Xu Mei, Wang Siying, Qi Yuanlin, Chen Li, Frank Jacqueline A, Yang Xiuwei H, Zhang Zhuo, Shi Xianglin, Luo Jia
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.
Mol Carcinog. 2016 May;55(5):1002-11. doi: 10.1002/mc.22343. Epub 2015 May 25.
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.
流行病学研究表明，饮酒与结直肠癌（CRC）风险增加有关。除了促进致癌作用外，酒精还可能加速现有CRC的进展。我们假设酒精可能会增强CRC的侵袭性。在本研究中，我们调查了酒精对CRC迁移/侵袭和转移的影响。酒精以浓度依赖的方式增加了结肠癌细胞（DLD1、HCT116、HT29和SW480）的迁移/侵袭。在这些结肠癌细胞系中，HCT116细胞对乙醇刺激的细胞迁移/侵袭反应最为敏感，而HT29细胞反应最不敏感。这些体外结果得到了动物研究的支持，动物研究表明乙醇增强了结肠癌细胞向肝脏和肺的转移。单核细胞趋化蛋白-1（MCP-1）是一种趋化因子，在调节肿瘤微环境和转移中起重要作用。酒精在蛋白质和mRNA水平上均增加了MCP-1及其受体CCR2的表达。酒精诱导的MCP-1表达变化模式与其对迁移/侵袭的影响一致；HCT116细胞在暴露于酒精后显示出MCP-1/CCR2的最高上调。CCR2拮抗剂可阻断酒精刺激的迁移。酒精通过抑制GSK3β活性导致β-连环蛋白最初在细胞质中积累，随后发生核转位。酒精以β-连环蛋白依赖的方式刺激MCP-1基因启动子的活性。此外，敲低MCP-1/CCR2或β-连环蛋白足以抑制酒精诱导的细胞迁移/侵袭。总之，这些结果表明酒精可能通过调节GSK3β/β-连环蛋白/MCP-1途径促进CRC的转移。
