Date of Graduation
12-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Gabriel Lopez-Berestein
Committee Member
Anil K. Sood
Committee Member
George A. Calin
Committee Member
Zahid Siddik
Committee Member
Mien Chie-Hung
Abstract
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.