Identification of eIF3f as a New Tumor Suppressor in Pancreatic Cancer.
Jiaqi Shi, Fushi Wen, Renyuan Zhou, Achyut Bhattacharyya. University of Arizona, Tucson; Fifth People's Hospital of Shanghai, Shanghai, China
Background: Misregulated mRNA translation is one of the most important factors in cancer development and progression in humans. Prominent nucleoli have been recognized to be one of the key features of many malignant cells in pathology for decades, which implicates increased ribosome generation and translation. However translational control mechanisms in cancer development are poorly understood. Previously, we identified the translation initiation factor eIF3f as a protein involved in apoptotic signaling. We were the first to report a decreased expression of eIF3f in more than 90% of the pancreatic cancer cases. Restoration of eIF3f expression in cancer cells led to ribosomal RNA degradation, decreased translation and increased apoptosis.
Design: In the present study, we stably silenced eIF3f expression in the immortalized normal human pancreatic ductal epithelial (HPDE) cells using lentiviral RNAi to assess whether the benign epithelial cells can be transformed to malignant cells. We have also established an in vitro 3D-cell culture model to better mimic the in vivo growth environment and tissue architecture.
Results: The eIF3f-silenced HPDE cells showed increased cell size, nuclear pleomorphism, aneuploidy, mesenchymal morphology, proliferation, clonogenicity, apoptotic and chemotherapy drug resistance, and migration compared to the control HPDE cells. We also demonstrated by 3D-culture that eIF3f-silenced HPDE cells formed masses that recapitulate malignant tumors (loss of normal epithelial cell orientation and architecture, disruption of the intact basement membrane shown by laminin V staining). On the contrary, the control HPDE cells developed into a single layer epithelial hollow spheres resembling normal pancreatic ductal structure.
Conclusions: Decreased eIF3f expression in pancreatic ductal epithelial cells led to malignant transformation. These data support our hypothesis that eIF3f is a tumor suppressor in pancreatic ductal adenocarcinoma.
Category: Liver & Pancreas
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 209, Monday Morning