Abstract
Abstract Terminal progression of colorectal cancer culminates in liver metastasis. To identify genes that are involved in the metastatic phenotype, cDNA microarrays were used to analyze mRNA expression profiles of CC531 rat colon adenocarcinoma cells for changes related to their homing into the liver. Briefly, CC531 cells were intraportally implanted into the liver of Wag-Rij rats and re-isolated after 3, 6, 9, 14 and 21 days. Compared to control CC531 cells, claudin1 and claudin4 were among the ≥8 fold initially down-regulated genes. The co-culture of tumor cells with isolated rat hepatocytes and Kupffer cells did not induce down-regulation of either claudin1 or 4. When the environment effective on circulating tumor cells was simulated by cell culture conditions favoring their adhesion, only claudin4 showed augmented expression. Knockdown of claudin1 and claudin4 mediated by siRNA caused significantly increased migration and decreased clonogenic growth of tumor cells (p<0.05), but had no effect on their proliferation. These experimental results were paralleled by increased claudin1 and claudin4 expression in human colorectal cancer samples in UICC stages l-lll, as evaluated by real-time PCR. Increased claudin4 levels were correlated with significantly reduced overall survival (log-rank test, p=0.018). Further, significantly (p<0.05) reduced expression of claudin1 and claudin4 was observed in stage IV and liver metastasis by immunohistochemistry. In conclusion, sequential biphasic changes in claudin1 and claudin4 expression occur during the homing of colorectal cancer cells to the liver. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5252. doi:10.1158/1538-7445.AM2011-5252
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