Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and β-arrestin pathways

Abstract

The CXC chemokine receptor 7 (CXCR7) has been reported to be involved in cell growth, metastasis and apoptosis in certain cancers. However, the function and molecular mechanisms of CXCR7 in human colorectal cancer (CRC) are still undefined. In the present study, sixty-eight cases of CRC tissues and corresponding adjacent non-cancer tissues (ANCT) were collected, and the expression of CXCR7 was assessed using immunohistochemistry (IHC) in biopsy samples. Furthermore, CXCR7 gene was silenced by small hairpin RNA-mediated lentiviral vector (Lv-shCXCR7), by transfection into human CRC cells (SW480 and HT-29). The levels of p-ERK, β-arrestin, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2) and caspase-3 (CAS-3) were detected by western blotting. Cell proliferative activities and invasive capability were respectively measured by MTT and Transwell assays. Cell apoptosis was analyzed by flow cytometry. The results demonstrated that CXCR7 expression was significantly upregulated in CRC tissues compared with the ANCT (54.4 vs. 36.8%, P=0.041), and correlated with Dukes staging and depth of invasion (P=0.007; P=0.002). Silencing of CXCR7 gene suppressed cell proliferation and invasion, and induced cell apoptosis in CRC cells with decreased expression of p-ERK, β-arrestin, PCNA and MMP-2 but increased expression of CAS-3. The tumor volumes in the SW480 subcutaneous tumor models treated with Lv-shCXCR7 were significantly smaller than those of the negative control (NC) and PBS groups (P<0.01). In conclusion, our findings indicate that upregulation of CXCR7 expression is associated with tumor invasion, and silencing of the CXCR7 gene represses the development of CRC cells through ERK and β-arrestin pathways, suggesting that CXCR7 may serve as a potential therapeutic target for the treatment of CRC.

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

“…Numerous studies have shown that chemokines and their receptors are expressed in cancer and affect its development . Recently, it has been reported that CXCR7 is overexpressed in many types of cancer (eg, ovarian, colorectal, and breast) . Studies have shown that CXCR7—a G protein‐coupled receptor—has attracted attention due to its increased expression in colorectal cancer .…”

“…23,24 Recently, it has been reported that CXCR7 is overexpressed in many types of cancer (eg, ovarian, colorectal, and breast). [25][26][27] Studies have shown that CXCR7-a G protein-coupled receptor-has attracted attention due to its F I G U R E 5 ELISA: Expression of CXCR7 regulates VEGF secretion Notes: A, The levels of VEGF were significantly increased in SW480 and Caco-2 cells overexpressing CXCR7. Treatment with inhibitors LY294002 and U0126 reduced the levels of VEGF.…”

Meta-analysis of CXCR7 Expression Related to Clinical Prognosis in Cancers

“…CXCR7, as a recently discovered chemokine receptor, has demonstrated its characteristics in six aspects out of the ten top hallmarks of tumors, including resisting cell death, inducing angiogenesis, sustaining proliferative signaling, activating invasion and metastasis, tumor-promoting inflammation, and cancer-related genes [14,[17][18][19][20][21][22]. Both CXCR4 and CXCR7 are receptors of chemokine CXCL12 and have been reported in multiple tumor types.…”

“…There are literatures indicating that CXCR7 binds to CXCL12 with greater affinity than CXCR4 to CXCL12 (Kd = 0.4 nM versus 3.6 nM) [10,11]. Furthermore, the roles of CXCR7 in neovascularization, tumor invasion and proliferation have been verified [12][13][14]. On the other hand, the clinical pattern of CXCR7 in various cancers has not been thoroughly summarized, and controversy still exists in different researches.…”

Trefoil factor 3 mediates resistance to apoptosis in colon carcinoma cells by a regulatory RNA axis

“…Furthermore, silencing of CXCR7 was shown to induce apoptosis in a β -arrestin- and ERK-dependent fashion. 13 However, whether β -arrestin and ERK pathway are involved in TFF3-dependent regulation of apoptosis in colon cancer progression and metastasis has still to be addressed.…”