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

Abstract

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.

• Authors: Wang Yang, Xinyue Wei, Yachong Jiao, Yingyu Bai, Wilfried Noel Sam, Qiushuang Yan, Xuguo Sun, Guangping Li, Jun Ma, Wei Wei, Derun Tian, Fang Zheng
• Journal: Molecular immunology (Mol Immunol) Vol. 142 Pg. 83-94 (02 2022) ISSN: 1872-9142 [Electronic] England
• PMID: 34971867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• FSCN1 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Microfilament Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Arthritis, Rheumatoid (pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Hypoxia (physiology)
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Cells, Cultured
• Humans
• Hyperplasia (pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Joints (injuries)
• Microfilament Proteins (genetics, metabolism)
• Osteoarthritis (pathology)
• RNA Interference
• RNA, Small Interfering (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Synovial Membrane (cytology, pathology)
• Synoviocytes (pathology)