P53 Mutant p53N236S Regulates Cancer-Associated Fibroblasts Properties Through Stat3 Pathway.

ABSTRACT

BACKGROUND: Cancer-associated fibroblasts (CAFs) play important roles in cancer development and progression. Recent studies show that p53 plays a cell non-autonomous tumor-suppressive role to restrict tumor growth in CAFs. However, the role of p53 mutant in CAFs remains obscure. METHODS: In this study, the contribution of p53 mutant p53N236S (p53S) to CAFs activation was examined using mouse embryonic fibroblasts (MEFs) from wild-type (WT), p53 deficient (p53-/- ) and p53S/S mice. The role of p53S in MEFs in inducing prostate cancer cell growth and metastasis was studied by utilizing xenograft models and transwell assays. The effects of p53S on the properties of CAFs were assessed by measuring CAFs-specific factors expression and functional collagen contraction assay. Moreover, Microarray data were analyzed by GSEA and Stat3 signaling was inhibited to further determine p53S's role in the CAFs activation. RESULTS: We found that p53S/S MEF accelerated cancer cells growth and metastasis compared with WT and p53-/- MEF. We also found that p53S induced significantly increasing collagen contraction in fibroblasts and overexpression of CAFs-specific factors, such as α-smooth muscle actin (α-SMA), FGF10 and CXCL12. p53S regulated these CAF-specific properties through Stat3 activation. CONCLUSION: Our results illustrate that p53S plays an important role in CAFs activation by the Stat3 pathway. The study indicates that cancer cells and fibroblasts interaction promotes prostate cancer cell growth, migration and invasion due to p53S expression in fibroblasts.