title: The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss.
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.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: L-H
authors.initials: LH
authors.lastname: Tsai
authors.affiliation: Department of Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, and College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: G-T
authors.initials: GT
authors.lastname: Sheu
authors.affiliation: Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*
chemical_list: D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C085969:MZF1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases