Downregulation of SS18-SSX1 expression in synovial sarcoma by small interfering RNA enhances the focal adhesion pathway and inhibits anchorage-independent growth in vitro and tumor growth in vivo.
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by a unique t(X;18) translocation resulting in expression of SS18-SSX fusion protein. In order to investigate the biological function of this fusion protein and to develop a novel therapeutic option, we examined downregulation of SS18-SSX1 expression by small interfering RNA targeting SS18-SSX1 in three human SS cell lines. Microarray analysis comparing SS18-SSX1-silenced cells with control cells in three SS cell lines showed that SS18-SSX1 mainly affected the focal adhesion pathway. In accord with the array data, silencing of SS18-SSX1 enhances adhesion to the extracellular matrix through the induction of expression of myosin light-chain kinase. Furthermore, the silencing of SS18-SSX1 inhibits anchorage-independent growth in vitro and systemic delivery of siRNA against SS18-SSX1 using a nanoparticle system inhibited tumor growth in a nude mouse xenograft model. Our results demonstrate that siRNA targeting of SS18-SSX1 has therapeutic potential for the treatment of SS.
Takenaka
Satoshi
S
Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan.
Naka
Norifumi
N
Araki
Nobuhito
N
Hashimoto
Nobuyuki
N
Ueda
Takafumi
T
Yoshioka
Kiyoko
K
Yoshikawa
Hideki
H
Itoh
Kazuyuki
K
D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D015536:Down-Regulation; D022001:Focal Adhesions / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C093961:SS18 protein, human; C116512:SYT-SSX fusion protein; C093962:synovial sarcoma X breakpoint proteins; C499378:MYLK protein, human; D009219:Myosin-Light-Chain Kinase