The proto-oncogene survivin splice variant 2B is induced by PDGF and leads to cell proliferation in rheumatoid arthritis fibroblast-like synoviocytes

Sho Mokuda,Eiji Sugiyama,Junya Masumoto,Tatsuhiko Miyazaki,Kiyoshi Takasugi,Yuki Ito,Masamoto Kanno,Hiroko Inoue,Weng-Sheng Kong,Satoshi Yamasaki,Yun Guo

doi:10.1038/srep09795

Abstract

Survivin is an independent prognostic factor for joint destruction in rheumatoid arthritis (RA). However, the expression and function of survivin in RA synoviocytes remain unclear. We certified the expression of survivin in RA synovial tissues and performed the experiment using RA fibroblast-like synoviocytes (RA-FLS) treated with siRNA. As a result, the expression levels of wild type (WT) survivin and the 2B splice variants in RA synovial tissues were higher than those in osteoarthritis tissue samples, and, these variants were highly expressed in RA-FLS. The expression levels of survivin-WT and -2B in the RA-FLS were upregulated by PDGF. Treatment with siRNA against survivin-2B led to decreased viability of PDGF-treated RA-FLS due to cell cycle suppression and apoptosis promotion, while the siRNA against all survivin isoforms did not affect the viability. Moreover, an overexpression of survivin-2B in RA-FLS led to cell proliferation through cell cycle activation and by conferring resistance to apoptosis. In conclusion, survivin-2B has an important role in RA-FLS proliferation. These data suggest that survivin-2B might contribute to rheumatoid synovial hyperplasia, and have the potential as a novel therapeutic target for RA.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplastic synovial tissue and destruction of articular cartilage and adjacent bone[1]
We evaluated the expression pattern of survivin and its splice variants in rheumatoid arthritis (RA) synovial tissues and compared them to osteoarthritis (OA) tissues, and examined whether survivin might be involved in pathological RA fibroblast-like synoviocytes (RA-fibroblast-like synoviocytes (FLS)) proliferation using small interfering RNA-mediated knockdown and in vitro-transcribed (IVT) mRNA transfection
The proto-oncogene survivin has attracted increasing attention as a therapeutic target for cancer since 2002, when its gene transcription was reported to be repressed by wild-type p5326–28

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplastic synovial tissue and destruction of articular cartilage and adjacent bone[1]. Proto-oncogene survivin is a member of the IAP (inhibitor-of-apoptosis) family of proteins. In 2005, it has been reported that the survivin protein and antibodies against survivin were measurable in blood and synovial fluid from RA patients[14]. They reported that the serum survivin level was capable of predicting the joint destruction in early RA15. We evaluated the expression pattern of survivin and its splice variants in RA synovial tissues and compared them to osteoarthritis (OA) tissues, and examined whether survivin might be involved in pathological RA-FLS proliferation using small interfering RNA (siRNA)-mediated knockdown and in vitro-transcribed (IVT) mRNA transfection

Methods

Results

Conclusion