The Effect Andmechanism Of DAB2IP In Regulating Pancreatic Cancer Growth, Metastasis And Chemoresistance

Background&Aims:Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a devastating disease with a 5-year overall survival rate of<5%, the highest fatality rate among all cancers. However, there is limited information about the molecular pathogenesis of PDAC. Here, we examined the functional role of the tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) and the underlying molecular mechanisms of disease progression in PDAC.Methods:1. Clinical correlations between DAB2IP expression and clinicopathological factors were determined by immunohistiochemical analysis of tumor tissue from PDAC patients. Cell proliferation, colony formation, and apoptosis analyses and xenograft transplantation were performed to evaluate the impact of DAB2IP on PDAC cells.2. Biological metastasis functions of DAB2IP and DAB2IP-mediated signaling pathways were determined in PDAC cell lines with DAB2IP knockdown or overexpression. Slug expression and promoter activity were determined using real-time quantitative polymerase chain reaction, western blot, and luciferase reporter assay.3. We analysed the role of DAB2IP in chemo-resistance of PDAC cells.The expression of DAB2IP and multidrug resistance (MDR) genes, as well as stem cell marker, were measured using Western-blot and quantitative PCR.Results:1. Loss of DAB2IP expression was an independent predictor of decreased survival and was significantly associated with a higher cellular grade and lymphatic invasion in patients with PDAC.2. PDAC cells with loss of DAB2IP expression showed significantly enhanced proliferation, migration, and invasiveness in viro, and tumor growth and metastasis in vivo.3. Loss of DAB2IP induced the expression of mesenchymal cell marker, which are regulated by the expression of Slug at the transcriptional level.4. PDAC cells that express high levels of DAB2IP exhibit decreased resistance to chemotherapeutic drugs (gemcitabine and salinomycin) in comparison with cells that express low levels of DAB2IP. In particular, levels of MRP 1 protein and cancer stem cell marker gene were significantly higher in the DAB2IP-low PDAC cells.Conclusions:The results of our study help to explain why the loss of DAB2IP expression is closely correlated with malignancy of PDAC. These results strongly suggest that DAB2IP could be a favorable prognostic indicator and promising target for therapeutics against PDAC.