Abstract
Increasing evidence support the critical roles of active stromal fibroblasts in breast cancer development and spread. However, the mediators and the mechanisms of regulation are still not well defined. We have shown here that the tumor suppressor p16(INK4A) protein inhibits the pro-carcinogenic effects of breast stromal fibroblasts through repressing the expression/secretion of IL-6. Indeed, p16(INK4A) suppresses IL-6 at the mRNA and protein levels. This effect is mediated trough miR-146b-5p, which inhibits IL-6 expression through a specific sequence at the IL-6 3'UTR. In addition, we present clear evidence that miR-146b-5p inhibition is sufficient to transactivate breast stromal fibroblasts, which promote epithelial-to-mesenchymal-transition in breast cancer cells in a paracrine manner. By contrast, ectopic expression of miR-146b-5p in active fibroblasts abrogated their pro-carcinogenic effects. The physiological importance of miR-146b-5p inhibition was revealed by showing that the levels of pre-miR-146b-5p as well as its mature form are reduced in cancer-associated fibroblasts as compared with their normal adjacent counterparts from cancer-free tissues isolated from the same patients. Interestingly, treatment of active breast stromal fibroblasts with curcumin increased the level of the p16(INK4A) coding CDKN2A mRNA and miR-146b-5p and suppressed IL-6, which confirms the repressive effect of these two tumor suppressor molecules on IL-6, and shows the possible "normalization" of cancer-related active fibroblasts. These results show that miR-146b-5p has non-cell-autonomous tumor suppressor function through inhibition of IL-6, suggesting that targeting this microRNA in breast stromal fibroblasts could be of great therapeutic value.
Highlights
In a tumor, cancer cells are surrounded by various types of cells, which compose the tumor microenvironment
These results show that miR-146b-5p has non-cell-autonomous tumor suppressor function through inhibition of IL-6, suggesting that targeting this microRNA in breast stromal fibroblasts could be of great therapeutic value
These results indicate that deficiency of miR-146b-5p in breast stromal fibroblasts triggers epithelial-to-mesenchymal transition (EMT) in breast cancer cells in a paracrine manner, which demonstrates their active status and their non-cell-autonomous tumor suppressor functions
Summary
Cancer cells are surrounded by various types of cells, which compose the tumor microenvironment. Active cancer-associated fibroblasts (CAFs) support the growth and dissemination of cancer cells in a non-cell-autonomous manner through secretion of various chemokines, cytokines and growth factors [1, 2] These secretions are under the control of several tumor suppressor genes, including the cyclin-dependent kinase inhibitor p16INK4A (p16) [3, 4]. We have recently shown the role of p16 downregulation in the activation of breast stromal fibroblasts [3, 5] This effect is mediated through the up-regulation and increase in the secretion of SDF1 [3]. MiRNAs are defined as single stranded short (19–25 nucleotides in length), noncoding endogenous RNAs, which negatively regulate plethora of genes implicated in various biochemical pathways Alteration of their expression is related to various diseases including cancer [13, 14]. We present clear evidence that miR-146b-5p has non-cell-autonomous tumor suppressive functions
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