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The purpose of this study was to investigate whether pancreatic and duodenal homeobox factor 1 (PDX-1) could serve as a potential molecular target for the treatment of pancreatic cancer.Cell proliferation, invasion capacity, and protein levels of cell cycle mediators were determined in human pancreatic cancer cells transfected with mouse PDX-1 (mPDX-1) alone or with mPDX-1 short hairpin RNA (shRNA) and/or human PDX-1 shRNA (huPDX-1 shRNA). Tumor cell growth and apoptosis were also evaluated in vivo in PANC-1 tumor-bearing severe combined immunodeficient mice receiving multiple treatments of intravenous liposomal huPDX-1 shRNA.mPDX-1 overexpression resulted in the significant increase of cell proliferation and invasion in MIA PaCa2, but not PANC-1 cells. This effect was blocked by knocking down mPDX-1 expression with mPDX-1 shRNA. Silencing of huPDX-1 expression in PANC-1 cells inhibited cell proliferation in vitro and suppressed tumor growth in vivo which was associated with increased tumor cell apoptosis. PDX-1 overexpression resulted in dysregulation of the cell cycle with up-regulation of cyclin D, cyclin E, and Cdk2 and down-regulation of p27.PDX-1 regulates cell proliferation and invasion in human pancreatic cancer cells. Down-regulation of PDX-1 expression inhibits pancreatic cancer cell growth in vitro and in vivo, implying its use as a potential therapeutic target for the treatment of pancreatic cancer.