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.
Highlights
Pancreatic cancer (PC) confers a near 100% mortality, a dismal 5-year survival rate of 5% and a median survival of 5-8 months [1]
We demonstrate that MUC16-Cter mediated enrichment of cancer stem cell (CSC) is partly responsible for tumorigenic, metastatic and drug-resistant properties of pancreatic cancer (PC) cells
Previous studies addressed the functional significance of various lengths of carboxyl-terminal MUC16 fragments (283 and 413 amino acids) in ovarian, breast and colon cancer cells, none demonstrated whether a cleaved MUC16 is generated following ectopic expression of these fragments [19,24,34]
Summary
Pancreatic cancer (PC) confers a near 100% mortality, a dismal 5-year survival rate of 5% and a median survival of 5-8 months [1]. Recent studies using lineage tracing in genetically engineered mouse models and mathematical modeling using patient datasets have proposed early dissemination of PC cells to establish the metastatic disease [2,3]. These early-disseminated cells called circulatory pancreatic cells (CPCs) are of mesenchymal type and possess the characteristics of cancer stem cells (CSCs) [2]. A number of recent studies have demonstrated the significance of CSC in metastasis, www.impactjournals.com/oncotarget chemo resistance and disease recurrence in various cancers including PC [4,5,6]. Our understanding of the mechanism(s) of CSC enrichment and maintenance will be critical in devising successful therapeutic strategies against the lethal PC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
