miR-17 acts as a tumor suppressor by negatively regulating the miR-17-92 cluster

Yan Sweat; Ryan J. Ries; Mason Sweat; Dan Su; Fan Shao; Steven Eliason; Brad A. Amendt

doi:10.1016/j.omtn.2021.10.021

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miR-17 acts as a tumor suppressor by negatively regulating the miR-17-92 cluster

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miR-17 acts as a tumor suppressor by negatively regulating the miR-17-92 cluster

Yan Sweat, Ryan J. Ries, Mason Sweat, Dan Su, Fan Shao, Steven Eliason and Brad A. Amendt

Molecular therapy. Nucleic acids, Vol.26, pp.1148-1158

12/03/2021

DOI: 10.1016/j.omtn.2021.10.021

PMCID: PMC8601969

PMID: 34853714

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Abstract

Anaplastic thyroid cancer (ATC) is an aggressive, highly metastatic cancer that expresses high levels of the microRNA (miR)-17-92 cluster. We employ an miR inhibitor system to study the function of the different miRs within the miR-17-92 cluster based on seed sequence homology in the ATC SW579 cell line. While three of the four miR-17-92 families were oncogenic, we uncovered a novel role for miR-17 as a tumor suppressor in vitro and in vivo. Surprisingly, miR-17 inhibition increased expression of the miR-17-92 cluster and significantly increased the levels of the miR-18a and miR-19a mature miRs. miR-17 inhibition increased expression of the cell cycle activator CCND2, associated with increased cell proliferation and tumor growth in transplanted SW579 cells in xenograft mice. miR-17 regulates MYCN and c-MYC expression in SW579 cells, and the inhibition of miR-17 increased MYCN and c-MYC expression, which increased pri-miR-17-92 transcripts. Thus, inhibition of miR-17 activated the expression of the oncogenic miRs, miR-18a and miR-19a. While many cancers express high levels of miR-17, linking it with tumorigenesis, we demonstrate that miR-17 inhibition does not inhibit thyroid tumor growth in SW579 and MDA-T32 ATC cells but increases expression of the other miR-17-92 family members and genes to induce cancer progression. [Display omitted] Cancer cells and tumors have characteristic microRNA (miR) profiles and high-expressing miRs are linked to poor survival rates in patients and maybe therapeutic targets. In contrast, inhibiting miR-17 in anaplastic thyroid cancer (ATC) results in significantly increased tumor formation due to activation of the miR-17-92 cluster and tumor-inducing genes.

miR mouse model

miR-17

miR-17 tumor suppressor

miR-17-92 cluster

plasmid-based microRNA inhibitor system (PMIS)

thyroid cancer

Details

Title: Subtitle: miR-17 acts as a tumor suppressor by negatively regulating the miR-17-92 cluster
Creators: Yan Sweat - Harvard University
Ryan J. Ries - Cornell University
Mason Sweat - Harvard University
Dan Su - University of Iowa
Fan Shao - University of Iowa
Steven Eliason - University of Iowa
Brad A. Amendt - University of Iowa
Resource Type: Journal article
Publication Details: Molecular therapy. Nucleic acids, Vol.26, pp.1148-1158
DOI: 10.1016/j.omtn.2021.10.021
PMID: 34853714
PMCID: PMC8601969
NLM abbreviation: Mol Ther Nucleic Acids
ISSN: 2162-2531
eISSN: 2162-2531
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: 5T90DE023520, DE028527
Language: English
Date published: 12/03/2021
Academic Unit: Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984284351002771

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