STAT3/HIF-1α/fascin-1 axis promotes RA FLSs migration and invasion ability under hypoxia

Rheumatoid arthritis (RA) synovium was identified as "tumor-like" tissues because of the hypoxic microenvironment, significant cell proliferation, and invasion phenotypes. It was reported that hypoxia promoted tumor aggressiveness via up-regulated expression of fascin-1 in cancer. However, the role of fascin-1 in RA synovial hyperplasia and joint injury progression remains unknown. In the current study, we first identified that both fascin-1 and HIF-1α were highly expressed in the RA synovium, in which they were widely colocalized, compared to osteoarthritis(OA). As well, levels of fascin-1 in RA fibroblast-like synoviocytes(FLSs) were found significantly higher than those in OA FLSs. Further, it was demonstrated that the mRNA and protein levels of fascin-1 in RA FLSs were up-regulated in hypoxia (3 % O₂) and experimental hypoxia induced by cobalt chloride. Mechanistically, the HIF-1α-mediated hypoxia environment activated the gene expression of the fascin-1 protein, which in turn promoted the migration and invasion of RA FLSs. Accordingly, the restoration of FLSs migration and invasion was observed following siRNA-mediated silencing of fascin-1 and HIF-1α expression. Notably, under the experimental hypoxia, we found that the expression levels of fascin-1, HIF-1α, and p-STAT3 were increased in a time-dependent manner, and fascin-1and HIF-1α expressions were dependent on p-STAT3. Our results indicated that hypoxia-induced fascin-1 up-regulation promoted RA FLSs migration and invasion through the STAT3/HIF-1α/fascin-1 axis, which might represent a novel therapeutic target for the treatment of RA.