Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells

Abstract

BackgroundIn spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC) patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells.MethodsWe constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7.ResultsCXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo.ConclusionsIncreased CXCR7 expression was found in hepatocellular carcinoma tissues. Knockdown of CXCR7 expression by transfected with CXCR7shRNA significantly inhibits SMMC-7721 cells invasion, adhesion and angiogenesis. Finally, down-regulation of CXCR7 expression lead to a reduction of tumor growth in a xenograft model of HCC. This study provides new insights into the significance of CXCR7 in invasion and angiogenesis of HCC.

The ubiquitin-like modifier FAT10 in cancer development

“…The microarray expression analysis of FAT10 overexpressing NeHepLxHT and HCT116 cells by Gao et al (2014) revealed that the chemokine receptors CXCR4 and CXCR7 were highly up-regulated in FAT10 overexpressing NeHepLxHT cells, consistent with other data showing that NF-B is a transcription factor for both genes (Katoh and Katoh, 2010;Tarnowski et al, 2010). CXCR4 and −7 are both described to promote invasion and tumor growth in several cancer types (Gao et al, 2010;Heinrich et al, 2012;Liang et al, 2005;Zheng et al, 2010). In accordance with these data, an siRNA-mediated knockdown of p65 or overexpression of I B␣ in FAT10 overexpressing NeHepLxHT cells significantly attenuated cell invasion and migration in vitro, precisely as silencing of CXCR4 and CXCR7 did.…”

CXC chemokine receptor 7 expression in cervical intraepithelial neoplasia

“…However, the upregulation was not observed in the vasculature of corresponding healthy tissues (12), indicating that angiogenesis is influenced by CXCR7. Hepatocarcinoma cells treated with vascular endothelial growth factor results in a positive feedback for CXCR7 expression (17), further supporting the notion that CXCR7 impacts on vascular growth, therefore favoring precancerosis and subsequently cancerous lesions.…”

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

“…Past report has implied that CXCR7 may play a more critical role in pancreatic cancer progression and prognosis. Shen et al regarded CXCR4 as a key receptor involved in tumor invasion and prognosis, while Liu et al [9] considered CXCR7 to be more important for long term survival in pancreatic cancer patients [9,23,24]. Implications of CXCR7 have been revealed in various tumors, including nervous system, digestive system, endocrine system, genital system, blood system, respiratory system, and urinary system, respectively [9,15,[25][26][27][28][29].…”