FGFR3 signaling is essential for gastric cancer cell triggering the transition of BM-MSCs into tumor-associated MSCs

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) tend to migrate towards tumor sites and interact with tumor cells, thus incorporating into tumor microenvironment by transition into various stromal cells, particularly tumor-associated MSCs. However, the mechanisms involved in this process is still not clarified. Herein, we focused on miR-99a-5p and confirmed its reduction in gastric cancer-associated MSCs (GC-MSCs) compared to BM-MSCs. Under-expression of miR-99a-5p stimulated BM-MSCs transition into GC-MSCs-like cells, while overexpression of this miRNA abrogated tumor-promoting roles of GC-MSCs. miR-99a-5p not only targeted modulation of fibroblast growth factor receptor (FGFR3) but also negatively affected its phosphorylated levels. Suppression of FGFR3 signaling by AZD4547 or siRNA against FGFR3 notably blocked the miR-99a-5p inhibitor-induced BM-MSCs transition and the oncogenic roles of GC-MSCs. However, miR-99a-5p overexpression did not diminish the ability of gastric cancer cells to educate BM-MSCs. The levels of phosphorylated FGFR3, but not total FGFR3, was increased in BM-MSCs educated by gastric cancer cells. AZD4547 significantly suppressed the education capacity of gastric cancer cells on BM-MSCs. Taken together, although manipulating miR-99a-5p to mimic its levels in GC-MSCs promotes the transition of BM-MSCs into GC-MSCs-like cells, FGFR3 signaling, rather than miR-99a-5p, is unexpectedly essential for the education of BM-MSCs by gastric cancer cells. This discovery provides a novel mechanism underlying the transition of BM-MSCs into tumor-associated MSCs and identifies potential therapeutic targets for gastric cancer.