Research Papers:

Overexpression of Nodal induces a metastatic phenotype in pancreatic cancer cells via the Smad2/3 pathway

Wanxing Duan _, Rong Li, Jiguang Ma, Jianjun Lei, Qinhong Xu, Zhengdong Jiang, Ligang Nan, Xuqi Li, Zheng Wang, Xiongwei Huo, Liang Han, Zheng Wu, Erxi Wu and Qingyong Ma

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Oncotarget. 2015; 6:1490-1506. https://doi.org/10.18632/oncotarget.2686

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Wanxing Duan1,*, Rong Li1,2,*, Jiguang Ma3, Jianjun Lei1, Qinhong Xu1, Zhengdong Jiang1, Ligang Nan1, Xuqi Li4, Zheng Wang1, Xiongwei Huo4, Liang Han1, Zheng Wu1, Erxi Wu5, Qingyong Ma1

1Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi’an 710061, China

2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

3Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University, Xi’an 710061, China

4Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi’an 710061, China

5Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, USA

*These authors contributed equally to this work

Correspondence to:

Qingyong Ma, e-mail: [email protected]

Keywords: Nodal, metastasis, pancreatic cancer, Smad2/3 pathway

Received: August 11, 2014     Accepted: November 02, 2014     Published: December 01, 2014


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.

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