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Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-β1/FAK/ERK pathway.

Authors
  • Jahan, Rahat1
  • Macha, Muzafar A2
  • Rachagani, Satyanarayana1
  • Das, Srustidhar1
  • Smith, Lynette M3
  • Kaur, Sukhwinder1
  • Batra, Surinder K4
  • 1 Department of Biochemistry and Molecular Biology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA.
  • 2 Department of Biochemistry and Molecular Biology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA; Department of Otolaryngology-Head and Neck Surgery, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA.
  • 3 Department of Biostatistics, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA.
  • 4 Department of Biochemistry and Molecular Biology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE-68198, USA. Electronic address: [email protected]
Type
Published Article
Journal
Biochimica et Biophysica Acta
Publisher
Elsevier
Publication Date
Aug 01, 2018
Volume
1864
Issue
8
Pages
2538–2549
Identifiers
DOI: 10.1016/j.bbadis.2018.05.008
PMID: 29777904
Source
Medline
Keywords
License
Unknown

Abstract

Alternative splicing is evolving as an eminent player of oncogenic signaling for tumor development and progression. Mucin 4 (MUC4), a type I membrane-bound mucin, is differentially expressed in pancreatic cancer (PC) and plays a critical role in its progression and metastasis. However, the molecular implications of MUC4 splice variants during disease pathogenesis remain obscure. The present study delineates the pathological and molecular significance of a unique splice variant of MUC4, MUC4/X, which lacks the largest exon 2, along with exon 3. Exon 2 encodes for the highly glycosylated tandem repeat (TR) domain of MUC4 and its absence creates MUC4/X, which is devoid of TR. Expression analysis from PC clinical samples revealed significant upregulation of MUC4/X in PC tissues with most differential expression in poorly differentiated tumors. In vitro studies suggest that overexpression of MUC4/X in wild-type-MUC4 (WT-MUC4) null PC cell lines markedly enhanced PC cell proliferation, invasion, and adhesion to extracellular matrix (ECM) proteins. Furthermore, MUC4/X overexpression leads to an increase in the tumorigenic potential of PC cells in orthotopic transplantation studies. In line with these findings, doxycycline-induced expression of MUC4/X in an endogenous WT-MUC4 expressing PC cell line (Capan-1) also displayed enhanced cell proliferation, invasion, and adhesion to ECM, compared to WT-MUC4 alone, emphasizing its direct involvement in the aggressive behavior of PC cells. Investigation into the molecular mechanism suggested that MUC4/X facilitated PC tumorigenesis via integrin-β1/FAK/ERK signaling pathway. Overall, these findings revealed the novel role of MUC4/X in promoting and sustaining the oncogenic features of PC.

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