Identification of Overexpressed Genes in Malignant Pleural Mesothelioma

Our plain-English summary of Identification of Overexpressed Genes in Malignant Pleural Mesothelioma, by F. Morani, L. Bisceglia, G. Rosini, et al (International Journal of Molecular Sciences, 2021).

The study

• Authors: F. Morani, L. Bisceglia, G. Rosini, L. Mutti, O. Melaiu, S. Landi, F. Gemignani
• Journal: International Journal of Molecular Sciences
• Published: 2021;22(5)
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.

In plain English

This laboratory and computer-based study looked for genes that are more active in malignant pleural mesothelioma (MPM). The authors analyzed publicly available RNA sequencing data from the tumor tissue of 85 MPM patients in The Cancer Genome Atlas. Data from healthy pleura were not available, so they compared these with three normal lung samples, a reference they described as not optimal. They narrowed the gene list using earlier published studies and links to patient survival, and built three gene signatures covering 15 genes. For all three signatures, patients sorted into a high-risk group (43) had shorter overall survival than those in a low-risk group (42) (p less than 0.0001). The authors then measured the 15 proteins in six MPM cell lines and compared them with one nonmalignant line, Met-5A. CTHRC1 was higher in all six lines. E-selectin, SPARC and UHRF1 were higher in five, PRSS23 and BAG2 in four, and MDK in three. Seven others were high in only one or two lines, and DSC3 was not detected. The authors concluded that these molecules could be explored as prognostic markers and treatment targets, and said more laboratory work is needed. The study did not examine asbestos exposure.

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: Computational gene-expression analysis of public RNA sequencing data, combined with a laboratory (Western blot) protein analysis of cell lines
• Who was studied: Tumor tissue RNA sequencing data from 85 malignant pleural mesothelioma patients (TCGA), compared with 3 normal lung samples from the Gene Expression Omnibus; in the laboratory, 6 MPM cell lines (Mero-14, Mero-41, Mero-95, ZL-55, REN, MSTO) and 1 nonmalignant mesothelial cell line (Met-5A)
• Exposure: Not studied: the article analyzed gene and protein expression in tumors and cell lines and did not assess asbestos or other exposures
• Main results:
  • Compared with the 3 normal lung samples, 18,048 genes were differentially expressed in the 85 MPM tumor samples (9536 higher, 8512 lower)
  • After cross-checking with genes reported in earlier published studies, 839 differentially expressed genes remained (600 higher, 239 lower)
  • First ('unreduced') survival signature: seven genes (CIT, KIF23, PODXL, PRSS23, SPARC, TRAF2, UHRF1)
  • Second ('FDR-reduced') survival signature: six genes (ADAMTS1, BAG2, KIF23, MAD2L1, TNNT1, UHRF1)
  • Third ('GO-reduced') survival signature: four genes (CTHRC1, DSC3, MDK, SELE, which encodes E-selectin)
  • For all three signatures, patients in the high-risk group (43 samples) had shorter overall survival than those in the low-risk group (42 samples) (log-rank p less than 0.0001)
  • Signatures a and b predicted survival with an area under the curve ranging from 0.816 (1-year survival, signature a) to 0.896 (2-year survival, signature b)
  • Signature c performed slightly lower, with an area under the curve of 0.729 for 1-year and 0.764 for 2-year survival
  • In single-factor analysis, tumor histological type and the three risk scores were the only factors significantly associated with survival; age, gender and stage were not
  • In the multi-factor model, only the FDR-reduced and GO-reduced risk scores remained statistically significant, which the authors read as suggesting an independent prognostic factor
  • Compared with nonmalignant Met-5A cells, CTHRC1 was overexpressed in all six MPM cell lines, and E-selectin, SPARC and UHRF1 in 5 of 6
  • PRSS23 and BAG2 were abundant in 4 MPM cell lines, and MDK in 3
  • Seven proteins (ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, TRAF2) were high in only one or two MPM cell lines
  • DSC3 could not be detected in the cell lines
• The authors' conclusion: The authors concluded that the identified molecules could be used as prognostic biomarkers and new treatment targets for MPM, and that further laboratory studies on MPM cell lines are needed
• Limitations the authors state:
  • Healthy pleural tissue data were unavailable, so normal lung samples (only 3) were used as the reference, which the authors called not optimal
  • Cell lines do not fully represent the tumors they came from
  • It is unknown whether overexpression of these genes drives the cancer or is only a by-product of it
  • The role of these candidate biomarkers still needs to be clarified

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Overall Survival, Apoptosis.

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