Abstract
Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.
Highlights
Lung cancer accounts for 30% of tumor-related deaths [1]
To investigate whether CCAAT/enhancer binding protein a (C/EBPa) performs its tumor-suppressing function by restraining BMI1 expression, we examined the correlation between C/EBPa and BMI1 protein amounts in primary lung cancer patient specimens through immunohistochemistry (IHC)
To investigate whether BMI1 expression correlates with prognosis in lung cancer for patients with negative/low C/ EBPa expression, we compared overall survival in 490 lung adenocarcinoma samples available in The Cancer Genome Atlas [TCGA; lung adenocarcinoma (LUAD) data set at https://tcga-data.nci.nih.gov/tcga/], as well as three different publicly available microarray expression databases [18,19,20], containing data from additional 490 non–small cell lung cancer (NSCLC) patients
Summary
Lung cancer accounts for 30% of tumor-related deaths [1]. Most patients are refractory to current treatments; understanding the mechanisms that control lung tumorigenesis is essential to design new therapies. C/EBPa controls tissue-specific gene expression and promotes proliferation arrest in terminally differentiated cells from several tissues, including pulmonary cells [4]. Lung-specific in utero loss of C/EBPa results in delayed maturation of the lung, respiratory arrest, and lethality after birth, caused by epithelial cell expansion and loss of airspace [14, 15]. C/EBPa loss causes lack of differentiation, hyperproliferation, and increased survival of type II alveolar cells, with an overall down-regulation of genes involved in differentiation, and up-regulation of proliferation, tumor progression, and cell survival genes [14]. Induction of C/EBPa expression in human lung cancer cells resulted in differentiation and growth reduction, attributable to proliferation arrest and apoptosis [16]
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