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.
Highlights
Pancreatic cancer is one of the most lethal cancers, causing an estimated 227000 deaths per year worldwide [1]
We found that Nodal expression is upregulated widely in pancreatic cancer cells, in cancer stem cells (CSCs), and in tumor-associated stromal cells, and it induces a metastatic phenotype in pancreatic cancer cells by promoting epithelial-mesenchymal transition (EMT) and enhancing the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4) via the Smad2/3 pathway, indicating that Nodal signaling is a critical mechanism in the metastasis of pancreatic cancer and might be a therapeutic target for the treatment of pancreatic cancer
We further demonstrated that tumorassociated pancreatic stellate cells (PSCs), which are the critical stromal cells in pancreatic cancer, exhibit increased Nodal expression compared to quiescent PSCs
Summary
Pancreatic cancer is one of the most lethal cancers, causing an estimated 227000 deaths per year worldwide [1]. Cancer cell proliferation, self-renewal, and epithelial-mesenchymal transition (EMT) are defined features of hESCs. EMT generally occurs during embryonic development and is an important element in cancer progression, endowing cells with migratory www.impactjournals.com/oncotarget and aggressive properties that lead to tumor metastasis [3]. Nodal expression in malignancies correlates with cancer growth and progression and may be a prognostic marker [16]. These studies demonstrated that abnormally expressed Nodal promotes cancer cell proliferation, invasion, migration and inhibits apoptosis; Nodal induces angiogenesis by accelerating VEGF and PDGF expression and secretion [17,18,19]. Whether Nodal is expressed widely in pancreatic cancer cells or impacts the behavior of the majority of pancreatic cancer cells is ill-defined
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