title: Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells.
abstract: Epidemiological studies demonstrate that alcohol consumption is associated with an increased risk of colorectal cancer (CRC). In addition to promoting carcinogenesis, alcohol may also accelerate the progression of existing CRC. We hypothesized that alcohol may enhance the aggressiveness of CRC. In this study, we investigated the effect of alcohol on the migration/invasion and metastasis of CRC. Alcohol increased the migration/invasion of colorectal cancer cells (DLD1, HCT116, HT29, and SW480) in a concentration-dependent manner. Among these colon cancer cell lines, HCT116 cells were most responsive while HT29 cells were the least responsive to ethanol-stimulated cell migration/invasion. These in vitro results were supported by animal studies which demonstrated that ethanol enhanced the metastasis of colorectal cancer cells to the liver and lung. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays an important role in regulating tumor microenvironment and metastasis. Alcohol increased the expression of MCP-1 and its receptor CCR2 at both protein and mRNA levels. The pattern of alcohol-induced alterations in MCP-1 expression was consistent with its effect on migration/invasion; HCT116 cells displayed the highest up-regulation of MCP-1/CCR2 in response to alcohol exposure. An antagonist of CCR2 blocked alcohol-stimulated migration. Alcohol caused an initial cytosolic accumulation of β-catenin and its subsequent nuclear translocation by inhibiting GSK3β activity. Alcohol stimulated the activity of MCP-1 gene promoter in a β-catenin-dependent manner. Furthermore, knock-down of MCP-1/CCR2 or β-catenin was sufficient to inhibit alcohol-induced cell migration/invasion. Together, these results suggested that alcohol may promote the metastasis of CRC through modulating GSK3β/β-catenin/MCP-1 pathway.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.|Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Xiuwei H
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000431:Ethanol / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D000431:Ethanol
keywords: Chemokines; Wnt signaling; ethanol; metastasis; tumor promotion