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Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice.

Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K, Fostel J, Yamamoto M, Kleeberger SR - PLoS ONE (2011)

Bottom Line: However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance.Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia.Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America. alison.bauer@ucdenver.edu

ABSTRACT
Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2(+/+) and Nrf2(-/-) mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2(-/-) mice compared to Nrf2(+/+) mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2(-/-) mice than in Nrf2(+/+) mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2(+/+) mice relative to Nrf2(-/-) mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

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Adenoma development and persistent lung inflammation at 22 wk.(A) Average number of adenomas per whole lung from each animal (tumor multiplicity) and number of tumors per size ranges and average size (mm) of individual tumors were assessed in lungs fixed with Tellyesniczky's fixative. Mean±SD are presented (n = 4−5/group saline; n = 14/group for tumor multiplicity; n = 14−20/group for tumor size). This study was repeated once with similar n and responses determined. *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice. (B) Bronchoalveolar lavage (BAL) analysis of the number of neutrophils in Nrf2+/+ and Nrf2-/- mice at 22 wk after urethane treatment. Mean±SD are presented (n = 7−10/group urethane treated and n = 3−5/group for saline). *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice.
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pone-0026590-g003: Adenoma development and persistent lung inflammation at 22 wk.(A) Average number of adenomas per whole lung from each animal (tumor multiplicity) and number of tumors per size ranges and average size (mm) of individual tumors were assessed in lungs fixed with Tellyesniczky's fixative. Mean±SD are presented (n = 4−5/group saline; n = 14/group for tumor multiplicity; n = 14−20/group for tumor size). This study was repeated once with similar n and responses determined. *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice. (B) Bronchoalveolar lavage (BAL) analysis of the number of neutrophils in Nrf2+/+ and Nrf2-/- mice at 22 wk after urethane treatment. Mean±SD are presented (n = 7−10/group urethane treated and n = 3−5/group for saline). *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice.

Mentions: Multiplicity (∼43%) of small (≤1.6 mm) adenomas was significantly reduced in Nrf2-/- mice compared to Nrf2+/+ mice at 22 wk after urethane treatment (Figure 3A). However, no differences were found in overall tumor size or tumor morphology between genotypes. Large tumors were located primarily at the lung pleural surface, while small developing tumors were more frequent in internal regions. While no specific differences were observed in other BAL phenotypes, the numbers of neutrophils were significantly lower in Nrf2-/- mice compared to Nrf2+/+ mice at 22 wk (Figure 3B).


Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice.

Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K, Fostel J, Yamamoto M, Kleeberger SR - PLoS ONE (2011)

Adenoma development and persistent lung inflammation at 22 wk.(A) Average number of adenomas per whole lung from each animal (tumor multiplicity) and number of tumors per size ranges and average size (mm) of individual tumors were assessed in lungs fixed with Tellyesniczky's fixative. Mean±SD are presented (n = 4−5/group saline; n = 14/group for tumor multiplicity; n = 14−20/group for tumor size). This study was repeated once with similar n and responses determined. *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice. (B) Bronchoalveolar lavage (BAL) analysis of the number of neutrophils in Nrf2+/+ and Nrf2-/- mice at 22 wk after urethane treatment. Mean±SD are presented (n = 7−10/group urethane treated and n = 3−5/group for saline). *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198791&req=5

pone-0026590-g003: Adenoma development and persistent lung inflammation at 22 wk.(A) Average number of adenomas per whole lung from each animal (tumor multiplicity) and number of tumors per size ranges and average size (mm) of individual tumors were assessed in lungs fixed with Tellyesniczky's fixative. Mean±SD are presented (n = 4−5/group saline; n = 14/group for tumor multiplicity; n = 14−20/group for tumor size). This study was repeated once with similar n and responses determined. *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice. (B) Bronchoalveolar lavage (BAL) analysis of the number of neutrophils in Nrf2+/+ and Nrf2-/- mice at 22 wk after urethane treatment. Mean±SD are presented (n = 7−10/group urethane treated and n = 3−5/group for saline). *, p<0.05 vs. genotype-matched controls. +, p<0.05 vs. urethane-treated Nrf2+/+ mice.
Mentions: Multiplicity (∼43%) of small (≤1.6 mm) adenomas was significantly reduced in Nrf2-/- mice compared to Nrf2+/+ mice at 22 wk after urethane treatment (Figure 3A). However, no differences were found in overall tumor size or tumor morphology between genotypes. Large tumors were located primarily at the lung pleural surface, while small developing tumors were more frequent in internal regions. While no specific differences were observed in other BAL phenotypes, the numbers of neutrophils were significantly lower in Nrf2-/- mice compared to Nrf2+/+ mice at 22 wk (Figure 3B).

Bottom Line: However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance.Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia.Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America. alison.bauer@ucdenver.edu

ABSTRACT
Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2(+/+) and Nrf2(-/-) mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2(-/-) mice compared to Nrf2(+/+) mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2(-/-) mice than in Nrf2(+/+) mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2(+/+) mice relative to Nrf2(-/-) mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

Show MeSH
Related in: MedlinePlus