Tsai L-H, Wu J-Y, Cheng Y-W, Chen C-Y, Sheu G-T, Wu T-C, Lee H
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, and College of Medicine, Tzu Chi University, Hualien, Taiwan.
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.
肺腺癌中肝激酶B1（LKB1）缺失通常由基因突变引起，但这些突变在亚洲患者中很少发生。我们最近报道了通过NKX2-1/p53轴改变导致野生型LKB1缺失，从而促进肿瘤侵袭，并预测肺腺癌患者预后不良。野生型LKB1缺失在肿瘤进展中的作用机制尚不清楚。LKB1对MYC的抑制作用控制上皮组织；因此，我们假设野生型LKB1缺失可增加MYC表达并促进肿瘤进展。在此，MYC转录通过LKB1缺失介导的MZF1表达上调。野生型LKB1缺失介导的MZF1/MYC轴负责肺腺癌细胞在软琼脂中的生长、迁移和侵袭。此外，MYC抑制剂（10058-F4和JQ1）可显著抑制野生型LKB1缺失诱导的细胞侵袭。与高LKB1/低MZF1或高LKB1/低MYC肿瘤患者相比，低LKB1/高MZF1或低LKB1/高MYC肿瘤患者的总生存期和无复发生存期更短。总之，MZF1介导的MYC表达可能促进肿瘤进展，导致野生型LKB1低表达的肺腺癌患者预后不良。
