Dataset Information

Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

ABSTRACT: microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

SUBMITTER: Reid G

PROVIDER: S-EPMC7020748 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

Reid Glen G Johnson Thomas G TG van Zandwijk Nico N

Frontiers in oncology 20200207

microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MP ...[more]

PMID: 32117755

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Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

Project description:Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a variable incidence among different countries. Occupational asbestos exposure is the most important etiological factor and a very long latency period is widely reported. In the early phase of the disease, clinical signs are absent or not specific. For this reason, the diagnosis is frequently achieved only in the advanced stages. The histopathological diagnosis per se is also very complex, and no known factor can predict the prognosis with certainty. Nonetheless, current survival rates remain very low, despite the use of standard treatments, which include surgery, chemotherapy and radiotherapy. The identification of new prognostic and/or diagnostic biomarkers, and the discovery of therapeutic targets is a priority and could lead to a real significant impact on the management of malignant pleural mesothelioma. In this scenario, the role of microRNAs is becoming increasingly relevant, with the promise of a quick translation in the current clinical practice. Despite the relative novelty of this field, the number of works and candidate microRNAs that are present in literature is striking. Unfortunately, to date the microRNAs with the most clinical relevance for MPM are still matter of debate, probably due to the variety of approaches, techniques, and collected samples. Although specific microRNAs (e.g., let-7, miR-15 and miR-16, miR-21, miR-34a, and the miR-200 family) have been reported several times from different groups, the heterogeneity of published data reinforces the need of more comprehensive and unified studies on this topic. In this review we collect and discuss the studies focused on the involvement of microRNAs in different aspects of MPM, from their biological role in tumorigenesis and progression, to their possible application as diagnostic, prognostic and predictive biomarkers. Lastly, we examine their potential value as for the design of therapeutic approaches that could benefit MPM patients.

Dataset Information

Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

Publications

Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

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