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, Surinder Kumar Batra

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5772-5787
Number of pages16
JournalOncotarget
Volume6
Issue number8
StatePublished - 2015

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Pancreatic Neoplasms
Neoplastic Stem Cells
Epitopes
G2 Phase
Luciferases
Drug Resistance
Cell Division
Histones
Glycoproteins
Phosphorylation
Apoptosis
Pharmaceutical Preparations
Genes
Neoplasms

Keywords

  • CA125
  • Cancer stem cells
  • JAK2
  • Mucin 16 (MUC16)
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. / Das, Srustidhar; Rachagani, Satyanarayana; Torres-Gonzalez, Maria P.; Lakshmanan, Imayavaramban; Majhi, Prabin D.; Smith, Lynette M; Wagner, Kay Uwe; Batra, Surinder Kumar.

In: Oncotarget, Vol. 6, No. 8, 2015, p. 5772-5787.

Research output: Contribution to journalArticle

Das, Srustidhar ; Rachagani, Satyanarayana ; Torres-Gonzalez, Maria P. ; Lakshmanan, Imayavaramban ; Majhi, Prabin D. ; Smith, Lynette M ; Wagner, Kay Uwe ; Batra, Surinder Kumar. / Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. In: Oncotarget. 2015 ; Vol. 6, No. 8. pp. 5772-5787.
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AU - Rachagani, Satyanarayana

AU - Torres-Gonzalez, Maria P.

AU - Lakshmanan, Imayavaramban

AU - Majhi, Prabin D.

AU - Smith, Lynette M

AU - Wagner, Kay Uwe

AU - Batra, Surinder Kumar

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