Upregulation of MUC1 by its novel activator 14-3-3ζ promotes tumor invasion and indicates poor prognosis in lung adenocarcinoma

Oncol Rep. 2017 Nov;38(5):2637-2646. doi: 10.3892/or.2017.5948. Epub 2017 Sep 7.

Abstract

Lung adenocarcinoma (LAC) is currently the predominant histological subtype of lung cancer. Despite recent advancement in targeted therapies, the average 5-year survival rate is only 15%, highlighting the need to identify previously unrecognized molecular events that propel cancer development. Herein, we showed knockdown of 14-3-3ζ suppresses cell proliferation, migration and invasion capability of A549 and H1299 cells. MUC1 was then identified as a novel target of 14-3-3ζ protein. Overexpression of MUC1 is found to induce epithelial-mesenchymal transition and promote metastasis of lung cancer cells, while knockdown of 14-3-3ζ can completely abolish the oncogenic function of MUC1.Furthermore, we unraveled a novel mechanism that 14-3-3ζ activates NF-κB signaling pathway, and therefore enhanced MUC1/NF-κB feedback loop to upregulate MUC1 expression. From a clinical point of view, we evaluated the expression of14-3-3ζ and MUC1 in GSE68465 datasets, in which high expression of14-3-3ζ and MUC1 emerged as poor prognostic factors in LAC patients. In conclusion, we provide novel evidence that 14-3-3ζ regulates MUC1 through MUC1/NF-κB feedback loop. 14-3-3ζ and MUC1 is a promising prognostic biomarker for lung cancer patients and therapeutic targeting of 14-3-3ζ and MUC1 may be a potential treatment option for patients with LAC.

MeSH terms

  • 14-3-3 Proteins / genetics*
  • 14-3-3 Proteins / metabolism
  • A549 Cells
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mucin-1 / genetics*
  • Mucin-1 / metabolism
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Prognosis
  • Signal Transduction
  • Up-Regulation*

Substances

  • 14-3-3 Proteins
  • MUC1 protein, human
  • Mucin-1
  • NF-kappa B
  • YWHAZ protein, human