Limits...
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.

Show MeSH

Related in: MedlinePlus

Lung gene expression profiles during urethane-induced tumorigenesis.(A) Urethane effects on gene expression during lung tumorigenesis were compared by biological function and disorder categories of genes significantly changed in pre-/early-neoplastic stage at 12 wk (top), in uninvolved tissues (UN) at 22 wk (middle), and in tumors at 22 wk (bottom) using Ingenuity Pathway Analysis (IPA). Top-ranked categories are depicted against -log(p) determined by IPA. (B) Among the lung gene transcripts significantly (p<0.05) changed in uninvolved (UN, n = 1564) and tumor (n = 8683) tissues compared to saline-treated lung tissues, Venn diagram analysis identified genes changed in either tissue or in common at 22 wk after the initial urethane treatment (top). Expression profiles of all tumor genes (n = 8683, 22 wk UT-Tum) are depicted in pre-/early neoplastic microenvironment (12 wk) and in UN tissues of tumor-bearing lungs at 22 wk (bottom). Color bar indicates expression intensity of individual transcripts normalized to their time-matched saline control levels expressed in yellow (yellow to blue, down-regulation; yellow to red, up-regulation). Y axis = log2 (normalized average intensity), Sal = saline-treated whole lung, UT = urethane-treated (whole lung for 12 wk, UN or Tum for 22 wk), UN = uninvolved tissue, Tum = tumor tissue.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198791&req=5

pone-0026590-g005: Lung gene expression profiles during urethane-induced tumorigenesis.(A) Urethane effects on gene expression during lung tumorigenesis were compared by biological function and disorder categories of genes significantly changed in pre-/early-neoplastic stage at 12 wk (top), in uninvolved tissues (UN) at 22 wk (middle), and in tumors at 22 wk (bottom) using Ingenuity Pathway Analysis (IPA). Top-ranked categories are depicted against -log(p) determined by IPA. (B) Among the lung gene transcripts significantly (p<0.05) changed in uninvolved (UN, n = 1564) and tumor (n = 8683) tissues compared to saline-treated lung tissues, Venn diagram analysis identified genes changed in either tissue or in common at 22 wk after the initial urethane treatment (top). Expression profiles of all tumor genes (n = 8683, 22 wk UT-Tum) are depicted in pre-/early neoplastic microenvironment (12 wk) and in UN tissues of tumor-bearing lungs at 22 wk (bottom). Color bar indicates expression intensity of individual transcripts normalized to their time-matched saline control levels expressed in yellow (yellow to blue, down-regulation; yellow to red, up-regulation). Y axis = log2 (normalized average intensity), Sal = saline-treated whole lung, UT = urethane-treated (whole lung for 12 wk, UN or Tum for 22 wk), UN = uninvolved tissue, Tum = tumor tissue.

Mentions: To identify potential mechanisms of urethane-induced tumorigenesis, we then used trancriptomics of tumor and uninvolved tissue to identify differentiating gene networks. Significant changes in 6519 lung gene transcripts were found in Nrf2+/+ mice relative to saline controls in 12 wk, and expression changes were mostly 2-fold or lower (Table S1; n = 3 mice/group). Functional classification by Ingenuity Pathway Analysis (IPA) determined that lung genes changed during early tumorigenesis have roles in cellular growth and proliferation, cell and tissue development, cell cycle and cellular assembly, small molecule biochemistry, lipid metabolism, and molecular transport (Figure 5A, top panel; Table S1).


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)

Lung gene expression profiles during urethane-induced tumorigenesis.(A) Urethane effects on gene expression during lung tumorigenesis were compared by biological function and disorder categories of genes significantly changed in pre-/early-neoplastic stage at 12 wk (top), in uninvolved tissues (UN) at 22 wk (middle), and in tumors at 22 wk (bottom) using Ingenuity Pathway Analysis (IPA). Top-ranked categories are depicted against -log(p) determined by IPA. (B) Among the lung gene transcripts significantly (p<0.05) changed in uninvolved (UN, n = 1564) and tumor (n = 8683) tissues compared to saline-treated lung tissues, Venn diagram analysis identified genes changed in either tissue or in common at 22 wk after the initial urethane treatment (top). Expression profiles of all tumor genes (n = 8683, 22 wk UT-Tum) are depicted in pre-/early neoplastic microenvironment (12 wk) and in UN tissues of tumor-bearing lungs at 22 wk (bottom). Color bar indicates expression intensity of individual transcripts normalized to their time-matched saline control levels expressed in yellow (yellow to blue, down-regulation; yellow to red, up-regulation). Y axis = log2 (normalized average intensity), Sal = saline-treated whole lung, UT = urethane-treated (whole lung for 12 wk, UN or Tum for 22 wk), UN = uninvolved tissue, Tum = tumor tissue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198791&req=5

pone-0026590-g005: Lung gene expression profiles during urethane-induced tumorigenesis.(A) Urethane effects on gene expression during lung tumorigenesis were compared by biological function and disorder categories of genes significantly changed in pre-/early-neoplastic stage at 12 wk (top), in uninvolved tissues (UN) at 22 wk (middle), and in tumors at 22 wk (bottom) using Ingenuity Pathway Analysis (IPA). Top-ranked categories are depicted against -log(p) determined by IPA. (B) Among the lung gene transcripts significantly (p<0.05) changed in uninvolved (UN, n = 1564) and tumor (n = 8683) tissues compared to saline-treated lung tissues, Venn diagram analysis identified genes changed in either tissue or in common at 22 wk after the initial urethane treatment (top). Expression profiles of all tumor genes (n = 8683, 22 wk UT-Tum) are depicted in pre-/early neoplastic microenvironment (12 wk) and in UN tissues of tumor-bearing lungs at 22 wk (bottom). Color bar indicates expression intensity of individual transcripts normalized to their time-matched saline control levels expressed in yellow (yellow to blue, down-regulation; yellow to red, up-regulation). Y axis = log2 (normalized average intensity), Sal = saline-treated whole lung, UT = urethane-treated (whole lung for 12 wk, UN or Tum for 22 wk), UN = uninvolved tissue, Tum = tumor tissue.
Mentions: To identify potential mechanisms of urethane-induced tumorigenesis, we then used trancriptomics of tumor and uninvolved tissue to identify differentiating gene networks. Significant changes in 6519 lung gene transcripts were found in Nrf2+/+ mice relative to saline controls in 12 wk, and expression changes were mostly 2-fold or lower (Table S1; n = 3 mice/group). Functional classification by Ingenuity Pathway Analysis (IPA) determined that lung genes changed during early tumorigenesis have roles in cellular growth and proliferation, cell and tissue development, cell cycle and cellular assembly, small molecule biochemistry, lipid metabolism, and molecular transport (Figure 5A, top panel; Table S1).

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