title: FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma.
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.
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Mikse
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Blake
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Jones
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Gallagher
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarus
authors.forename: Judith
authors.initials: J
authors.lastname: Weisz
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Herzog
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D003043:Cocarcinogenesis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D002273:Carcinogens; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide