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Paracrine induction of epithelial-mesenchymal transition between colorectal cancer cells and its suppression by a p53/miR-192/215/NID1 axis.

BACKGROUND & AIMS: Intratumor-heterogeneity is a common feature of colorectal cancer (CRC). Here, we analyzed whether mesenchymal-like CRC cells promote the progression of epithelial-like CRC cells via paracrine mechanisms.

METHODS: Five CRC cell lines that exhibit an epithelial phenotype were treated with conditioned media (CM) from CRC cell lines that display a mesenchymal phenotype, and effects on epithelial-mesenchymal transition (EMT), migration, invasion, and chemo-resistance were determined. Secreted factors potentially mediating these effects were identified by using cytokine arrays. Associations of these factors with tumor progression and patient survival were determined.

RESULTS: CM obtained from mesenchymal-like CRC cells induced EMT associated with increased migration, invasion and chemo-resistance in epithelial-like CRC cell lines. Notably, activation of p53 in mesenchymal-like CRC cells prevented these effects of CM. Elevated concentrations of several cytokines were identified in CM from mesenchymal-like CRC cell lines and a subset of these cytokines showed repression by p53. The down-regulation of Nidogen-1/NID1 was particularly significant and was due to p53-mediated induction of miR-192 and miR-215, which directly target the NID1 mRNA. NID1 was found to be required and sufficient for inducing EMT, invasion and migration in epithelial-like CRC cells. In primary CRCs, elevated NID1 expression was associated with p53 mutation and miR-192/215 down-regulation. Importantly, elevated NID1 expression in CRCs correlated with enhanced tumor progression and poor patient survival.

CONCLUSIONS: Taken together, our results show that CRC cells promote tumor progression via secreting NID1, which induces EMT in neighboring tumor cells. Importantly, the interference of p53 with this paracrine signaling between tumor cells may critically contribute to tumor suppression.

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