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Pathways affected by asbestos exposure in normal and tumour tissue of lung cancer patients.

Ruosaari S, Hienonen-Kempas T, Puustinen A, Sarhadi VK, Hollmén J, Knuutila S, Saharinen J, Wikman H, Anttila S - BMC Med Genomics (2008)

Bottom Line: Differences between asbestos-related and non-related lung tumours were detected in pathways associated with, e.g., ion transport, NF-kappaB signalling, DNA repair, as well as spliceosome and nucleosome complexes.A notable fraction of the pathways down-regulated in both normal and tumour tissue of the asbestos-exposed patients were related to protein ubiquitination, a versatile process regulating, for instance, DNA repair, cell cycle, and apoptosis, and thus being also a significant contributor of carcinogenesis.Even though UBA1 or UBA7, the early enzymes involved in protein ubiquitination and ubiquitin-like regulation of target proteins, did not underlie the exposure-related deregulation of ubiquitination, a difference was detected in the UBA1 and UBA7 levels between squamous cell carcinomas and respective normal lung tissue (p = 0.02 and p = 0.01) without regard to exposure status.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biological Mechanisms and Prevention of Work-related Diseases, Health and Work Ability, Finnish Institute of Occupational Health, Topeliuksenkatu 41aA, FI-00250 Helsinki, Finland. salla.ruosaari@helsinki.fi

ABSTRACT

Background: Studies on asbestos-induced tumourigenesis have indicated the role of, e.g., reactive oxygen/nitrogen species, mitochondria, as well as NF-kappaB and MAPK signalling pathways. The exact molecular mechanisms contributing to asbestos-mediated carcinogenesis are, however, still to be characterized.

Methods: In this study, gene expression data analyses together with gene annotation data from the Gene Ontology (GO) database were utilized to identify pathways that are differentially regulated in lung and tumour tissues between asbestos-exposed and non-exposed lung cancer patients. Differentially regulated pathways were identified from gene expression data from 14 asbestos-exposed and 14 non-exposed lung cancer patients using custom-made software and Iterative Group Analysis (iGA). Western blotting was used to further characterize the findings, specifically to determine the protein levels of UBA1 and UBA7.

Results: Differences between asbestos-related and non-related lung tumours were detected in pathways associated with, e.g., ion transport, NF-kappaB signalling, DNA repair, as well as spliceosome and nucleosome complexes. A notable fraction of the pathways down-regulated in both normal and tumour tissue of the asbestos-exposed patients were related to protein ubiquitination, a versatile process regulating, for instance, DNA repair, cell cycle, and apoptosis, and thus being also a significant contributor of carcinogenesis. Even though UBA1 or UBA7, the early enzymes involved in protein ubiquitination and ubiquitin-like regulation of target proteins, did not underlie the exposure-related deregulation of ubiquitination, a difference was detected in the UBA1 and UBA7 levels between squamous cell carcinomas and respective normal lung tissue (p = 0.02 and p = 0.01) without regard to exposure status.

Conclusion: Our results indicate alterations in protein ubiquitination related both to cancer type and asbestos. We present for the first time pathway analysis results on asbestos-associated lung cancer, providing important insight into the most relevant targets for future research.

No MeSH data available.


Related in: MedlinePlus

Presentation of asbestos-induced effects. Schematic presentation of asbestos-induced effects, modified from Upadhyay and Kamp [38]. Mechanisms or cellular compartments affected by asbestos-exposure according to the pathway analysis are marked with black dots.
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Figure 1: Presentation of asbestos-induced effects. Schematic presentation of asbestos-induced effects, modified from Upadhyay and Kamp [38]. Mechanisms or cellular compartments affected by asbestos-exposure according to the pathway analysis are marked with black dots.

Mentions: When GO terms from all levels of specificity were considered, several differentially regulated pathways (GO terms) were identified both in normal and tumour tissue of asbestos-exposed patients as compared to the non-exposed (Additional files 1 and 2). The detection of a large number of potentially affected pathways was expected owing to the presence of thousands of GO terms, all of which were tested for differences between the two groups. The findings implicated alterations in many vital aspects of cell homeostasis (Figure 1). The pathway analysis revealed some previously presented asbestos-associated molecular alterations, such as deregulation of NF-κB pathway that was observed in the normal tissue samples from asbestos-exposed patients. Additional somewhat expected findings included changes in DNA repair and mitochondrial functions.


Pathways affected by asbestos exposure in normal and tumour tissue of lung cancer patients.

Ruosaari S, Hienonen-Kempas T, Puustinen A, Sarhadi VK, Hollmén J, Knuutila S, Saharinen J, Wikman H, Anttila S - BMC Med Genomics (2008)

Presentation of asbestos-induced effects. Schematic presentation of asbestos-induced effects, modified from Upadhyay and Kamp [38]. Mechanisms or cellular compartments affected by asbestos-exposure according to the pathway analysis are marked with black dots.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2612681&req=5

Figure 1: Presentation of asbestos-induced effects. Schematic presentation of asbestos-induced effects, modified from Upadhyay and Kamp [38]. Mechanisms or cellular compartments affected by asbestos-exposure according to the pathway analysis are marked with black dots.
Mentions: When GO terms from all levels of specificity were considered, several differentially regulated pathways (GO terms) were identified both in normal and tumour tissue of asbestos-exposed patients as compared to the non-exposed (Additional files 1 and 2). The detection of a large number of potentially affected pathways was expected owing to the presence of thousands of GO terms, all of which were tested for differences between the two groups. The findings implicated alterations in many vital aspects of cell homeostasis (Figure 1). The pathway analysis revealed some previously presented asbestos-associated molecular alterations, such as deregulation of NF-κB pathway that was observed in the normal tissue samples from asbestos-exposed patients. Additional somewhat expected findings included changes in DNA repair and mitochondrial functions.

Bottom Line: Differences between asbestos-related and non-related lung tumours were detected in pathways associated with, e.g., ion transport, NF-kappaB signalling, DNA repair, as well as spliceosome and nucleosome complexes.A notable fraction of the pathways down-regulated in both normal and tumour tissue of the asbestos-exposed patients were related to protein ubiquitination, a versatile process regulating, for instance, DNA repair, cell cycle, and apoptosis, and thus being also a significant contributor of carcinogenesis.Even though UBA1 or UBA7, the early enzymes involved in protein ubiquitination and ubiquitin-like regulation of target proteins, did not underlie the exposure-related deregulation of ubiquitination, a difference was detected in the UBA1 and UBA7 levels between squamous cell carcinomas and respective normal lung tissue (p = 0.02 and p = 0.01) without regard to exposure status.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biological Mechanisms and Prevention of Work-related Diseases, Health and Work Ability, Finnish Institute of Occupational Health, Topeliuksenkatu 41aA, FI-00250 Helsinki, Finland. salla.ruosaari@helsinki.fi

ABSTRACT

Background: Studies on asbestos-induced tumourigenesis have indicated the role of, e.g., reactive oxygen/nitrogen species, mitochondria, as well as NF-kappaB and MAPK signalling pathways. The exact molecular mechanisms contributing to asbestos-mediated carcinogenesis are, however, still to be characterized.

Methods: In this study, gene expression data analyses together with gene annotation data from the Gene Ontology (GO) database were utilized to identify pathways that are differentially regulated in lung and tumour tissues between asbestos-exposed and non-exposed lung cancer patients. Differentially regulated pathways were identified from gene expression data from 14 asbestos-exposed and 14 non-exposed lung cancer patients using custom-made software and Iterative Group Analysis (iGA). Western blotting was used to further characterize the findings, specifically to determine the protein levels of UBA1 and UBA7.

Results: Differences between asbestos-related and non-related lung tumours were detected in pathways associated with, e.g., ion transport, NF-kappaB signalling, DNA repair, as well as spliceosome and nucleosome complexes. A notable fraction of the pathways down-regulated in both normal and tumour tissue of the asbestos-exposed patients were related to protein ubiquitination, a versatile process regulating, for instance, DNA repair, cell cycle, and apoptosis, and thus being also a significant contributor of carcinogenesis. Even though UBA1 or UBA7, the early enzymes involved in protein ubiquitination and ubiquitin-like regulation of target proteins, did not underlie the exposure-related deregulation of ubiquitination, a difference was detected in the UBA1 and UBA7 levels between squamous cell carcinomas and respective normal lung tissue (p = 0.02 and p = 0.01) without regard to exposure status.

Conclusion: Our results indicate alterations in protein ubiquitination related both to cancer type and asbestos. We present for the first time pathway analysis results on asbestos-associated lung cancer, providing important insight into the most relevant targets for future research.

No MeSH data available.


Related in: MedlinePlus