title: LKB1 loss by alteration of the NKX2-1/p53 pathway promotes tumor malignancy and predicts poor survival and relapse in lung adenocarcinomas.
abstract: LKB1 loss is a frequent homozygous deletion and/or gene mutation found in lung adenocarcinomas. However, few cases of LKB1 loss by either deletion or mutation are seen in Asian patients. Our preliminary data showed that LKB1 loss was associated with p53 mutation in lung tumors from Taiwanese adenocarcinoma patients and p53 transcription is directly regulated by NKX2-1. Therefore, we hypothesized that LKB1 loss could occur due to aberration of p53 regulation mediated by NKX2-1. In the present study, 16 lung adenocarcinoma cell lines were investigated to determine if LKB1 transcription could be deregulated by NKX2-1-mediated p53 aberration. Mechanistic studies indicated that LKB1 was directly upregulated by p53 and that NKX2-1-mediated p53 expression may positively regulate LKB1 expression in p53 wild-type cells. However, in p53-mutated cells, LKB1 transcription was deregulated by NKX2-1 via suppression of SP1 binding onto the LKB1 promoter. Therefore, the action of the NKX2-1/p53 pathway on LKB1 loss differed in p53 wild-type versus p53-mutated cells. As expected, soft-agar growth and invasion capability was significantly reduced by ectopic expression of NKX2-1 in p53 wild-type cells, but it was markedly elevated by silencing NKX2-1 in p53-mutated cells. Similar reciprocal observations were also seen in lung tumors from lung adenocarcinoma patients with either wild-type or mutated p53 tumors. Cox regression analysis showed that patients with low-LKB1 tumors had poorer overall survival (OS) and relapse-free survival (RFS) when compared with patients with high-LKB1 tumors. In p53 wild-type patients, shorter OS and RFS periods were predicted for low-NKX2-1/low-LKB1 tumors than for high-NKX2-1/high-LKB1 tumors. In patients with p53-mutated tumors, poorer OS and RFS were predicted for high-NKX2-1/low-LKB1 tumors than for low-NKX2-1/high-LKB1 tumors. In summary, losses of LKB1 at the transcriptional level by altered activity of the NKX2-1/p53 pathway may promote tumor malignancy and poor patient outcome.
authors.affiliation: 1] Institute of Medical and Molecular Toxicology, Taichung, Taiwan [2] Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: L-H
authors.initials: LH
authors.lastname: Tsai
authors.affiliation: 1] Institute of Medical and Molecular Toxicology, Taichung, Taiwan [2] Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: P-M
authors.initials: PM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, 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: 1] Institute of Medical and Molecular Toxicology, Taichung, Taiwan [2] Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan [3] Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases