Down-regulation of p16INK4a inhibits miR-146b-5p and modulates IL-6 in breast stromal fibroblasts
, Mysoon M. Al-Ansari . 2014
Breast cancer is a major health problem that threatens millions of women’s lives each year worldwide. Cancer-associated fibroblasts (CAFs), which constitute the major component of the tumor stroma, have been reported to actively contribute to tumor cells proliferation and invasion. Recently, we have shown down-regulation of the tumor suppressor p16INK4a protein in breast cancer-associated fibroblasts. Moreover, p16INK4a deficiency led to the activation of the stromal fibroblasts, which express/secrete elevated levels of IL-6, a major player in breast carcinogenesis. We have shown here that p16INK4a negatively regulates the IL-6 expression and secretion in breast stromal fibroblasts. Furthermore, we have shown that IL-6 is playing a major role in mediating the paracrine pro-carcinogenic effect of p16-deficient fibroblasts. We have also shown that p16INK4a inhibits the IL-6 expression in a miRNA-146b-5p-dependent manner. Importantly, we present clear evidence that miR-146b-5p inhibition activates breast stromal fibroblast. Indeed, miR-146b-5p inhibition increased the migration/invasion abilities of breast stromal fibroblasts, and the paracrine effect of these cells on the migration/invasion of breast cancer cells. Furthermore, miR-146b-5p-deficient stromal fibroblasts triggered epithelial to mesenchymal transition in breast cancer cells in a paracrine manner. In addition, we have shown that miR-146b-5p is down-regulated in CAFs as compared to their adjacent counterpart fibroblasts. These results indicate that p16INK4a negatively regulates IL-6 through the activation of miR-146b-5p, which plays a major role in repressing breast stromal fibroblasts and inhibiting their pro-carcinogenic effects. This indicates that miR-146b-5p has cell-non-autonomous tumor suppressor function. Therefore, this miRNA could be of great therapeutic value
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