Extracellular Vesicle Enriched miR-625-3p Is Associated with Survival of Malignant Mesothelioma Patients

Our plain-English summary of Extracellular Vesicle Enriched miR-625-3p Is Associated with Survival of Malignant Mesothelioma Patients, by K. Goričar, M. Holcar, N. Mavec, et al (Journal of Personalized Medicine, 2021).

The study

• Authors: K. Goričar, M. Holcar, N. Mavec, V. Kovač, M. Lenassi, V. Dolžan
• Journal: Journal of Personalized Medicine
• Published: 2021;11(10)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is characterized by poor prognosis and short survival. Extracellular vesicles (EVs) are membrane-bound particles released from cells into various body fluids, and their molecular composition reflects the characteristics of the origin cell. Blood EVs or their miRNA cargo might serve as new minimally invasive biomarkers that would enable earlier detection of MM or treatment outcome prediction. Our aim was to evaluate miRNAs enriched in serum EVs as potential prognostic biomarkers in MM patients in a pilot longitudinal study. EVs were isolated from serum samples obtained before and after treatment using ultracentrifugation on 20% sucrose cushion. Serum EV-enriched miR-103-3p, miR-126-3p and miR-625-3p were quantified using qPCR. After treatment, expression of miR-625-3p and miR-126-3p significantly increased in MM patients with poor treatment outcome (p = 0.012 and p = 0.036, respectively). A relative increase in miR-625-3p expression after treatment for more than 3.2% was associated with shorter progression-free survival (7.5 vs. 19.4 months, HR = 3.92, 95% CI = 1.20-12.80, p = 0.024) and overall survival (12.5 vs. 49.1 months, HR = 5.45, 95% CI = 1.06-28.11, p = 0.043) of MM patients. Bioinformatic analysis showed enrichment of 33 miR-625-3p targets in eight biological pathways. Serum EV-enriched miR-625-3p could therefore serve as a prognostic biomarker in MM and could contribute to a more personalized treatment.

In plain English

This pilot study, from the Institute of Oncology Ljubljana in Slovenia, asked whether small molecules called microRNAs, collected from blood together with tiny particles called extracellular vesicles, could predict how mesothelioma patients fared after chemotherapy. The authors chose 20 patients treated between 2009 and 2016: 10 who survived less than 15 months and 10 who survived more than 20 months. After quality checks, 18 remained. Of these, 17 had pleural mesothelioma and 1 had peritoneal mesothelioma, and 13 were recorded as asbestos-exposed. Three microRNAs were measured in serum at diagnosis and after chemotherapy. Levels at diagnosis did not differ significantly between the two outcome groups. One microRNA, miR-625-3p, rose after treatment in all 8 analysed patients with poor outcome. The authors set a cut-off from these same patients' data. Patients whose miR-625-3p rose by more than 3.2% had shorter progression-free survival (7.5 vs. 19.4 months, HR 3.92, 95% CI 1.20–12.80) and shorter overall survival (12.5 vs. 49.1 months, HR 5.45, 95% CI 1.06–28.11). The authors concluded that miR-625-3p might serve as a prognostic biomarker. They named the small sample size as the main limitation.

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: Pilot longitudinal biomarker study (described by the authors as proof-of-concept), comparing blood samples taken before and after chemotherapy
• Who was studied: 20 malignant mesothelioma patients treated with chemotherapy at the Institute of Oncology Ljubljana, Slovenia, between 1 February 2009 and 31 July 2016. They were selected as 10 with poor outcome (overall survival under 15 months) and 10 with good outcome (overall survival over 20 months). 18 were analysed after quality control: 17 with pleural and 1 with peritoneal mesothelioma, of whom 13 were recorded as asbestos-exposed.
• Exposure: Asbestos exposure was not the factor studied, and no fiber types are given. The study measured three microRNAs (miR-103a-3p, miR-126-3p, miR-625-3p) in serum samples enriched for extracellular vesicles, at diagnosis and after chemotherapy. Treatment was gemcitabine plus cisplatin in 12 patients and pemetrexed plus cisplatin in 6.
• Main results:
  • Across all 17 patients with paired samples, miR-126-3p rose after treatment in 12 (70.6%) patients (p = 0.035). miR-625-3p and miR-103a-3p did not differ significantly after treatment.
  • In patients with poor outcome, miR-625-3p rose after treatment in all 8 (p = 0.012) and miR-126-3p rose in 6 (75.0%) (p = 0.036). No differences between diagnosis and after treatment were seen in patients with good outcome.
  • At diagnosis, microRNA levels did not differ significantly between patients with poor and good outcome.
  • The change in miR-625-3p after treatment was a median increase of 85.2% in poor-outcome patients and a median decrease of 17.5% in good-outcome patients (p = 0.036). Area under the curve was 0.806 (0.588–1.000). At a 3.2% cut-off, sensitivity was 0.667 and specificity was 1.000.
  • Patients with a rise in miR-625-3p of more than 3.2% had shorter progression-free survival (7.5 vs. 19.4 months; HR = 3.92, 95% CI = 1.20–12.80, p = 0.024). After adjustment for CRP, HR = 4.13, 95% CI = 1.25–13.65, p = 0.020.
  • Patients with a rise in miR-625-3p of more than 3.2% had shorter overall survival (12.5 vs. 49.1 months; HR = 5.45, 95% CI = 1.06–28.11, p = 0.043). After adjustment for CRP, HR = 6.32, 95% CI = 1.18–33.99, p = 0.032.
  • miR-103a-3p and miR-126-3p were not associated with survival.
  • A database search listed 33 experimentally confirmed targets of miR-625-3p. The most significant pathway among them was PD-L1 expression and the PD-1 checkpoint pathway in cancer.
• The authors' conclusion: The authors concluded that serum extracellular-vesicle-enriched miR-625-3p was associated with treatment outcome and survival in their proof-of-concept study and might serve as a prognostic biomarker.
• Limitations the authors state:
  • Small sample size; the authors say larger studies are needed to validate the results.
  • No data were available on BAP1 mutation status or other germline mutations.
  • The method did not measure only microRNA enclosed inside the vesicles, because samples were not treated with RNAse A and microRNAs can also bind to the vesicle surface.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Biomarker, Progression-Free Survival, Overall Survival.

Related studies

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• Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease — T. Cavalleri, L. Angelici, et al. (2017)
• Extracellular Vesicles-Based Drug Delivery Systems: A New Challenge and the Exemplum of Malignant Pleural Mesothelioma — S. Burgio, L. Noori, et al. (2020)
• Extracellular vesicles as biomarkers in malignant pleural mesothelioma: A review — T. Ahmadzada, S. Kao, et al. (2020)
• Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion — J. Javadi, A. Görgens, et al. (2021)
• Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers — L. Kara-Terki, L. Treps, et al. (2020)

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