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

Our plain-English summary of Pathways affected by asbestos exposure in normal and tumour tissue of lung cancer patients, by S. Ruosaari, T. Hienonen-Kempas, A. Puustinen, et al (BMC Medical Genomics, 2008).

The study

• Authors: S. Ruosaari, T. Hienonen-Kempas, A. Puustinen, V.K. Sarhadi, J. Hollmén, S. Knuutila, J. Saharinen, H. Wikman, S. Anttila
• Journal: BMC Medical Genomics
• Published: 2008;1:55
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined lung tissue from 14 heavily asbestos-exposed and 14 non-exposed Finnish lung cancer patients. Heavy exposure was based on work history and more than 5 million asbestos fibres per gram of dry lung tissue; fibre types were not specified for these patients. The authors measured gene expression in tumour and normal tissue, then used a computer method grouping genes into biological pathways. Gene expression patterns in exposed patients showed up-regulated ion transport pathways and down-regulated protein ubiquitination pathways (a system cells use to tag proteins for control or breakdown) in both tissue types. Follow-up protein tests on 12 patients found no exposure-related differences in UBA1 and UBA7, enzymes involved in the early stages of protein ubiquitination and ubiquitin-like modification. Regardless of exposure, both were lower in squamous cell carcinoma tumours than in matching normal tissue (p = 0.02 and p = 0.01). The authors concluded that ubiquitination changes relate both to cancer type and to asbestos. They noted that limited fresh frozen tissue restricted follow-up to two enzymes.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of patient tissue samples: gene expression microarrays with computer-based (in silico) pathway analysis, followed by Western blot protein measurements
• Who was studied: Normal and tumour lung tissue from 14 heavily asbestos-exposed and 14 non-exposed Finnish lung cancer patients (all male). A subset of 6 exposed and 6 non-exposed cases (each group 3 adenocarcinomas and 3 squamous cell carcinomas) was used for protein tests. Study dates are not given.
• Exposure: Heavy asbestos exposure, defined by employment history and a lung tissue asbestos fibre count above 5 million fibres per gram of dry lung tissue. Fibre types are not specified for these patients.
• Main results:
  • Comparing exposed with non-exposed patients, the authors identified 30 down-regulated and 40 up-regulated pathways in normal tissue, and 22 down-regulated and 37 up-regulated pathways in tumour tissue
  • Among terms changed in both normal and tumour tissue of exposed patients, ion transport-related terms were among those up-regulated, and three of the eight down-regulated terms were related to ubiquitination
  • Protein levels of UBA1 and UBA7 did not differ by asbestos exposure in normal or tumour tissue
  • In squamous cell carcinoma cases, regardless of exposure, UBA1 and UBA7 protein levels were lower in tumour than in normal tissue (p = 0.02 and p = 0.01)
  • UBA1 and UBA7 mRNA levels were also lower in squamous cell carcinomas than in the respective normal tissue
• The authors' conclusion: The authors concluded that ion transport pathways were up-regulated and protein ubiquitination functions down-regulated in normal and tumour tissue of exposed patients, and that ubiquitination changes relate both to asbestos and to cancer type
• Limitations the authors state:
  • Limited fresh frozen tissue meant only two proteins were chosen for follow-up
  • Many other enzymes besides UBA1 and UBA7 take part in ubiquitination, so the cause of the exposure-related change was not identified
  • The large number of statistical tests raises the chance of false findings
  • Pathway analysis depends on current knowledge of gene functions

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Lung Cancer, Carcinogenesis, Apoptosis, Squamous Cell Carcinoma.

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