SET contributes to the epithelial-mesenchymal transition of pancreatic cancer
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Hardik R. Mody2,3,*, Sau Wai Hung3,*, Kineta Naidu4, Haesung Lee4, Caitlin A. Gilbert4, Toan Thanh Hoang4, Rakesh K. Pathak2, Radhika Manoharan2, Shanmugam Muruganandan2 and Rajgopal Govindarajan1,2,3
1The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
2Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA
3Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, GA, USA
4Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA, USA
*These authors have contributed equally to this work
Rajgopal Govindarajan, email: email@example.com
Keywords: SET, EMT, pancreatic cancer, N-cadherin, signaling
Received: December 20, 2016 Accepted: May 22, 2017 Published: July 07, 2017
Pancreatic cancer has a devastating prognosis due to 80-90% of diagnostic cases occurring when metastasis has already presented. Activation of the epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis because it allows for the dissemination of tumor cells to blood stream and secondary organs. Here, we sought to determine the role of SET oncoprotein, an endogenous inhibitor of PP2A, in EMT and pancreatic tumor progression. Among the two major isoforms of SET (isoform 1 and isoform 2), higher protein levels of SET isoform 2 were identified in aggressive pancreatic cancer cell lines. Overexpressing SET isoform 2, and to a lesser extent SET isoform 1, in epithelial cell lines promoted EMT-like features by inducing mesenchymal characteristics and promoting cellular proliferation, migration, invasion, and colony formation. Consistently, knockdown of SET isoforms in the mesenchymal cell line partially resisted these characteristics and promoted epithelial features. SET-induced EMT was likely facilitated by increased N-cadherin overexpression, decreased PP2A activity and/or increased expression of key EMT-driving transcription factors. Additionally, SET overexpression activated the Rac1/JNK/c-Jun signaling pathway that induced transcriptional activation of N-cadherin expression. In vivo, SET isoform 2 overexpression significantly correlated with increased N-cadherin in human PDAC and to tumor burden and metastatic ability in an orthotopic mouse tumor model. These findings identify a new role for SET in cancer and have implications for the design and targeting of SET for intervening pancreatic tumor progression.
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