Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism

Our plain-English summary of Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism, by C. De Santi, O. Melaiu, A. Bonotti, et al (Scientific Reports, 2017).

The study

• Authors: C. De Santi, O. Melaiu, A. Bonotti, L. Cascione, G. Di Leva, R. Foddis, A. Cristaudo, M. Lucchi, M. Mora, A. Truini, A. Tironi, B. Murer, R. Boldorini, M. Cipollini, F. Gemignani, P. Gasparini, L. Mutti, S. Landi
• Journal: Scientific Reports
• Published: 2017;7(1):3140
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.

In plain English

This laboratory study measured microRNAs (small RNA molecules that help control genes) in tumour tissue from patients with malignant pleural mesothelioma. The authors profiled stored biopsies from 96 patients, collected from 2005 to 2009 at four Italian hospitals, and compared them with 10 non-cancer pleura samples. They found 63 microRNAs at significantly different levels in the tumours: 55 lower and 8 higher. In a separate group of 16 tumours and 17 control tissues, lower levels of miR-197, miR-185 and miR-299 were confirmed. In the 52 patients with survival data, a risk score based on two microRNAs, Let-7c-5p and miR-151a-5p, was linked to survival. Survival was lower in the high-risk group (P = 0.004), with similar results in a public mesothelioma dataset (P = 0.021) and in the 16 separate tumours (P = 0.038). Of the 22 mesothelioma patients who gave biopsies for this confirmation step, about 70% had a known history of asbestos exposure, but the study did not analyse asbestos exposure. The authors concluded that the two-microRNA signature is a useful prognostic biomarker. They noted that missing clinical information left small numbers for the survival analyses.

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 tumour tissue: microRNA profiling of stored mesothelioma biopsies (nanoString nCounter), validation by RT-qPCR in an independent set of fresh frozen tissues, survival analysis, and computer-based (in silico) prediction of target genes
• Who was studied: Profiling set: 105 formalin-fixed paraffin-embedded malignant pleural mesothelioma biopsies collected 2005 to 2009 at the University Hospital of Pisa, the Hospital of Brescia, the Hospital of Venice and IRCCS San Martino-IST in Genoa. 96 had usable RNA, and survival data were available for 52. Controls were 10 pleural samples from Novara (6 chronic pleuritis, 4 mesothelial hyperplasia). Validation set: 22 mesothelioma biopsies from Pisa (16 with usable RNA) and 20 normal pleura samples from lung cancer surgery patients (17 with usable RNA).
• Exposure: Asbestos exposure was not the subject of analysis. Among the mesothelioma patients whose 22 biopsies were collected for the validation study, about 70% had a confirmed history of asbestos exposure. The article does not give this figure separately for the 16 tumours with usable RNA, and it reports no fiber types or doses.
• Main results:
  • Comparing 96 mesothelioma samples with 10 controls, 63 microRNAs differed significantly: 55 were lower and 8 were higher in mesothelioma samples.
  • The top five microRNAs were retested in an independent group of 16 mesothelioma and 17 control tissues. Lower levels in mesothelioma were confirmed for miR-197, miR-185 and miR-299 after Bonferroni correction. The results for miR-337 and miR-485 could not be confirmed.
  • The profiling also found significantly lower levels of miR-126-3p, miR-15b-5p and miR-145-5p in mesothelioma samples, consistent with earlier reports.
  • Among 52 mesothelioma patients with survival data, overall survival was significantly lower in the group with a high risk score based on Let-7c-5p and miR-151a-5p (P = 0.004, log-rank test).
  • In the TCGA mesothelioma dataset, patients with a low risk score had significantly better survival than those with a high risk score (P = 0.021).
  • In the separate group of 16 fresh frozen mesothelioma samples, the two-microRNA signature was also associated with survival (P = 0.038).
  • In a multivariate model of the 52 patients, histologic subtype (P = 0.34) and gender (P = 0.20) were not associated with survival. Age under 65 at diagnosis was associated with better prognosis (P = 0.001). The risk score was an independent predictor of survival (P = 0.002).
  • Among 27 patients with treatment information, non-symptomatic therapy (surgery, chemotherapy or radiotherapy) was associated with better prognosis (P = 0.008). The risk score remained an independent factor (P = 0.027).
  • Computer-based target prediction for six of the microRNAs identified 5 genes predicted to be targeted by two microRNAs each.
• The authors' conclusion: The authors concluded that microRNA expression is highly deregulated in malignant pleural mesothelioma. They identified the two-microRNA signature as a useful biomarker for prognosis that points to a role of metabolism in tumour aggressiveness. They stated that further studies are needed.
• Limitations the authors state:
  • Clinical information was partly missing for several patients because samples came from different hospitals.
  • The prognostic calculations rested on small numbers: 52 patients, with treatment information for only 27.
  • The analysis could not distinguish between different treatments. Patients were grouped only as non-symptomatic versus symptomatic therapy.
  • Enough RNA could not be obtained from all samples, reducing the number available for analysis.

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: Pleural Mesothelioma, Prognosis, Pleura, Kaplan-Meier Curve, Overall Survival, Hypoxia.

Related studies

• CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma -A miRNA microarray analysis — M. Guled, L. Lahti, et al. (2009)
• MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications — S. Busacca, S. Germano, et al. (2010)
• A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people — S. Garritano, C. De Santi, et al. (2014)
• Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease — T. Cavalleri, L. Angelici, et al. (2017)
• Expression status of candidate genes in mesothelioma tissues and cell lines — O. Melaiu, E. Melissari, et al. (2015)
• Serum Expression Levels of Certain miRNAs in Predicting Diagnosis, Prognosis, and Response to Chemotherapy in Malignant Pleural Mesothelioma — M. Metintaş, G. Ak, et al. (2022)

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