MicroRNA-206 suppresses mesothelioma progression via the Ras signaling axis

Our plain-English summary of MicroRNA-206 suppresses mesothelioma progression via the Ras signaling axis, by A. Singh, N. Pruett, R. Pahwa, et al (Molecular Therapy. Nucleic Acids, 2021).

The study

• Authors: A. Singh, N. Pruett, R. Pahwa, A.P. Mahajan, D.S. Schrump, C.D. Hoang
• Journal: Molecular Therapy. Nucleic Acids
• Published: 2021;24:669-681
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an incurable surface neoplasm with peculiar pathobiology. MPM proliferates by using the tyrosine-kinase-Ras pathway. Despite representing an attractive therapeutic target, there are no standard agent(s) specifically inhibiting Ras signaling adopted in clinical settings. We posited that biologic effects of microRNA (miRNA) can disrupt this molecular network. Using patient samples, cell lines, and murine tumor xenograft models, we confirmed specific genes in the Ras pathway are targeted by an MPM-associated miRNA and then examined its therapeutic effects. We verified significant and consistent downregulation of miR-206 in MPM tissues. When miR-206 is ectopically re-expressed in MPM cells and delivered to tumor xenografts in mice, it exerted significant cell killing by suppressing multiple components of the receptor-tyrosine-kinase-Ras-cell-cycle-signaling network; some of which were prognostic when overexpressed and/or have not been druggable. Of note, we validated CDK6 as a novel target of miR-206. Overall, this miR-206-targeting mechanism manifested as induced G1/S cell cycle arrest. In addition, we identified a novel MPM therapeutic combination by adding systemic-route abemaciclib with local-route miR-206, which showed additive efficacy translating to improved survival. Our pre-clinical study suggests a potential pathophysiologic role for, and therapeutic relevance of, miR-206 in MPM.

In plain English

This laboratory study used human tissue, cell lines and mice. It did not examine asbestos exposure. The authors measured microRNA-206 (miR-206), a short noncoding RNA that helps regulate genes, in 45 pleural mesothelioma tumors and 18 unmatched normal pleural tissues. Average miR-206 levels were 6.8-fold lower in the tumors (p less than 0.001). Restoring miR-206 in mesothelioma cell lines reduced their growth, colony formation and invasion. A normal mesothelial cell line showed no significant change in growth. In 85 mesothelioma cases from a public database (TCGA), higher levels of each of four genes that miR-206 acts on were associated with poorer overall survival. The authors also identified CDK6 as a new target of miR-206. In mice with human mesothelioma cells implanted in the chest (5 per group), median survival was 43 days with miR-206 and 36 days with control. In a second experiment, median survival was 51 days with miR-206 plus the drug abemaciclib, 44 with miR-206 alone, 41 with abemaciclib alone, and 34 with control or drug vehicle. The authors concluded that miR-206-based therapy should be studied further in mesothelioma.

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: Preclinical laboratory study: human tumor and normal tissue samples, analysis of a public tumor database (TCGA), cell-line experiments, and mouse xenograft (implanted human tumor) experiments
• Who was studied: 45 malignant pleural mesothelioma tumors (41 epithelioid, 3 biphasic, 1 sarcomatoid) and 18 non-patient-matched, non-malignant pleural tissues; a separate TCGA cohort of 85 MPM specimens; multiple MPM cell lines; and NSG mice carrying xenografts of the H2373 mesothelioma cell line (n = 5 per group)
• Exposure: Asbestos exposure was not studied. The experimental treatments were a miR-206 mimic, delivered to cells or injected near or into the tumor area in mice, and the CDK4/6 inhibitor drug abemaciclib, given orally to mice at 50 mg/kg/day over 14 days, alone or in combination
• Main results:
  • Mean miR-206 expression was 6.8-fold lower (p < 0.001) in the 45 MPM tumors than in the 18 normal pleural tissues
  • In MPM cell lines, re-expression of miR-206 reduced growth, colony formation, anchorage-independent growth (p < 0.05) and invasion compared with control
  • In a normal mesothelial cell line (NP4), miR-206 did not significantly change growth compared with control cells
  • In the TCGA cohort of 85 MPM specimens, relatively high expression of IGF1R, KRAS, CCND1, or CDK4 was associated with poor overall survival (p < 0.05)
  • The authors verified CDK6 as a new direct target of miR-206
  • In mice with tumors implanted in the chest (n = 5 per group), miR-206 treatment gave a median survival of 43 days, compared with 36 days for control (p < 0.05)
  • In the combination experiment (five groups of n = 5 mice), median survival was 51 days with abemaciclib plus miR-206
  • In the same experiment, median survival was 44 days with miR-206 alone and 41 days with abemaciclib alone, compared with 34 days for both the control and the drug-vehicle groups (p < 0.05 for each comparison)
• The authors' conclusion: The authors concluded that miR-206 acts as a tumor suppressor in MPM, that combining it with abemaciclib showed additive effects in mice, and that miRNA-based therapy should be studied and developed further in MPM

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Neoplasm.

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