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Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression

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posted on 2022-09-09, 03:42 authored by Janson Tse, T Pierce, Annalisa Leandra Elena CarliAnnalisa Leandra Elena Carli, Mariah Grace Alorro, S Thiem, EG Marcusson, Matthias ErnstMatthias Ernst, Michael BuchertMichael Buchert
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammationassociated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.

Funding

This project was supported by the National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (1079257), Program Grant (1092788) and Investigator Grant (1173814) to ME. The authors also acknowledge support from Austin Medical Research Foundation (Heidelberg, Australia) to JT and the Operational Infrastructure Support Program of the Victorian Government, Australia, to the Olivia Newton-John Cancer Research Institute.

History

Publication Date

2022-01-06

Journal

Cancers

Volume

14

Issue

2

Article Number

264

Pagination

22p.

Publisher

MDPI

ISSN

2072-6694

Rights Statement

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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