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

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

Mol Ther Nucleic Acids. 2021 Oct 21:26:1148-1158. doi: 10.1016/j.omtn.2021.10.021. eCollection 2021 Dec 3.

Authors

Yan Sweat¹, Ryan J Ries², Mason Sweat¹, Dan Su^{3

4}, Fan Shao^{3

4}, Steven Eliason^{3

4}, Brad A Amendt^{3

4

5}

Affiliations

¹ Harvard University, Boston, MA 02115, USA.
² Weill-Cornell Medical College, Cornell University, New York, NY 10075, USA.
³ The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA 52242, USA.
⁴ Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
⁵ Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA 52242, USA.

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.

Keywords: miR mouse model; miR-17; miR-17 tumor suppressor; miR-17-92 cluster; plasmid-based microRNA inhibitor system (PMIS); thyroid cancer.