Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1: ERK signaling axis
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Ryan L. Hanson1, Roger B. Brown2, Maria M. Steele1, Paul M. Grandgenett1, James A. Grunkemeyer1, Michael A. Hollingsworth1
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
2University of New Mexico, Albuquerque, NM 87131, USA
Michael A. Hollingsworth, email: firstname.lastname@example.org
Keywords: FRA-1, MUC1, ERK, pancreatic cancer, invasion
Received: April 04, 2016 Accepted: May 10, 2016 Published: May 23, 2016
The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases.
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