FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma

Oliver R. Mikse, Daniel C. Blake, Nathan R. Jones, Yuan Wan Sun, Shantu Amin, Carla J. Gallagher, Philip Lazarus, Judith Weisz, Christopher R. Herzog

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6205-6215
Number of pages11
JournalCancer Research
Volume70
Issue number15
DOIs
StatePublished - Aug 1 2010

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Carcinogens
Transcription Factors
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Neoplasms
Apoptosis
Gene Deletion
Caspases
Cell Cycle Checkpoints
Non-Small Cell Lung Carcinoma
DNA Damage
Squamous Cell Carcinoma
Lung Neoplasms
Carcinogenesis
Oxidative Stress
Adenocarcinoma of lung
Lung
Messenger RNA
DNA
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Mikse, Oliver R. ; Blake, Daniel C. ; Jones, Nathan R. ; Sun, Yuan Wan ; Amin, Shantu ; Gallagher, Carla J. ; Lazarus, Philip ; Weisz, Judith ; Herzog, Christopher R. / FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma. In: Cancer Research. 2010 ; Vol. 70, No. 15. pp. 6205-6215.
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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.",
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FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma. / Mikse, Oliver R.; Blake, Daniel C.; Jones, Nathan R.; Sun, Yuan Wan; Amin, Shantu; Gallagher, Carla J.; Lazarus, Philip; Weisz, Judith; Herzog, Christopher R.

In: Cancer Research, Vol. 70, No. 15, 01.08.2010, p. 6205-6215.

Research output: Contribution to journalArticle

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T1 - FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma

AU - Mikse, Oliver R.

AU - Blake, Daniel C.

AU - Jones, Nathan R.

AU - Sun, Yuan Wan

AU - Amin, Shantu

AU - Gallagher, Carla J.

AU - Lazarus, Philip

AU - Weisz, Judith

AU - Herzog, Christopher R.

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N2 - 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.

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