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. 2018 Apr 3;9(25):17300-17308.
doi: 10.18632/oncotarget.24644.

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

Lorenzo Nicolè  1 , Rocco Cappellesso  1 , Tiziana Sanavia  2 , Vincenza Guzzardo  1 , Ambrogio Fassina  1
Affiliations

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

Lorenzo Nicolè et al. Oncotarget. .

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.

Keywords: PDCD4; immunohistochemistry; malignant pleural mesothelioma; miR-21; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Immunohistochemical and qRT-PCR data analysis in MPM and NNP cohorts
(A-B) distribution of IHC-based nuclear scores of PDCD4 in the two cohorts (A) and in the MPM histological subtypes (B); (C-D) PDCD4 expression in terms of ΔCt values in the two cohorts (C) and in the MPM histological subtypes (D); (E-F) miR-21 expression in terms of ΔCt values in the two cohorts (E) and in the MPM histological subtypes (F). Legend for the MPM subtypes: E: epithelioid, B: biphasic, S: sarcomatoid.
Figure 2
Figure 2. Representative figures of PDCD4 immunohistochemistry and in situ hybridization analysis of miR-21
(A-C) Normal mesothelial cells showed positive immunostain for nuclear PDCD4 (A) and undetectable level of miR-21 (C). (B-D) Malignant mesothelioma samples showed negative/low immunostain for PDCD4 (B) and high level of miR-21 (D).
Figure 3
Figure 3. Kaplan-Meier curves of overall survival between PDCD4 expression-based subgroups
Survival analysis performed on published MPM microarray data divided according to high (gray curve) and low (black curve) PDCD4 expression values.
See this image and copyright information in PMC

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