Delivery of CD44 shRNA/Nanoparticles within Cancer Cells: PERTURBATION OF HYALURONAN/CD44v6 INTERACTIONS AND REDUCTION IN ADENOMA GROWTH IN Apc Min/+ MICE*
AUTOR(ES)
Misra, Suniti
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
Our studies have shown that constitutive interactions between hyaluronan and CD44 on tumor cells induces various anti-apoptotic cell survival pathways through the formation of a multimeric signaling complex that contains activated receptor tyrosine kinases. Inhibition of the hyaluronan-CD44 interactions on tumor cells by hyaluronan-CD44 interaction antagonists suppresses these activities by disassembling the complex. Although the anti-tumor activity of hyaluronan-oligosaccharides, a hyaluronan-CD44 interaction antagonist, is effective in sensitizing tumor cells to chemotherapeutic agents and reducing tumor growth in xenografts, hyaluronan-oligosaccharide alone was not effective in reducing tumor progression in Apc Min/+ mice. We now show in vitro and in vivo that targeted inhibition of the expression of CD44v6 depletes the ability of the colon tumor cells to signal through hyaluronan-CD44v6 interactions. First, we cloned oligonucleotides coding CD44v6 shRNA into a conditionally silenced pSico vector. Second, using pSico-CD44v6 shRNA and a colon-specific Fabpl promoter-driven Cre recombinase expression vector packaged into transferrin-coated nanoparticles, we successfully delivered the CD44v6 shRNA within pre-neoplastic and neoplastic colon malignant cells. Third, using the Apc Min/+ mice model, we demonstrated that inhibition of the CD44v6 expression reduces the signaling through a hyaluronan/CD44v6-pErbB2-Cox-2 interaction pathway and reduced adenoma number and growth. Together, these data provide insight into the novel therapeutic strategies of short hairpin RNA/nanoparticle technology and its potential for silencing genes associated with colon tumor cells.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2673310Documentos Relacionados
- RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy
- Mom1 Is a Semi-Dominant Modifier of Intestinal Adenoma Size and Multiplicity in Min/+ Mice
- Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein.
- Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice
- Análise da expressão da molécula CD44 e suas isoformas no câncer de próstata