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.
Highlights
In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC) patients remains poor
Expression of CXCR7 in hepatocellular carcinoma tissues from patients Little is known about the expression of CXCR7 in HCC
To investigate whether CXCR7 might play a role in HCC development, we first examined its expression in 35 hepatocellular carcinoma tissues and 25 normal liver tissues using immunohistochemistry
Summary
In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC) patients remains poor. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. 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. There is abundant evidence to show that chemokine CXCL12 and its receptors (CXCR4, CXCR7) are involved in progression of tumors [3,4]. Stromal cell-derived factor-1 (SDF-1, called CXCL12) is a member of the CXC subfamily of chemokines and express in a variety of tissues including lung, liver, bone marrow and lymph nodes [5,6,7]. CXCL12 plays a crucial role in the process of invasion and metastasis of tumor cells [3]. CXCL12 stimulates proliferation, dissociation, migration, and invasion in a wide variety of tumor cells, including breast cancer cells, pancreatic cancer cells and HCC cells [3,10,11]
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