ABSTRACT
Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. In this study, we investigated the effects of recombinant adeno-associated virus (AAV)-mediated delivery of K5 in mouse models of human ovarian cancer. A single intramuscular injection of AAV-K5 resulted in sustained expression of K5 reaching a maximum serum level of 800 ng ml(-1). Gene therapy inhibited both vascular endothelial growth factor (VEGF)-induced and tumor cell-induced angiogenesis in matrigel plug assays. Furthermore, a single injection of AAV-K5 significantly inhibited both subcutaneous and intraperitoneal growth of human ovarian cancer cells. Immunofluorescence studies of residual tumors surgically resected from the treated animals showed reduced tumor burden, which correlated with the inhibition of tumor neovascularization. In addition, AAV-K5 gene therapy differentially affected the nascent vessels more than mature vasculature and induced apoptotic death of tumor cells. These data show that AAV-K5 can be effectively used to inhibit ovarian cancer.
Subject(s)
Genetic Therapy , Neovascularization, Pathologic/therapy , Ovarian Neoplasms/therapy , Peptide Fragments/genetics , Plasminogen/genetics , Animals , Apoptosis , Dependovirus , Female , Genetic Vectors , Humans , Mice , Mice, Nude , Neovascularization, Physiologic/genetics , Ovarian Neoplasms/blood supply , Vascular Endothelial Growth Factors/pharmacologyABSTRACT
Metastasis-associated protein 1 (MTA1), a master chromatin modifier, has been shown to regulate cancer progression and is widely upregulated in human cancer, including hepatitis B virus-associated hepatocellular carcinomas (HCCs). Here we provide evidence that hepatitis B virus transactivator protein HBx stimulates the expression of MTA1 but not of MTA2 or MTA3. The underlying mechanism of HBx stimulation of MTA1 involves HBx targeting of transcription factor nuclear factor (NF)-kappaB and the recruitment of HBx/p65 complex to the NF-kappaB consensus motif on the relaxed MTA1 gene chromatin. We also discovered that MTA1 depletion in HBx-expressing cells severely impairs the ability of HBx to stimulate NF-kappaB signaling and the expression of target proinflammatory molecules. Furthermore, the presence of HBx in HBx-infected HCCs correlated well with increased MTA1 and NF-kappaB-p65. Collectively, these findings revealed a previously unrecognized integral role of MTA1 in HBx stimulation of NF-kappaB signaling and consequently, the expression of NF-kappaB targets gene products with functions in inflammation and tumorigenesis.
