Abstract
Transmembrane mucins, MUC4 and MUC16 are associated with tumor progression and metastatic potential in human pancreatic adenocarcinoma. We discovered that miR-200c interacts with specific sequences within the coding sequence of MUC4 and MUC16 mRNAs, and evaluated the regulatory nature of this association. Pancreatic cancer cell lines S2.028 and T3M-4 transfected with miR-200c showed a 4.18 and 8.50 fold down regulation of MUC4 mRNA, and 4.68 and 4.82 fold down regulation of MUC16 mRNA compared to mock-transfected cells, respectively. A significant reduction of glycoprotein expression was also observed. These results indicate that miR-200c overexpression regulates MUC4 and MUC16 mucins in pancreatic cancer cells by directly targeting the mRNA coding sequence of each, resulting in reduced levels of MUC4 and MUC16 mRNA and protein. These data suggest that, in addition to regulating proteins that modulate EMT, miR-200c influences expression of cell surface mucins in pancreatic cancer.
Highlights
MicroRNAs are small (~20-22 nucleotides) noncoding RNAs that regulate gene expression by interacting with either the 3’ untranslated region (3’ UTR) or coding region of target mRNAs
We demonstrate for the first time that a mirR-200c targets high molecular weight mucin glycoproteins by targeting their coding sequence for degradation or translational inhibition
We have shown that miR-200c is differentially expressed in pancreatic cancer cells
Summary
MicroRNAs (miRNAs) are small (~20-22 nucleotides) noncoding RNAs that regulate gene expression by interacting with either the 3’ untranslated region (3’ UTR) or coding region of target mRNAs. It has been shown that miR-200c is differentially expressed in pancreatic cancer, where high expression was associated with better survival and low expression is associated with worse survival [10]. Overexpression of miR-200c inhibits cancer cell invasion by modulating factors important in EMT [10]. Ectopic expression of miR-200c induces higher levels of E-cadherin in breast and pancreatic cancer cells through the direct targeting of transcription factor 8 (TCF8/ ZEB1), a negative regulator of E-cadherin [11,12,13,14]. Cells with high levels of miR-200c have a more epithelial and less mesenchymal phenotype that may impact metastasis. Overexpression of miR-200c was shown to inhibit melanoma tumor progression and drug resistance [15]
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