PDX-1 acts as a potential molecular target for treatment of human pancreatic cancer.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Liu
Shihe
S
Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Ballian
Nikiforos
N
Belaguli
Narasimhaswamy S
NS
Patel
Sanjeet
S
Li
Min
M
Templeton
Nancy Smyth
NS
Gingras
Marie-Claude
MC
Gibbs
Richard
R
Fisher
William
W
Brunicardi
F Charles
FC
D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein