the ERK/AKT signaling pathway and expression of VEGF in colon cancer in vitro and in vivo. Our previous study revealed that CXCR7 is a key factor in tumorigenesis by promoting cell proliferation and angiogenesis (24). The results of the present study support the current conclusions and also indicate that changes in the expression of CXCR7 are key factors in the development and progression of colon cancer.…”

“…Over the last 8 years, a number of studies have confirmed that CXCR7 is also expressed in other types of cancer, such as pancreatic cancer, thyroid cancer, prostate cancer, breast cancer, esophageal cancer, liver cancer, and bladder cancer, and it has been shown to promote tumor growth and metastasis (5,(18)(19)(20)(21)(22)(23). The results of our previous study (24) indicated that the protein and mRNA expression of CXCR7 in Caco-2 cells was low compared with that in RKO, SW480, and HCT116 colon cancer cells. However, whether CXCR7 has similar functions in Caco-2 and HCT116 cells remains to be elucidated.…”

“…The wound healing assay and Transwell assay results revealed that the migration area and the number of migrating cells were significantly reduced in the siRNA3 transfection group compared with that in the NC group. In our previous study (24), SW480 and Caco-2 cells were inoculated subcutaneously into the right lower limb tissue of mice. CXCR7 was upregulated or downregulated prior to inoculation in mice.…”

Advances in CXCR7 Modulators

“…CXCR7 is up-regulated in disease states including post-ischemic stroke [29,30], multiple sclerosis [31], Alzheimer's disease [32], epilepsy [33], rheumatoid arthritis [34], autism [35], and coronary artery disease [36]. Increased expression is also observed in many cancers, including prostate [16], pancreatic [37], ovarian [38], colon [39], kidney [40], liver [40], lung and breast [41] and CXCR7 is involved in the growth, metastasis and survival of these tumor cell lines. The receptor additionally functions as a coreceptor for various human immunodeficiency virus (HIV) strains [42].…”

“…CXCR7 has been implicated in the growth, metastasis, and survival of tumor cell lines such as prostate [16], glioma [12], bladder [50], pancreatic [37], Kaposi sarcoma [51], ovarian [38], cervical [52], colon [39], uterine [40], kidney [40], liver [40], stomach [40], lung and breast [41] as well as hepatocellular carcinoma [3]. CXCR7 is present on tumor endothelial, glioma and microglial cells, and is often colocalized with CXCL12 [12].…”