Accumulating evidences have clearly demonstrated that microRNA (miRNA) system plays an active role in tumor-associated epithelial-mesenchymal transition (EMT) and tumor progression. Our PubMed-based search revealed that there are overwhelmingly more miRNAs serving as EMT suppressors than those promoting EMT in ovarian cancer (23 vs 3), indicating that overall miRNA system play an EMT-suppressive role in ovarian cancer. This is consistent with our observation that impairing miRNA biogenesis by silencing Drosha and Dicer induces the occurrence of EMT traits in epithelial-like ovarian cancer cells. Comparing the abundance of EMT- suppressive miRNAs in ovarian cancer cells, we noticed that levels of EMT-suppressive miRNAs are much less in mesenchymal-like cell lines than epithelial-like ones. Intriguingly, levels of the respective primary miRNAs (pri-miRNAs) in majority of these miRNAs are similar between mesenchymal- and epithelial-like ovarian cancer cells. These results indicate that the biogenesis of miRNA (processing of pri-miRNA to miRNA) is not efficient in mesenchymal-like ovarian cancer cells. We showed that blockage of miRNA biogenesis requires the presence of interleukin enhancer-binding factor 3 (ILF3) because knockdown of ILF3 increases miRNA biogenesis. In an effort to understand how ILF3 inhibits miRNA biogenesis, we found that protein kinase C? (PKC?), a novel PKC isoform, can phosphorylate ILF3 and that PKC? is required for the deterrence of miRNA biogenesis in mesenchymal-like ovarian cancer cells. Based on these findings, we formed our central hypothesis: PKC? promotes ovarian cancer EMT and tumor development by conferring ILF3 with the ability to deter the biogenesis of EMT-suppressive miRNAs. These findings also provide the basis to develop a novel ovarian cancer-targeted therapeutic modality that is to establish efficient miRNA processing in ovarian cancer cells through the interference of PKC? function.
Three aims are proposed in this application: 1) Elucidate the mechanism underlying PKC? regulation of miRNA processing; 2) Define mechanisms associated with PKC?/ILF3 regulation of EMT in ovarian cancer cells; and 3) Investigate the potential of interfering with PKC? function to suppress ovary tumorigenesis. The success of this application will help our understanding on how PKC?/ILF3 functional axis blocks miRNA biogenesis and also demonstrate the potential of suppressing ovary tumorigenesis by targeting PKC?.
Epithelial-mesenchymal transition (EMT) is a critical step for ovarian cancer progression and development. This proposal aims to understand the molecular mechanism underlying the poor expression of EMT- suppressive microRNAs in mesenchymal-like cells (aggressive cancer cells). This aim also aims to develop an ovarian cancer-targeted therapeutic strategy by elevating the expression of EMT-suppressive microRNAs.
