miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma

Our plain-English summary of miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma, by R. El Bezawy, S. Percio, C.M. Ciniselli, et al (Cancer Gene Therapy, 2022).

The study

• Authors: R. El Bezawy, S. Percio, C.M. Ciniselli, M. De Cesare, G. Colella, M. Dugo, S. Veneroni, V. Doldi, S. Martini, D. Baratti, S. Kusamura, P. Verderio, M. Deraco, P. Gandellini, N. Zaffaroni, V. Zuco
• Journal: Cancer Gene Therapy
• Published: 2022;29(10):1394-1404
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and rapidly lethal tumor, poorly responsive to conventional treatments. In this regards, the identification of molecular alterations underlying DMPM onset and progression might be exploited to develop novel therapeutic strategies. Here, we focused on miR-550a-3p, which we found downregulated in 45 DMPM clinical samples compared to normal tissues and whose expression levels were associated with patient outcome. Through a gain-of-function approach using miRNA mimics in 3 DMPM cell lines, we demonstrated the tumor-suppressive role of miR-550a-3p. Specifically, miRNA ectopic expression impaired cell proliferation and invasiveness, enhanced the apoptotic response, and reduced the growth of DMPM xenografts in mice. Antiproliferative and proapoptotic effects were also observed in prostate and ovarian cancer cell lines following miR-550a-3p ectopic expression. miR-550a-3p effects were mediated, at least in part, by the direct inhibition of HSP90AA1 and the consequent downregulation of its target proteins, the levels of which were rescued upon disruption of miRNA-HSP90AA1 mRNA pairing, partially abrogating miR-550a-3p-induced cellular effects. Our results show that miR-550a-3p reconstitution affects several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy for DMPM.

© 2022. The Author(s).

In plain English

This laboratory study examined miR-550a-3p, a small RNA molecule, in diffuse malignant peritoneal mesothelioma (DMPM), a cancer of the abdominal lining. It did not study asbestos exposure. Tumor samples came from 45 adult patients in Milan treated with surgery plus heated abdominal chemotherapy (CRS + HIPEC) from 1997 to 2013. These samples had lower levels of the molecule than 11 normal tissue samples (p = 0.003). Higher levels were associated with longer relapse-free survival (hazard ratio 0.802, 95% CI 0.671 to 0.959). The overall-survival association was not statistically significant, possibly because of few events, the authors said. In DMPM cell lines, a synthetic copy of the molecule reduced growth and invasion and increased cell death. Cells treated before injection into mice formed tumors that grew more slowly than tumors from control-treated cells. At day 19, the largest gap, mean tumor volume was 59% lower than in controls. Ovarian and prostate cancer cell lines showed growth and cell-death effects too. The effects appeared to act partly through the gene HSP90AA1. The authors concluded their preclinical data support pursuing a miR-550a-3p-based treatment for DMPM.

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 combining analysis of stored patient tumor samples (expression and association with outcome), cell-line experiments, and a mouse xenograft experiment
• Who was studied: Frozen DMPM tumor samples from 45 adult patients treated with CRS + HIPEC from 1997 to 2013 at the Istituto Nazionale dei Tumori, Milan (16 female, 29 male; 40 epithelioid). The study also used 11 normal peritoneum specimens from patients operated on for non-cancer diseases, three DMPM cell lines (STO, MP8, MP115), ovarian and prostate cancer cell lines, and mice (five per group).
• Exposure: No asbestos exposure was studied; asbestos is mentioned only in the introduction as a possible association with DMPM. The experimental intervention was transfection of cells with a synthetic miR-550a-3p mimic (20 nM) or a negative control, in some experiments combined with a 'miR-Mask' blocking its binding to HSP90AA1. In the mouse experiment, cells were transfected before being injected.
• Main results:
  • miR-550a-3p was lower in 45 DMPM tumor samples than in 11 normal samples (p = 0.003)
  • In the patient cohort, miR-550a-3p expression (continuous scale) was associated with relapse-free survival: HR 0.802, 95% CI 0.671 to 0.959, p = 0.015
  • The relapse-free survival association remained significant when expression was split at the median (p = 0.007)
  • No statistically significant association with overall survival in the patient cohort (HR 0.876, 95% CI 0.711 to 1.080)
  • In all three DMPM cell lines, the miR-550a-3p mimic inhibited proliferation over time
  • In DMPM cells, the mimic reduced invasiveness in a matrigel-based assay (p less than 0.001)
  • In STO and MP8 DMPM cells, the mimic increased the percentage of apoptotic (TUNEL-positive) cells compared with control-transfected cells (p less than 0.05)
  • In mice, tumors from STO cells transfected with miR-550a-3p before injection grew more slowly than tumors from control-transfected cells (p = 0.02)
  • In the mouse experiment, maximum tumor volume inhibition (mean volume of miR-550a-3p tumors relative to mean volume of control tumors) was 59%, recorded 19 days after cell injection
  • In ovarian and prostate cancer cell lines, the mimic inhibited growth, to a variable extent
  • In IGROV-1/Pt1 ovarian cancer cells, blocking the miRNA's binding site with a miR-Mask restored HSP90AA1 transcript levels
  • In STO and IGROV-1/Pt1 cells, the miR-Mask reduced the antiproliferative and proapoptotic effects of miR-550a-3p (p less than 0.05)
• The authors' conclusion: The authors concluded that miR-550a-3p directly targets HSP90AA1, that its effects are mediated at least in part through this route, and that their preclinical data support pursuing a miR-550a-3p-based approach as a novel therapeutic strategy for DMPM.
• Limitations the authors state:
  • The lack of a significant association with overall survival may reflect the low number of events
  • Clinical application of miRNA-based strategies is constrained by the need for safe and efficient delivery
  • miRNA-based therapeutics might activate resistance mechanisms

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Biomarker, Peritoneal Mesothelioma, Ovarian Cancer.

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• Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin — M. De Cesare, D. Cominetti, et al. (2015)
• Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma — R. Sciarrillo, A. Wojtuszkiewicz, et al. (2019)
• miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma — M. Piccioni, F. Di Meo, et al. (2025)
• Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism — R. El Bezawy, M. De Cesare, et al. (2017)
• Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma — A. Belfiore, A. Busico, et al. (2019)

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