miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma

Our plain-English summary of miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma, by M. Piccioni, F. Di Meo, A. Valentino, et al (Journal of Experimental & Clinical Cancer Research, 2025).

The study

• Authors: M. Piccioni, F. Di Meo, A. Valentino, V. Campani, M. Arigoni, M. Tanori, M. Mancuso, R. Cuciniello, M. Tomasetti, F. Monaco, G. Goteri, E.P. Spugnini, R.A. Calogero, G. De Rosa, G. Peluso, A. Baldi, S. Crispi
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2025;44(1):65
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.

Methods: miRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples.

Results: In vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin.

Conclusions: Our study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM.

© 2025. The Author(s).

In plain English

This was a laboratory study of human mesothelioma cell lines, mice and stored human tissue. It did not study asbestos exposure. The authors first looked at how the drug cisplatin, given alone or with piroxicam, changed small regulatory molecules called microRNAs in mesothelioma cells, and picked out one, miR-503. They then blocked miR-503 in three mesothelioma cell lines. Cell viability fell by about 50% at 48 hours. The share of dying (apoptotic) cells was 33%, 35% and 16% in the three lines, against 6%, 4% and 4% in controls. Colony formation and cell migration also fell. In mice with implanted human mesothelioma cells (7 treated, 7 controls), the blocker, carried in lipid nanoparticles, reduced tumor growth by 53.4% by the end of the experiment. In human tumor samples, miR-503 levels were higher than in normal tissue. The authors concluded that miR-503 acts as a cancer-promoting microRNA in mesothelioma and that blocking it has the potential to be considered as a new treatment strategy. The study did not test this in patients.

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: experiments on human mesothelioma cell lines, a mouse model with human mesothelioma cells implanted under the skin, and gene-expression analysis of stored human tissue samples
• Who was studied: Three human mesothelioma cell lines (MSTO-211 H, NCI-H2452, IST-Mes2). Male NU/NU CD1 mice, 7 per group. Human samples from two Italian centers: 19 unmatched samples (14 mesothelioma, 5 normal) from Naples collected 2004 to 2005, and 17 mesothelioma samples with adjacent normal tissue from Ancona collected 2004 to 2010
• Exposure: No asbestos exposure was studied. The treatments tested were cisplatin alone or combined with piroxicam on cells, and a miR-503 inhibitor (anti-miR-503). In mice the inhibitor was given in lipid nanoparticles at 2 mg/kg intravenously, 6 injections in total, compared with empty nanoparticles
• Main results:
  • In MSTO cells, compared with untreated cells, cisplatin alone and cisplatin with piroxicam each changed the levels of about 350 microRNAs; 117 were changed by both treatments
  • On checking by a second method (q-PCR), only miR-503 levels were linked to the treatments
  • Blocking miR-503 in the cell lines reduced cell proliferation by about 50% at 48 hours
  • After 48 hours, apoptotic cells were 33% (MSTO), 35% (NCI) and 16% (Mes2) with the miR-503 blocker, against 6%, 4% and 4% with the control treatment
  • Colony numbers fell by 50% (MSTO), 50% (NCI) and 45% (Mes2) after blocking miR-503
  • In a wound-healing test, the gap in cells treated with the blocker closed by about 80% after 48 hours, while it closed completely in control-treated cells
  • In mice, tumor growth with the nanoparticle-delivered blocker was reduced by 12% after the first dose and by 53.4% at the end of the experiment; empty nanoparticles had no anticancer effect
  • Treated mice showed no significant change in total body weight, or in liver and spleen weight
  • Tumors from treated mice showed more apoptosis on TUNEL testing than tumors from control mice, while the proliferation marker Ki67 showed no significant difference between the groups
  • In human samples, miR-503 levels were higher in mesothelioma tissue than in normal tissue
  • Of seven candidate target genes tested, only BTG1, CCNG1, EDG1 and TIMP2 moved in the opposite direction to miR-503 in mesothelioma cells
  • Blocking miR-503 in MSTO cells increased the activity of 264 genes and decreased 238. In human mesothelioma samples, the opposite pattern was confirmed for only three of the selected marker genes: CXCL8, SERPINE1 and Osteopontin
• The authors' conclusion: The authors concluded that miR-503 acts as a cancer-promoting microRNA (oncomiR) in mesothelioma, and that blocking it with lipid nanoparticle delivery has the potential to be considered as a new treatment strategy

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: Mesothelioma, Malignant Mesothelioma, Cisplatin, Apoptosis, Pleura, Biomarker, Osteopontin.

Related studies

• Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies — L. Santarelli, S. Gaetani, et al. (2019)
• Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines — H.A. Kim, M.C. Kim, et al. (2015)
• Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy — K. Schelch, M.A. Hoda, et al. (2014)
• Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair — K. Kryeziu, U. Jungwirth, et al. (2013)
• miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma — M. Williams, M.B. Kirschner, et al. (2015)
• Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma — A. Baldi, M.T. Piccolo, et al. (2011)

Browse return to medical research.