Work

Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells

Year: 2015

Type: article

Abstract: // Srustidhar Das 1 , Satyanarayana Rachagani 1,* , Maria P. Torres-Gonzalez 1,* , Imayavaramban Lakshmanan 1 , Prabin D. Majhi 1 , Lynette M. Smith 2 , Kay-Uwe Wagner 1,4 and Surinder K. Batra 1,3,4 1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA 2 Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA 3 Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA 4 Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA * These authors contributed equally to this work Correspondence: Surinder K. Batra, email: // Keywords : Mucin 16 (MUC16), CA125, pancreatic cancer, JAK2, cancer stem cells Abbreviations : C-Ter, carboxy-terminal; CSC, cancer stem cell; SEA, sperm protein, enterokinase, agrin; JAK2, janus kinase 2 Received : December 13, 2014 Accepted : January 02, 2015 Published : January 21, 2015 Abstract MUC16 (CA125) is a type-I transmembrane glycoprotein that is up-regulated in multiple cancers including pancreatic cancer (PC). However, the existence and role of carboxyl-terminal MUC16 generated following its cleavage in PC is unknown. Our previous study using a systematic dual-epitope tagged domain deletion approach of carboxyl-terminal MUC16 has demonstrated the generation of a 17-kDa cleaved MUC16 (MUC16-Cter). Here, we demonstrate the functional significance of MUC16-Cter in PC using the dual-epitope tagged version (N-terminal FLAG- and C-terminal HA-tag) of 114 carboxyl-terminal residues of MUC16 (F114HA). In vitro analyses using F114HA transfected MiaPaCa-2 and T3M4 cells showed enhanced proliferation, motility and increased accumulation of cells in the G2/M phase with apoptosis resistance, a feature associated with cancer stem cells (CSCs). This was supported by enrichment of ALDH + CSCs along with enhanced drug-resistance. Mechanistically, we demonstrate a novel function of MUC16-Cter that promotes nuclear translocation of JAK2 resulting in phosphorylation of Histone-3 up-regulating stemness-specific genes LMO2 and NANOG. Jak2 dependence was demonstrated using Jak2 +/+ and Jak2 –/– cells. Using eGFP-Luciferase labeled cells, we demonstrate enhanced tumorigenic and metastatic potential of MUC16-Cter in vivo . Taken together, we demonstrate that MUC16-Cter mediated enrichment of CSCs is partly responsible for tumorigenic, metastatic and drug-resistant properties of PC cells.

Source: Oncotarget

DOI: 10.18632/oncotarget.3308