title: Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells.
abstract: The amount of monocyte chemoattractant protein-1 (MCP-1/CCL2) produced by a transitional cell carcinoma is directly correlated with high recurrence and poor prognosis in bladder cancer. However, the mechanisms underlying the effects of CCL2 on tumor progression remain unexplored. To investigate the role played by CCL2, we examined cell migration in various bladder cancer cell lines. We found that high-grade cancer cells expressing high levels of CCL2 showed more migration activity than low-grade bladder cancer cells expressing low levels of the chemokine. Although the activation of CCL2/CCR2 signals did not appreciably affect cell growth, it mediated cell migration and invasion via the activation of protein kinase C and phosphorylation of tyrosine in paxillin. Blocking CCL2 and CCR2 with small hairpin RNA (shCCL2) or a specific inhibitor reduced CCL2/CCR2-mediated cell migration. The antagonist of CCR2 promoted the survival of mice bearing MBT2 bladder cancer cells, and CCL2-depleted cells showed low tumorigenicity compared with shGFP cells. In addition to observing high-levels of CCL2 in high-grade human bladder cancer cells, we showed that the CCL2/CCR2 signaling pathway mediated migratory and invasive activity, whereas blocking the pathway decreased migration and invasion. In conclusion, high levels of CCL2 expressed in bladder cancer mediates tumor invasion and is involved with advanced tumorigenesis. Our findings suggest that this CCL2/CCR2 pathway is a potential candidate for the attenuation of bladder cancer metastases.
authors.affiliation: Institute of Bioscience and Biotechnology, Center of Excellence for Marine Bioenvironment and Biotechnology (CMBB), National Taiwan Ocean University, Keelung, Taiwan.
authors.forename: Hsiao-Ying
authors.initials: HY
authors.lastname: Chiu
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Sun
authors.forename: Shiow-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: Hsiao-Hsien
authors.initials: HH
authors.lastname: Wang
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Lee
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Tsou
authors.forename: Shyh-Chuan
authors.initials: SC
authors.lastname: Jwo
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.forename: Shye-Jye
authors.initials: SJ
authors.lastname: Tang
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology*
chemical_list: D018932:Chemokine CCL2; D051419:Paxillin; D054390:Receptors, CCR2; D019000:Phosphotyrosine; D011493:Protein Kinase C