title: Overexpression of Nodal induces a metastatic phenotype in pancreatic cancer cells via the Smad2/3 pathway.
abstract: Metastasis is the major cause for the high mortality rate of pancreatic cancer. Human embryonic stem cell (hESC) associated genes frequently correlate with malignant disease progression. Recent studies have demonstrated that the embryonic protein Nodal, which plays a critical role during embryonic development, is re-expressed in several types of tumors and promotes cancers progression. However, little is known about the role of Nodal in pancreatic cancer. Here, we show that Nodal expression is upregulated in human pancreatic cancer tissues. Moreover, Nodal expression levels correlate well with the grade of pancreatic cancer differentiation. In addition, we present clear evidence that Nodal induces signal transduction through the Smad2/3-dependent pathway in vitro. Furthermore, we show that Nodal promotes pancreatic cancer cell migration and invasion, induces epithelial-mesenchymal transition (EMT) and enhances the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4). Using an in vivo liver metastasis model of pancreatic cancer, we observed that blocking Nodal signaling activity with the small-molecule inhibitor SB431542 decreases the number and size of liver metastases. Taken together, our results suggest that Nodal overexpression induces a metastatic phenotype in pancreatic cancer cells, and that targeting Nodal signaling may be a promising therapeutic strategy for pancreatic cancer.
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Wanxing
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.|Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Nan
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xuqi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D055457:Nodal Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein