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

Sci Rep. 2015 May 22:5:9795. 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.

MeSH terms

  • Aged
  • Apoptosis / drug effects
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Becaplermin
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Female
  • Fibroblasts / cytology
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Interleukin-1beta / metabolism
  • Leptin / metabolism
  • Male
  • Middle Aged
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-sis / pharmacology*
  • RNA Splicing
  • RNA, Small Interfering / metabolism
  • Survivin
  • Synovial Membrane / cytology
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Interleukin-1beta
  • Leptin
  • MAS1 protein, human
  • Protein Isoforms
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-sis
  • RNA, Small Interfering
  • Survivin
  • Tumor Necrosis Factor-alpha
  • Becaplermin