| Summary: | 博士 === 中山醫學大學 === 醫學研究所 === 102 === LKB1 loss is a frequent homozygous deletion and/or gene mutation in lung adenocarcinomas. However, few cases of LKB1 loss by either deletion or mutation are seen in Asian patients including Taiwanese. Therefore, other factors may also result in the loss of LKB1. 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. Herein, 16 lung adenocarcinoma cell lines were investigated to determine if LKB1 transcription could be deregulated by NKX2-1-mediated p53 aberration. Mechanistically, 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. 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. 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. We next explored the possibility that MYC expression can be increased via LKB1 loss and promoted tumor progression. Mechanistically, MYC transcription is up-regulated by LKB1 loss-mediated MZF1 expression. The LKB1 loss-mediated MZF1/MYC axis is responsible for soft-agar growth, migration, and invasion in lung adenocarcinoma cells. Consistently, LKB1 loss-induced cell invasiveness was markedly suppressed by MYC inhibitors (10058-F4 and JQ1). In conclusion, LKB1 loss at transcription levels, not gene mutations and LOH, is mediated through the NKX2-1/p53 axis. In addition, MZF1-mediated MYC expression due to LKB1 loss is responsible for tumor progression and consequently resulting in poor outcomes in lung adenocarcinoma.
|
|---|
