Oncotarget

Research Papers:

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

Srustidhar Das, Satyanarayana Rachagani, Maria P. Torres-Gonzalez, Imayavaramban Lakshmanan, Prabin D. Majhi, Lynette M. Smith, Kay-Uwe Wagner and Surinder K. Batra _

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Oncotarget. 2015; 6:5772-5787. https://doi.org/10.18632/oncotarget.3308

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Abstract

Srustidhar Das1, Satyanarayana Rachagani1,*, Maria P. Torres-Gonzalez1,*, Imayavaramban Lakshmanan1, Prabin D. Majhi1, Lynette M. Smith2, Kay-Uwe Wagner1,4 and Surinder K. Batra1,3,4

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.


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