Abstract
BackgroundUnder physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed.MethodsFirst, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice.ResultsIn clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo.ConclusionsThis study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.
Highlights
Under physiological conditions, Chemokine ligand 12 (CXCL12) modulates cell proliferation, survival, angiogenesis, and migration mainly through C-X-C chemokine receptor type 4 (CXCR4)
C-X-C chemokine receptor type 7 (CXCR7) expression was upregulated in lung tumor tissue compared with normal tissue, whereas CXCR4 expression was not significantly changed The clinical lung adenocarcinoma tissue samples and para-tumor tissue samples gained from Huadong Hospital Affiliated to Fudan University, Shanghai, China
Western blot was performed for CXCR7 and CXCR4 protein expression in human lung adenocarcinoma cell line A549 and large cell lung cancer cell line H460.Human umbilical vein endothelial cells (HUVEC) were used as a normal control
Summary
CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. The incidence of lung cancer ranks the top place in all kinds of malignant tumors worldwide and is progressively increasing year by year, with adenocarcinoma accounting for the most prevalent histological type. Lung cancer is the most leading cause of death in men and the second cause of cancer-associated death in women worldwide [1]. Chemokines are a superfamily of chemoattractant cytokines with diversity of biological and pathological functions, relating to immunocyte migration, hematopoietic stem cells homing, angiogenesis and tumor progression. Binding of chemokines to their receptors initiates a cascade of many cellular downstream signaling transduction pathways, including cyclic adenosine monophosphate-protein kinase A (cAMP-PKA), phosphatidylinositol and calcium fluxes mobilization or protein kinase C (PI-Ca2+/PKC) and cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway [5]
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