MiR-21 over-expression and Programmed Cell Death 4 down-regulation features malignant pleural mesothelioma

Our plain-English summary of MiR-21 over-expression and Programmed Cell Death 4 down-regulation features malignant pleural mesothelioma, by L. Nicolè, R. Cappellesso, T. Sanavia, et al (Oncotarget, 2018).

The study

• Authors: L. Nicolè, R. Cappellesso, T. Sanavia, V. Guzzardo, A. Fassina
• Journal: Oncotarget
• Published: 2018;9(25):17300-17308
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Differential diagnosis between malignant pleural mesothelioma (MPM) and benign mesothelial conditions is still challenging and there is a lack of useful markers. Programmed cell death 4 (PDCD4) is a well-known tumor suppressor gene in several cancers, its post-transcriptional activity is directly controlled by miR-21, whose over-expression has been recently reported in MPM compared to normal mesothelium. Aim of this study was to test this suppressor gene as a possible new marker of malignant transformation in mesothelial cells, as well as a new prognostic marker.

Methods: PDCD4 nuclear expression was assessed by immunohistochemistry (IHC) in 40 non-neoplastic pleural (NNP) and 40 MPM formalin-fixed and paraffin-embedded specimens. PDCD4 and miR-21 expressions were analyzed by qRT-PCR in all cases. In situ hybridization (ISH) of miR-21 was performed in 5 representative cases of both groups. The prognostic relevance of PDCD4 was assessed in a public available gene expression dataset.

Results: IHC showed that PDCD4 nuclear expression was significantly lower in MPM than in NNP. PDCD4 was down-regulated, whereas miR-21 was over-expressed in MPM cases compared to NNP ones. ISH detected miR-21 only in MPM specimens. Down-expression of PDCD4 was found significantly associated with short overall survival in publicly available data.

Conclusions: These findings highlighted a switch between PDCD4 and miR-21 expression in MPM. Further studies should assess the diagnostic reliability of these two markers for MPM in biopsy and effusion specimens.

In plain English

Researchers at the University of Padova, Italy, studied archived biopsies collected from 2010 to 2014: 40 of malignant pleural mesothelioma and 40 of non-cancerous pleural tissue (8 with pleuritis, 32 normal pleura). They stained the tissue for a tumor-suppressor protein, PDCD4, and used a gene-expression test to measure PDCD4 and a small regulatory RNA, miR-21. Nuclear PDCD4 staining was significantly lower in mesothelioma: 22 of 40 mesothelioma samples showed no staining, compared with 3 of 40 non-cancerous samples. In mesothelioma, PDCD4 was lower and miR-21 was higher. A third test, done on 5 mesothelioma and 5 non-cancerous samples, found miR-21 in the mesothelioma samples, while all the non-cancerous samples were negative. Epithelioid mesotheliomas had higher PDCD4 than biphasic and sarcomatoid tumors combined. In a public dataset of 20 epithelioid mesotheliomas, low PDCD4 was associated with shorter overall survival (p=0.024). Adding gender, age and asbestos exposure to that analysis did not change the result. The study did not otherwise examine asbestos. The authors noted the small sample and concluded that PDCD4 could be a helpful marker for mesothelioma, to be tested in larger groups.

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 archived tissue (immunohistochemistry, qRT-PCR, in situ hybridization), plus a survival analysis of a publicly available gene expression dataset; described by the authors as explorative
• Who was studied: Biopsies from the archives of the University of Padova, Italy: 40 non-neoplastic pleura (8 pleuritis, 32 normal pleura) and 40 malignant pleural mesothelioma (26 epithelioid, 4 sarcomatoid, 10 biphasic). They came from patients who underwent surgical resection of malignancy or pleura biopsy from 2010 to 2014. The survival analysis used 20 epithelioid mesothelioma samples from a public dataset (de Reyniès et al.).
• Exposure: Not an asbestos exposure study. No fiber types or exposure levels are given. Asbestos exposure appears only as a factor included in the survival analysis of the public dataset.
• Main results:
  • Nuclear PDCD4 staining in mesothelioma samples was scored 0 in 22, 1 in 12, 2 in 5 and 3 in 1 case. This was significantly lower (p=8.64e-05) than in non-neoplastic pleura, scored 0 in 3, 1 in 25, 2 in 9 and 3 in 3 cases.
  • Epithelioid mesotheliomas had significantly higher PDCD4 staining scores than biphasic and sarcomatoid samples combined (p=0.037).
  • By qRT-PCR, PDCD4 expression was significantly lower in mesothelioma than in non-neoplastic pleura (p=0.0003).
  • By qRT-PCR, miR-21 was over-expressed in mesothelioma compared with non-neoplastic pleura (p=1.03e-08).
  • In situ hybridization was done on 5 randomly selected mesothelioma cases and 5 non-neoplastic cases. It detected miR-21 in mesothelioma specimens, and all non-neoplastic samples analyzed were negative.
  • In the public dataset of 20 epithelioid mesothelioma samples (10 low, 10 high PDCD4), low PDCD4 was significantly associated with short-term overall survival (p=0.024, log-rank test).
• The authors' conclusion: The authors concluded that their explorative study suggests PDCD4 could be a reliable and helpful immunohistochemical marker for malignant pleural mesothelioma. They said its diagnostic and prognostic value should be tested in large cohorts, and that functional experiments are needed to confirm the findings.
• Limitations the authors state:
  • The relatively small number of samples limits the evaluation of PDCD4 as a marker, with few pleuritis and sarcomatoid mesothelioma cases.
  • No functional tests on cell lines were done to directly show the effect of miR-21 on PDCD4 and on cell behavior.
  • The public dataset used for the survival analysis included only epithelioid cases, so survival could not be assessed for other subtypes.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Differential Diagnosis, Tumor Suppressor Gene, Mesothelium, Malignant Transformation, Mesothelial Cells, Immunohistochemistry, Overall Survival.

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