Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma

Our plain-English summary of Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma, by V. Laszlo, M.A. Hoda, T. Garay, et al (The Journal of Pathology, 2015).

The study

• Authors: V. Laszlo, M.A. Hoda, T. Garay, C. Pirker, B. Ghanim, T. Klikovits, Y.W. Dong, A. Rozsas, I. Kenessey, I. Szirtes, M. Grusch, M. Jakopovic, M. Samarzija, L. Brcic, I. Kern, A. Rozman, H. Popper, S. Zöchbauer-Müller, G. Heller, C. Altenberger, B. Ziegler, W. Klepetko, W. Berger, B. Dome, B. Hegedus
• Journal: The Journal of Pathology
• Published: 2015;237(2):203-14
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.

Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This laboratory and tissue study examined a gene called integrin alpha 7 (ITGA7) in malignant pleural mesothelioma (MPM). It did not study asbestos exposure. In mesothelioma cell lines grown in the lab, the authors found 139 genes that differed between fast-moving and slow-moving cells. Among 14 MPM cell lines, lower ITGA7 levels went with faster cell movement. When two cell lines with low ITGA7 were made to produce more of it, their movement decreased. ITGA7 levels were lower in MPM cells than in non-cancerous mesothelial cells. Higher chemical marking (methylation) of the gene's control region went with lower ITGA7 levels, although the difference in methylation between the two groups of cells was not statistically significant. In tumour samples from 200 MPM patients, median overall survival was 278 days (CI 201–354) for patients with low ITGA7 and 463 days (CI 343–582) for those with high ITGA7. Low ITGA7 remained linked to shorter survival after accounting for age, gender and tumour subtype. The authors concluded that ITGA7 appears to be an epigenetically regulated tumour suppressor gene and a prognostic factor in MPM.

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 mesothelioma and mesothelial cell lines (gene expression, cell migration, gene overexpression, promoter methylation), combined with an immunohistochemistry and survival analysis of patient tumour samples
• Who was studied: 14 MPM cell lines, the immortalized mesothelial cell line Met5a and three primary mesothelial cell cultures; formalin-fixed tumour samples from 200 MPM patients (where and when the patients were treated is not stated in the main text)
• Exposure: Asbestos or fiber exposure was not assessed. The factor studied was the level of ITGA7 (gene activity and protein) in MPM cells and tumours, and methylation of the ITGA7 promoter.
• Main results:
  • Across 14 MPM cell lines, baseline ITGA7 mRNA levels were inversely correlated with migratory activity (p = 0.021; R = −0.61)
  • Forced overexpression of ITGA7 in the low-ITGA7 cell lines CRL-5820 and VMC33 significantly decreased their migration (p < 0.0001 and p = 0.011, respectively)
  • Baseline ITGA7 levels were significantly lower in MPM cell lines than in mesothelial cells (p = 0.017)
  • The difference in mean ITGA7 methylation between mesothelial and MPM cell groups (6.5 versus 21.7) was not statistically significant (p = 0.15). Methylation correlated inversely with ITGA7 mRNA levels (R = −0.67, p = 0.0024).
  • Among the 200 patients, 47% had low and 53% had high tumour ITGA7 expression. Median overall survival was 278 days (CI 201–354 days) in the low group and 463 days (CI 343–582 days) in the high group (p = 0.020).
  • In the multivariate Cox model including age, gender and histology, low ITGA7 expression had an adjusted hazard ratio for death of 1.374 (95% CI 1.005–1.879; p = 0.047) compared with high expression
  • There was no significant association between ITGA7 expression and histological subtype in the patient samples (p = 0.14)
  • In 189 tissue specimens, the percentage of Ki-67-positive (dividing) tumour cells was higher in the low-ITGA7 group (mean 25.9%) than in the high-ITGA7 group (mean 21.6%) (p = 0.048)
• The authors' conclusion: The authors concluded that their data suggest ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Prognosis, Pleural Mesothelioma, Mesothelial Cells, Pleura, Multivariate Analysis, Histological Subtype, Median Overall Survival.

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• Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells — N.Y. Kim, M.C. Kim, et al. (2016)
• Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy — K. Schelch, M.A. Hoda, et al. (2014)
• CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome — E. Ortolan, A. Giacomino, et al. (2014)

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