RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells.

Abstract

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.

• Authors: Zhiyong Mi, Hongtao Guo, M Benjamin Russell, Yingmiao Liu, Bruce A Sullenger, Paul C Kuo
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 17 Issue 1 Pg. 153-61 (Jan 2009) ISSN: 1525-0024 [Electronic] United States
• PMID: 18985031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aptamers, Nucleotide
• Osteopontin

Topics

• Animals
• Aptamers, Nucleotide (chemistry, pharmacology)
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microscopy, Confocal
• Neoplasm Metastasis (drug therapy)
• Nucleic Acid Conformation
• Osteopontin (antagonists & inhibitors)
• Transfection