Regulation of protein synthesis is fundamentally important for the control of cell growth and proliferation. The eukaryotic initiation factor 3 (eIF3) is a multi-protein complex that plays an important role in translation. Deletion of certain eIF3 subunit is embryonic lethal in mouse. eIF3f is the p47 subunit of eIF3 complex and is highly conserved in Drosophila melanogaster, C. elegans, and Arabidopsis thaliana. This pilot project investigates the hypothesis that decreased eIF3f expression contributes to pancreatic cancer development by deregulating translation and apoptosis. The expression of eIF3f is significantly decreased in pancreatic cancer. Loss of eIF3f gene allele was observed in pancreatic cancer specimens. eIF3f was also shown to be a negative regulator of translation. Ectopic expression of eIF3f inhibits translation, cell proliferation and induces apoptosis in pancreatic cancer cells. However, no one has studied the direct role of eIF3f in pancreatic neoplasm. Pancreatic cancer has a five year survival rate under 5% because of late detection. Our long term goal is to develop novel biomarkers for early diagnosis and to identify new molecular targets for treatment of pancreatic cancer. To address our hypothesis, the following specific aims will be pursued: (1) To determine if decreased eIF3f contributes to pancreatic neoplastic transformation in vitro and in vivo. eIF3f expression will be knocked down using eIF3f shRNA lentiviral construct in immortal normal human pancreatic ductal epithelial cells to assess the ability of eIF3f to transform these cells in vitro and in the xenograft SCID mouse model. Quantitative immunolabeling analysis of eIF3f protein will be performed using novel Quantum Dot technology on tissue microarrays to define the expression of eIF3f in different stages of pancreatic cancer. (2) To characterize the molecular mechanism by which eIF3f inhibits translation and induces apoptosis. The function of eIF3f as a regulatory non-core subunit of eIF3 is not known. Our preliminary data suggest that eIF3f is a negative regulator of translation. Overexpression of eIF3f leads to reduced ribosomes and rRNA degradation. In this aim, we will investigate the molecular mechanism by which eIF3f regulates rRNA degradation, translation and apoptosis. This proposal will contribute to the exploration of novel molecular pathways and better understanding of the etiology of pancreatic cancer. Characterization of this important new signaling pathway will lead to identification of new biomarkers and therapeutic targets for pancreatic cancer.
Role of eIF3f in Pancreatic Cancer. Pancreatic cancer is the fourth leading cause of cancer death. This proposal will contribute to the exploration of novel molecular pathways and better understanding of the etiology of pancreatic cancer. Characterization of this important new signaling pathway will lead to identification of new diagnostic biomarkers and therapeutic targets for pancreatic cancer. ? ? ?
