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

Oncotarget. 2015 Mar 20;6(8):5772-87. doi: 10.18632/oncotarget.3308.


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.

Keywords: CA125; JAK2; cancer stem cells; mucin 16 (MUC16); pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CA-125 Antigen / metabolism*
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Cell Nucleus / metabolism
  • HeLa Cells
  • Heterografts
  • Humans
  • Janus Kinase 2 / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Protein Structure, Tertiary
  • Protein Transport


  • CA-125 Antigen
  • MUC16 protein, human
  • Membrane Proteins
  • JAK2 protein, human
  • Janus Kinase 2