MiR-192, miR-200c and miR-17 are fibroblast-mediated inhibitors of colorectal cancer invasion
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Volker Ast1,2,*, Theresa Kordaß3,*, Marcus Oswald1,2, Amol Kolte1,2, David Eisel3, Wolfram Osen3, Stefan B. Eichmüller3, Alexander Berndt4 and Rainer König1,2
1Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
2Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute Jena, 07745 Jena, Germany
3GMP & T Cell Therapy Unit, German Cancer Research Center, 69120 Heidelberg, Germany
4Institute of Forensic Medicine, Section Pathology, Jena University Hospital, 07747 Jena, Germany
*Shared first authors
Rainer König, email: [email protected]
Keywords: mixed-integer linear programming; piecewise linear regression; extracellular matrix; tumor-associated fibroblast; tumor cell invasion
Received: April 20, 2018 Accepted: October 06, 2018 Published: October 30, 2018
Colorectal cancer remains a leading cause of cancer-related death worldwide. A previous transcriptomics based study characterized molecular subgroups of which the stromal subgroup was associated with the worst clinical outcome. Micro-RNAs (miRNAs) are well-known regulators of gene expression and can follow a non-linear repression mechanism. We set up a model combining piecewise linear and linear regression and applied this combined regression model to a comprehensive colon adenocarcinoma dataset. We identified miRNAs involved in regulating characteristic gene sets, particularly extracellular matrix remodeling in the stromal subgroup. Comparison of expression data from separated (epithelial) cancer cells and stroma cells or fibroblasts associate these regulatory interactions with infiltrating stromal or tumor-associated fibroblasts. MiR-200c, miR-17 and miR-192 were identified as the most promising candidates regulating genes crucial for extracellular matrix remodeling. We validated our computational findings by in vitro assays. Enforced expression of either miR-200c, miR-17 or miR-192 in untransformed human colon fibroblasts down-regulated 85% of all predicted target genes. Expressing these miRNAs singly or in combination in human colon fibroblasts co-cultured with colon cancer cells considerably reduced cancer cell invasion validating these miRNAs as cancer cell infiltration suppressors in tumor associated fibroblasts.
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