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FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma
Oliver R Mikse1, Daniel C Blake, Nathan R Jones
1Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Abstract:
The FOXO family of transcription factors elicits cell cycle arrest, apoptosis, and resistance to various physiologic and pathologic stresses relevant to sporadic cancer, such as DNA damage and oxidative stress. Although implicated as tumor suppressors, FOXO genetic inactivation has not been observed in human cancer. In an investigation of the two major types of non-small cell lung cancer, here, we identify the FOXO3 gene as a novel target of deletion in human lung adenocarcinoma (LAC). Biallelic or homozygous deletion (HD) of FOXO3 was detected in 8 of 33 (24.2%) mostly early-stage LAC of smokers. Another 60.6% of these tumors had losses of FOXO3 not reaching the level of HD (hereafter referred to as sub-HD). In contrast, no HD of FOXO3 was observed in 19 lung squamous cell carcinoma. Consistent with the deletion of FOXO3 were corresponding decreases in its mRNA and protein levels in LAC. The potential role of FOXO3 loss in LAC was also investigated. The carcinogen (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) is strongly implicated as a cause of human lung cancer. Here, we show that FOXO3a is functionally activated and augments the level of caspase-dependent apoptosis in cells exposed to this DNA-damaging carcinogen. These results implicate FOXO3 as a suppressor of LAC carcinogenesis, a role frequently lost through gene deletion.
Insights
FOXO3 gene deletion is a frequent event in lung adenocarcinoma (LAC), particularly in smokers. Loss of FOXO3 suppresses cancer development by promoting apoptosis in response to DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- FOXO transcription factors are involved in cellular stress responses and cancer suppression.
- Genetic inactivation of FOXO factors has not been previously observed in human cancers.
- Lung adenocarcinoma (LAC) is a major type of non-small cell lung cancer.
Purpose of the Study:
- To investigate the role of FOXO genes in lung cancer, specifically lung adenocarcinoma.
- To identify if FOXO gene deletion is a mechanism contributing to LAC development.
Main Methods:
- Analysis of FOXO3 gene deletion (homozygous deletion and sub-homozygous deletion) in LAC and lung squamous cell carcinoma (LSCC) patient samples.
- Measurement of FOXO3 mRNA and protein levels in LAC.
- Functional studies assessing the role of FOXO3a in apoptosis induction upon exposure to the carcinogen BPDE.
Main Results:
- FOXO3 gene deletion was detected in 24.2% of early-stage LAC, with an additional 60.6% showing sub-homozygous deletion.
- No homozygous deletion of FOXO3 was observed in lung squamous cell carcinoma.
- FOXO3 deletion correlated with decreased mRNA and protein levels in LAC.
- FOXO3a activation enhanced apoptosis in cells exposed to the lung carcinogen BPDE.
Conclusions:
- FOXO3 acts as a tumor suppressor in lung adenocarcinoma.
- Gene deletion is a mechanism for FOXO3 loss in LAC, contributing to carcinogenesis.
- Loss of FOXO3 function may promote LAC development, especially in smokers.
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