MiR-192, miR-200c and miR-17 are fibroblast-mediated inhibitors of colorectal cancer invasion

Abstract

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.

The miR-200c/FUT4 axis prevents the proliferation of colon cancer cells by downregulating the Wnt/β-catenin pathway

“…The expression of miR-200c has been found to correlate with poor prognosis of colon cancer [6].The miR-200 family comprises 5 members, miR-200a/b/429 and miR-200c/141 [7]. Accumulating evidence suggests that miR-200c, a tumour suppressor, has low expression in colon cancer [8][9][10][11]. MiR-200c inhibitors could enhance the viability and proliferation of colorectal cancer cells (CRC), and low miR-200c expression was related to shortened survival of patients with CRC [8,11].…”

“…However, Chen J et al [6] reported an opposite conclusion in colon cancer showing that miR-200c was highly expressed in colorectal cancer and functions by inhibiting protein tyrosine phosphatase gene expression and p53 phosphorylation. The regulation of colon cancer metastasis by miR-200c is mediated by a complex biological network [9,10].…”

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives

“…Mechanistically, inhibition of Fli-1 or TCF12 in CAFs counteracts the contractile activity induced by CAFs, but overexpression of Fli-1 or TCF12 in NFs increases the contractile activity of these NFs. In another study, a combined regression model was used to identify the subgroup-specific miRNAs and functional gene sets in colorectal cancer, and that the results indicated that some miRNAs can regulate ECM target genes [139]. Further studies showed that the high expression of miR-192, miR-17 and miR-200c in fibroblasts can regulate ECM target gene expression at the protein level, thus regulating ECM remodeling.…”

<p>Levonorgestrel Ameliorates Adenomyosis via lncRNA H19/miR-17/TLR4 Pathway</p>

“…12,13 Abnormal expression of miR-17 is also associated with colorectal cancer, cervical cancer, pancreatic cancer, as well as non-small cell lung cancer. [14][15][16][17][18] Besides, miR-17 may be involved in endometriosis and adenomyosis. 19,20 Long non-coding RNAs (lncRNAs) are important upstream regulators of miRNA regulating physiological process by binding to miRNA.…”