RETRACTED: Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

Our plain-English summary of RETRACTED: Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma, by M. Schiavello, E. Gazzano, L. Bergandi, et al (Cancers, 2021).

The study

• Authors: M. Schiavello, E. Gazzano, L. Bergandi, F. Silvagno, R. Libener, C. Riganti, E. Aldieri
• Journal: Cancers
• Published: 2021;13(5)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.

In plain English

The library citation lists this article as retracted. The supplied text does not include a retraction notice or say why it was retracted. This was a laboratory study on human cells. The authors compared mesothelial cells from three patients who had fluid around the lungs caused by heart failure and no history of cancer with cells from nine malignant pleural mesothelioma samples from a hospital biobank in Alessandria, Italy. The nine samples were three each of the epithelioid, biphasic and sarcomatoid types. In protein tests, all three mesothelioma types showed higher levels of three redox-sensitive proteins (Nrf2, Ref-1 and FOXM1) and of several antioxidant enzymes than the normal mesothelial cells did. When normal mesothelial cells were exposed to crocidolite asbestos for 24 hours, at doses from 1 to 25 µg/cm2, levels of the three proteins rose with the dose compared with untreated cells. Synthetic silica spheres, which the authors described as inert, did not cause this rise. The mesothelioma cells had lower basic levels of reactive oxygen species than the normal cells. The authors proposed the three proteins as potential predictive markers of mesothelioma, while saying that many aspects remain to be clarified.

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 (in vitro) study on human cells; the citation lists the article as retracted
• Who was studied: Primary human mesothelial cells from 3 patients with pleural fluid secondary to congestive heart failure and no history of malignant disease; 9 primary human malignant pleural mesothelioma samples (3 epithelioid, 3 biphasic, 3 sarcomatous) obtained from diagnostic thoracoscopies via the Biologic Bank of Malignant Mesothelioma, SS. Antonio e Biagio Hospital, Alessandria, Italy; A549 lung cancer (NSCLC) cells were used as a positive control
• Exposure: Crocidolite asbestos fibers (UICC), sonicated, applied to normal mesothelial cells for 24 hours at 1, 5, 10 and 25 µg/cm2; compared with untreated cells and with synthetic amorphous silica spheres (MSS) described as inert and nonpathogenic
• Main results:
  • Nrf2, Ref-1 and FOXM1 showed increased basal expression in all three mesothelioma types (epithelioid, sarcomatoid, biphasic) compared with normal mesothelial cells (each n = 3, p less than 0.001)
  • The phosphorylated (activated) form of Nrf2 was present in all histological types of mesothelioma cells but not in the normal mesothelium
  • The antioxidant proteins SOD2, GST, CAT and HO-1 were more highly expressed in mesothelioma cells than in normal mesothelial cells (n = 3, p less than 0.001)
  • Mesothelioma cells showed more of the active p50 subunit of NF-kB in the nucleus than normal mesothelial cells. The tumor suppressors p53 and PTEN were expressed in the cytosol of mesothelioma cells; their decrease in the nucleus was described as partially not so significant
  • Phosphorylated Erk was increased in all three mesothelioma types and not in normal mesothelial cells
  • Normal mesothelial cells exposed to crocidolite showed significantly increased expression of Nrf2, Ref-1 and FOXM1 compared with untreated cells, in a dose-dependent manner (each n = 3, p less than 0.001)
  • Nrf2, Ref-1 and FOXM1 were overexpressed only after crocidolite exposure, not after exposure to synthetic silica spheres
  • Basal reactive oxygen species levels were significantly lower in mesothelioma cells than in normal mesothelial cells
• The authors' conclusion: The authors concluded that Nrf2, Ref-1 and FOXM1 are upregulated in mesothelioma and not in non-transformed mesothelium, presumably as a consequence of the toxic effect of asbestos fibers, and proposed them as potential predictive markers of malignant pleural mesothelioma
• Limitations the authors state:
  • Whether the Nrf2 expression seen in these mesothelioma cells is associated with possible KEAP-1 mutations remains to be confirmed
  • The authors state that many aspects remain to be clarified

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Asbestos Exposure, Oxidative Stress, Carcinogenesis, Mesothelioma, Mesothelium, Mesothelial Cells.

Related studies

• Asbestos induces inflammatory cytokines in the lung through redox sensitive transcription factors — M.I. Luster, P.P. Simeonova (1998)
• Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival — K. Brenne, D.A. Nymoen, et al. (2012)
• Identification of Highly Sensitive Pleural Effusion Protein Biomarkers for Malignant Pleural Mesothelioma by Affinity-Based Quantitative Proteomics — N.B. Palstrøm, M. Overgaard, et al. (2023)
• Long and short fiber amosite asbestos alters at a different extent the redox metabolism in human lung epithelial cells — C. Riganti, E. Aldieri, et al. (2003)
• Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma — K. Shiomi, Y. Hagiwara, et al. (2008)
• Insulinoma-associated protein 1 is a sensitive and specific marker of neuroendocrine lung neoplasms in cytology specimens — E.E. Doxtader, S. Mukhopadhyay (2018)

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