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

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

Author information

1
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
2
Department of Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, and College of Medicine, Tzu Chi University, Hualien, Taiwan.
3
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
4
Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
5
Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.

Abstract

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.

PMID:
24793789
DOI:
10.1038/onc.2014.118
[Indexed for MEDLINE]

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