miR-22 represses cancer progression by inducing cellular senescence

Xu Dan

Takeshita Fumitaka

Hino Yumiko

Fukunaga Saori

Kudo Yasusei

Tamaki Aya

Matsunaga Junko

Takahashi Ryou-u

Takata Takashi

Shimamoto Akira

Ochiya Takahiro

Tahara Hidetoshi

The journal of cell biology

Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22-induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.

Medical sciences [ 490 ]

eng

The Rockefeller University Press

Copyright (c) 2011 Xu et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

[ISSN] 0021-9525

[DOI] 10.1083/jcb.201010100

[NCID] AA00694812

[DOI] http://dx.doi.org/10.1083/jcb.201010100