RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells.
Osteopontin (OPN) is a secreted phosphoprotein which mediates tumorigenesis, local growth, and metastasis in a variety of cancers. It is a potential therapeutic target for the regulation of cancer metastasis. RNA aptamer technology targeting OPN may represent a clinically viable therapy. In this study, we characterize the critical sequence of an RNA aptamer, termed OPN-R3, directed against human OPN. It has a K(d) of 18 nmol/l and binds specifically to human OPN as determined by RNA electrophoretic mobility assays. In MDA-MB231 human breast cancer cells examined under fluorescence microscopy, OPN-R3 ablates cell surface binding of OPN to its cell surface CD44 and alpha(v)beta(3) integrin receptors. Critical enzymatic components of the OPN signal transduction pathways, PI3K, JNK1/2, Src and Akt, and mediators of extracellular matrix degradation, matrix metalloproteinase 2 (MMP2) and uroplasminogen activator (uPA), are significantly decreased following exposure to OPN-R3. OPN-R3 inhibits MDA-MB231 in vitro adhesion, migration, and invasion characteristics by 60, 50, and 65%, respectively. In an in vivo xenograft model of breast cancer, OPN-R3 significantly decreases local progression and distant metastases. On the basis of this "proof-of-concept" study, we conclude that RNA aptamer targeting of OPN has biologically relevance for modifying tumor growth and metastasis.
Mi
Zhiyong
Z
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Guo
Hongtao
H
Russell
M Benjamin
MB
Liu
Yingmiao
Y
Sullenger
Bruce A
BA
Kuo
Paul C
PC
D000818:Animals; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009690:Nucleic Acid Conformation; D053495:Osteopontin / Q000037:antagonists & inhibitors*; D014162:Transfection
D052157:Aptamers, Nucleotide; D053495:Osteopontin