Dual Assembly Nanoparticles Achieve Sustained Silencing of Znf304: A Novel Transcription Factor For Β1 Integrin

<p>Ovarian cancer (OC) is a highly metastatic disease, but no effective strategies to this process currently are known. Here, an integrated computational analysis of The Cancer Genome Atlas ovarian cancer dataset coupled with experimental validation identified a novel zinc finger transcriptional factor 304 (ZNF304) as one of the key factors for ovarian cancer metastasis. High tumoral ZNF304 expression was associated with poor overall survival in ovarian cancer patients. Through reverse phase protein array analysis, we demonstrated that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration, and invasion. ZNF304 transcriptionally regulates β1 integrin, which subsequently regulates Src/focal adhesion kinase and paxillin and prevents anoikis. Targeting ZNF304 using small interfering RNA (siRNA) reduces cell survival, anoikis and migration in vitro. A novel dual assembly nanoparticle system (DANP) was designed for in vivo delivery and sustained gene silencing. DANP-ZNF304 siRNA led to sustained ZNF304 silencing for 14 days, increased anoikis, and reduced tumor growth in orthotopic murine models of ovarian cancer. Taken together, ZNF304 is a novel transcriptional regulator of β1 integrin, promotes cancer cell survival, and protects against anoikis in ovarian vi cancer; DANP is a safe and efficient delivery system that provides prolonged gene silencing following systemic administration.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Aslan, Burcu

Contributors dc:contributor

• Gabriel Lopez-Berestein
• Anil K. Sood
• George A. Calin

• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/541

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1579