Milewski David, Balli David, Ustiyan Vladimir, Le Tien, Dienemann Hendrik, Warth Arne, Breuhahn Kai, Whitsett Jeffrey A, Kalinichenko Vladimir V, Kalin Tanya V
Division of Pulmonary Biology, the Perinatal Institute of Cincinnati Children's Research Foundation, Cincinnati, Ohio, United States of America.
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2017 Dec 21;13(12):e1007097. doi: 10.1371/journal.pgen.1007097. eCollection 2017 Dec.
Lung cancer remains one of the most prominent public health challenges, accounting for the highest incidence and mortality among all human cancers. While pulmonary invasive mucinous adenocarcinoma (PIMA) is one of the most aggressive types of non-small cell lung cancer, transcriptional drivers of PIMA remain poorly understood. In the present study, we found that Forkhead box M1 transcription factor (FOXM1) is highly expressed in human PIMAs and associated with increased extracellular mucin deposition and the loss of NKX2.1. To examine consequences of FOXM1 expression in tumor cells in vivo, we employed an inducible, transgenic mouse model to express an activated FOXM1 transcript in urethane-induced benign lung adenomas. FOXM1 accelerated tumor growth, induced progression from benign adenomas to invasive, metastatic adenocarcinomas, and induced SOX2, a marker of poorly differentiated tumor cells. Adenocarcinomas in FOXM1 transgenic mice expressed increased MUC5B and MUC5AC, and reduced NKX2.1, which are characteristics of mucinous adenocarcinomas. Expression of FOXM1 in KrasG12D transgenic mice increased the mucinous phenotype in KrasG12D-driven lung tumors. Anterior Gradient 2 (AGR2), an oncogene critical for intracellular processing and packaging of mucins, was increased in mouse and human PIMAs and was associated with FOXM1. FOXM1 directly bound to and transcriptionally activated human AGR2 gene promoter via the -257/-247 bp region. Finally, using orthotopic xenografts we demonstrated that inhibition of either FOXM1 or AGR2 in human PIMAs inhibited mucinous characteristics, and reduced tumor growth and invasion. Altogether, FOXM1 is necessary and sufficient to induce mucinous phenotypes in lung tumor cells in vivo.
肺癌仍然是最突出的公共卫生挑战之一，在所有人类癌症中发病率和死亡率最高。虽然肺浸润性黏液腺癌（PIMA）是侵袭性最强的非小细胞肺癌类型之一，但PIMA的转录驱动因素仍知之甚少。在本研究中，我们发现叉头框M1转录因子（FOXM1）在人类PIMA中高表达，并与细胞外黏液沉积增加和NKX2.1缺失相关。为了研究FOXM1在体内肿瘤细胞中的表达后果，我们采用了一种可诱导的转基因小鼠模型，在氨基甲酸乙酯诱导的良性肺腺瘤中表达激活的FOXM1转录本。FOXM1加速肿瘤生长，诱导从良性腺瘤进展为侵袭性、转移性腺癌，并诱导SOX2表达，SOX2是低分化肿瘤细胞的标志物。FOXM1转基因小鼠中的腺癌表达增加的MUC5B和MUC5AC，并降低NKX2.1，这是黏液腺癌的特征。FOXM1在KrasG12D转基因小鼠中的表达增加了KrasG12D驱动的肺肿瘤中的黏液表型。前梯度2（AGR2）是一种对黏蛋白的细胞内加工和包装至关重要的癌基因，在小鼠和人类PIMA中增加，并与FOXM1相关。FOXM1通过-257/-247 bp区域直接结合并转录激活人类AGR2基因启动子。最后，使用原位异种移植我们证明，抑制人类PIMA中的FOXM1或AGR2可抑制黏液特征，并减少肿瘤生长和侵袭。总之，FOXM1在体内诱导肺肿瘤细胞中的黏液表型既必要又充分。
