MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal CancerReportar como inadecuado




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Mucinous adenocarcinoma MAC represents a distinct histopathological entity of colorectal cancer CRC, which is associated with disease progression and poor prognosis. Here, we found that expression levels of miR-205 and miR-373 were specifically upregulated only in patients with mucinous colon cancers, but not in CRC that lack mucinous components. To investigate the effects of miR-205 and miR-373 on intestinal epithelial cell IEC biology by gain- and loss-of-function experiments in a proof-of-concept approach, we chose previously established in-vitro human Caco-2-based models of differentiated, non-invasive expressing TLR4 wild-type; termed Caco-2WT versus undifferentiated, invasive expressing TLR4 mutant D299G; termed Caco-2D299G IEC. Enterocyte-like Caco-2WT showed low levels of miR-205 and miR-373 expression, while both miRNAs were significantly upregulated in colorectal carcinoma-like Caco-2D299G, thus resembling the miRNA expression pattern of paired normal versus tumor samples from MAC patients. Using stable transfection, we generated miR-205- or miR-373-expressing and miR-205- or miR-373-inhibiting subclones of these IEC lines. We found that introduction of miR-205 into Caco-2WT led to expansion of mucus-secreting goblet cell-like cells, which was associated with induction of KLF4, MUC2 and TGFβ1 expression. Activation of miR-205 in Caco-2WT induced chemoresistance, while inhibition of miR-205 in Caco-2D299G promoted chemosensitivity. Caco-2WT overexpressing miR-373 showed mitotic abnormalities and underwent morphologic changes loss of epithelial polarity, cytoskeletal reorganization, and junctional disruption associated with epithelial-mesenchymal transition and progression to inflammation-associated colonic carcinoma, which correlated with induction of phosphorylated STAT3 and N-CADHERIN expression. Functionally, introduction of miR-373 into Caco-2WT mediated loss of cell-cell adhesion and increased proliferation and invasion. Reversely, inhibition of miR-373 allowed mesenchymal IEC to regain epithelial properties, which correlated with absence of neoplastic progression. Using xenografts in mice demonstrated miR-373-mediated acceleration of malignant intestinal tumor growth. In conclusion, our results provide first evidence that miR-205 and miR-373 may differentially contribute to the aggressive phenotype of MAC in CRC.



Autor: Annette Eyking, Henning Reis, Magdalena Frank, Guido Gerken, Kurt W. Schmid, Elke Cario

Fuente: http://plos.srce.hr/



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