Role of chemokine receptor CXCR7 in bladder cancer progression

• Published in: Biochemical pharmacology 2012-07, Vol.84 (2), p.204-214
• Main Authors: Hao, Mingang, Zheng, Jianghua, Hou, Kailin, Wang, Jinglong, Chen, Xiaosong, Lu, Xiaojiong, Bo, Junjie, Xu, Chen, Shen, Kunwei, Wang, Jianhua
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; antagonists; apoptosis; Bladder cancer; Butadienes - pharmacology; Chemokine receptor; chemokines; Chromones - pharmacology; CXCR7; Disease Progression; EMT; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; in vivo studies; interleukin-8; Interleukin-8 - metabolism; MAP Kinase Signaling System; metastasis; Mice; Mice, SCID; microarray technology; Morpholines - pharmacology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Nitriles - pharmacology; pharmacology; protein synthesis; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CXCR - genetics; Receptors, CXCR - physiology; RNA, Small Interfering; Signal Transduction - genetics; STAT3 Transcription Factor - metabolism; urinary bladder neoplasms; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2012.04.007

Bladder cancer is one of the most common tumors of the genitourinary tract; however, the molecular events underlying growth and invasion of the tumor remain unclear. Here, role of the CXCR7 receptor in bladder cancer was further explored. CXCR7 protein expression was examined using high-density tissue microarrays. Expression of CXCR7 showed strong epithelial staining that correlated with bladder cancer progression. In vitro and in vivo studies in bladder cancer cell lines suggested that alterations in CXCR7 expression were associated with the activities of proliferation, apoptosis, migration, invasion, angiogenesis and tumor growth. Moreover, CXCR7 expression was able to regulate expression of the proangiogenic factors IL-8 or VEGF, which may involve in the regulation of tumor angiogenesis. Finally, we found that signaling by the CXCR7 in bladder cancer cells activates AKT, ERK and STAT3 pathways. The AKT and ERK pathways may reciprocally regulate, which are responsible for in vitro and in vivo epithelial to mesenchymal transition (EMT) process of bladder cancer. Simultaneously targeting the two pathways by using U0126 and LY294002 inhibitors or using CCX733, a selective CXCR7 antagonist drastically reduced CXCR7-induced EMT process. Taken together, our data show for the first time that CXCR7 plays a role in the development of bladder cancer. Targeting CXCR7 or its downstream-activated AKT and ERK pathways may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for bladder cancer.