TY - JOUR
T1 - Upregulated SMAD3 promotes epithelial-mesenchymal transition and predicts poor prognosis in pancreatic ductal adenocarcinoma
AU - Yamazaki, Ken
AU - Masugi, Yohei
AU - Effendi, Kathryn
AU - Tsujikawa, Hanako
AU - Hiraoka, Nobuyoshi
AU - Kitago, Minoru
AU - Shinoda, Masahiro
AU - Itano, Osamu
AU - Tanabe, Minoru
AU - Kitagawa, Yuko
AU - Sakamoto, Michiie
N1 - Funding Information:
This study was supported by grants from The New Energy and Industrial Technology Development Organization (Project no. P10003) and from The Ministry of Health, Labour and Welfare of Japan (Grant-in-aid of The Third Term Comprehensive 10-Year Strategy for Cancer Control).
PY - 2014/6
Y1 - 2014/6
N2 - In pancreatic ductal adenocarcinoma (PDAC), features of epithelial-mesenchymal transition (EMT) are often seen in tumor tissue, and such features correlate with poor prognosis. Solitary infiltration of tumor cells represents a morphological phenotype of EMT, and we previously reported that a high degree of solitary cell infiltration correlates with EMT-like features, including reduced E-cadherin and elevated vimentin levels. Using solitary cell infiltration to evaluate the degree of EMT, gene-expression profiling of 12 PDAC xenografts was performed, and SMAD3 was identified as an EMT-related gene. Immunohistochemistry using clinical specimens (n=113) showed that SMAD3 accumulated in the nuclei of tumor cells, but was not detected in most epithelial cells in the pancreatic duct. Moreover, SMAD3 upregulation correlated with malignant characteristics, such as higher tumor grade and lymph node metastasis, as well as with EMT-like features. SMAD4, which plays a key role in transforming growth factor-β (TGF-β) signaling, is inactivated in approximately half of PDAC cases. In this study, the nuclear accumulation of SMAD3 was immunohistochemically detected even in SMAD4-negative cases. SMAD3 knockdown resulted in upregulated E-cadherin, downregulated vimentin, and reduced cell motility in pancreatic cancer cells regardless of SMAD4 status. In addition, TGF-β-treatment resulted in EMT induction in cells carrying wild-type SMAD4, and EMT was suppressed by SMAD3 knockdown. Patients with upregulated SMAD3 and a high degree of solitary cell infiltration had shorter times to recurrence and shorter survival times after surgery, and multivariate analysis showed that both factors were independent prognostic factors linked to unfavorable outcomes. These findings suggest that SMAD3 in PDAC is involved in the promotion of malignant potential through EMT induction in tumor cells regardless of SMAD4 status and serves as a potential biomarker of poor prognosis.
AB - In pancreatic ductal adenocarcinoma (PDAC), features of epithelial-mesenchymal transition (EMT) are often seen in tumor tissue, and such features correlate with poor prognosis. Solitary infiltration of tumor cells represents a morphological phenotype of EMT, and we previously reported that a high degree of solitary cell infiltration correlates with EMT-like features, including reduced E-cadherin and elevated vimentin levels. Using solitary cell infiltration to evaluate the degree of EMT, gene-expression profiling of 12 PDAC xenografts was performed, and SMAD3 was identified as an EMT-related gene. Immunohistochemistry using clinical specimens (n=113) showed that SMAD3 accumulated in the nuclei of tumor cells, but was not detected in most epithelial cells in the pancreatic duct. Moreover, SMAD3 upregulation correlated with malignant characteristics, such as higher tumor grade and lymph node metastasis, as well as with EMT-like features. SMAD4, which plays a key role in transforming growth factor-β (TGF-β) signaling, is inactivated in approximately half of PDAC cases. In this study, the nuclear accumulation of SMAD3 was immunohistochemically detected even in SMAD4-negative cases. SMAD3 knockdown resulted in upregulated E-cadherin, downregulated vimentin, and reduced cell motility in pancreatic cancer cells regardless of SMAD4 status. In addition, TGF-β-treatment resulted in EMT induction in cells carrying wild-type SMAD4, and EMT was suppressed by SMAD3 knockdown. Patients with upregulated SMAD3 and a high degree of solitary cell infiltration had shorter times to recurrence and shorter survival times after surgery, and multivariate analysis showed that both factors were independent prognostic factors linked to unfavorable outcomes. These findings suggest that SMAD3 in PDAC is involved in the promotion of malignant potential through EMT induction in tumor cells regardless of SMAD4 status and serves as a potential biomarker of poor prognosis.
KW - SMAD3
KW - TGF-β
KW - epithelial-mesenchymal transition
KW - pancreatic ductal adenocarcinoma
KW - prognosis
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UR - http://www.scopus.com/inward/citedby.url?scp=84904156674&partnerID=8YFLogxK
U2 - 10.1038/labinvest.2014.53
DO - 10.1038/labinvest.2014.53
M3 - Article
C2 - 24709776
AN - SCOPUS:84904156674
SN - 0023-6837
VL - 94
SP - 683
EP - 691
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 6
ER -
