Document Type

Journal Article

Publication Date

12-21-2012

Journal

PLoS ONE

Volume

Volume 7, Issue 12

Inclusive Pages

Article number e52397

Keywords

Actins--metabolism; Cell Movement--genetics; Genome; Human--genetics; MicroRNAs--metabolism; Neoplasms--enzymology; Neoplasms--genetics; Signal Transduction

Abstract

Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.

Comments

Reproduced with permission of PLoS ONE

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

Peer Reviewed

1

Open Access

1

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