Abstract
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (n = 4) with evident cancer cell budding. In all four cases, TNF-α mRNA was seen in a small subset of cancer cells at the invasive front. Evaluation of miR-21 and TNF-α mRNA expression was performed on digital slides obtained by confocal slide scanning microscopy. Both co-expression and lack of co-expression with miR-21 in the budding cancer cells was noted, suggesting non-correlated expression. miR-21 was more often seen in cancer cells than TNF-α mRNA. In conclusion, we report that miR-21 is not linked to expression of the pro-inflammatory cytokine TNF-α mRNA, but that miR-21 and TNF-α both take part in the cancer expansion at the invasive front of colon cancers. We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity.
Highlights
MicroRNAs are short regulatory RNAs that are formed as inactive precursors with hairpin-like structure from which a 3p and 5p strand containing 19–23 nucleotides are generated after cleavage by endonucleases [1,2,3]
Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers
We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity
Summary
MicroRNAs are short regulatory RNAs that are formed as inactive precursors with hairpin-like structure from which a 3p and 5p strand containing 19–23 nucleotides are generated after cleavage by endonucleases [1,2,3]. MiR-21 is expressed predominantly in stromal fibroblast-like cells, but is seen in populations of cancer cells [7,8]. We recently described the presence of miR-21 in budding cancer cells [9]. The prevalence of budding cancer cells in tumor microenvironment is associated with increased metastasis and poor prognosis [11,12]. The function of miR-21 in colon cancer fibroblasts and cancer cells is not clear, but its regulatory roles are likely different in different cell populations. MiR-21 is involved in fibrosis as part of the transforming growth factor (TGF-β) induced fibrosis pathway [13], and targets programmed cell death-4 (PDCD4) to sustain cell survival, cancer cell invasion and metastasis [14]. The function of miR-21 in colon cancer fibroblasts and cancer cells is not clear, but its regulatory roles are likely different in different cell populations. miR-21 is involved in fibrosis as part of the transforming growth factor (TGF-β) induced fibrosis pathway [13], and targets programmed cell death-4 (PDCD4) to sustain cell survival, cancer cell invasion and metastasis [14]. miR-21 is upregulated in inflammatory bowel disease [15,16,17], in which expression is seen in far uncharacterized inflammatory cells [16]
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