The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss

Oncogene. 2015 Mar 26;34(13):1641-9. doi: 10.1038/onc.2014.118. Epub 2014 May 5.


Liver kinase B1 (LKB1) loss in lung adenocarcinoma is commonly caused by genetic mutations, but these mutations rarely occur in Asian patients. We recently reported wild-type LKB1 loss via the alteration of NKX2-1/p53-axis-promoted tumor aggressiveness and predicted poor outcomes in cases of lung adenocarcinoma. The mechanistic action of wild-type LKB1 loss within tumor progression remains unknown. The suppression of MYC by LKB1 controls epithelial organization; therefore, we hypothesize that MYC expression can be increased via wild-type LKB1 loss and promotes tumor progression. Here, MYC transcription is upregulated by LKB1-loss-mediated MZF1 expression. The wild-type LKB1-loss-mediated MZF1/MYC axis is responsible for soft-agar growth, migration and invasion in lung adenocarcinoma cells. Moreover, wild-type LKB1 loss-induced cell invasiveness was markedly suppressed by MYC inhibitors (10058-F4 and JQ1). Patients with low-LKB1/high-MZF1 or low-LKB1/high-MYC tumors have shorter overall survival and relapse-free-survival periods than patients with high-LKB1/low-MZF1 or high-LKB1/low-MYC tumors. In summary, MZF1-mediated MYC expression may promote tumor progression, resulting in poor outcomes in cases of lung adenocarcinoma with low-wild-type-LKB1 tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology*
  • Adenocarcinoma of Lung
  • Cell Movement
  • Disease Progression
  • Humans
  • Kruppel-Like Transcription Factors / physiology*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Neoplasm Invasiveness
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-myc / physiology*


  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • MZF1 protein, human
  • Proto-Oncogene Proteins c-myc
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases