The pancreatic tumor microenvironment drives changes in miRNA expression that promote cytokine production and inhibit migration by the tumor associated stroma
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Song Han1, David H. Gonzalo2, Michael Feely2, Daniel Delitto1, Kevin E. Behrns1, Mark Beveridge1, DongYu Zhang1, Ryan Thomas1, Jose G. Trevino1, Thomas D. Schmittgen3 and Steven J. Hughes1
1Department of Surgery, University of Florida, Gainesville, FL 32610, USA
2Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
3College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Song Han, email: [email protected]
Keywords: miR-200, miR-205, tumor-associated stroma, pancreatic cancer, tumor microenvrionment
Received: May 10, 2016 Accepted: June 13, 2016 Published: July 20, 2016
The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.
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