TY - JOUR
T1 - Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models
AU - Shinkai, Kentaro
AU - Nakano, Kenji
AU - Cui, Lin
AU - Mizuuchi, Yusuke
AU - Onishi, Hideya
AU - Oda, Yoshinao
AU - Obika, Satoshi
AU - Tanaka, Masao
AU - Katano, Mitsuo
N1 - Funding Information:
Japanese Ministry of Health Labour and Welfare and Japan Science and Technology Agency; Grant number: 14524896 (to KN)
Publisher Copyright:
© 2016 UICC.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-Associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target.
AB - The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by S-phase kinase-Associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target.
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U2 - 10.1002/ijc.30075
DO - 10.1002/ijc.30075
M3 - Article
C2 - 26939718
AN - SCOPUS:84962659978
SN - 0020-7136
VL - 139
SP - 433
EP - 445
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -
