Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization

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.

miR-204-5p Inhibits Proliferation and Invasion and Enhances Chemotherapeutic Sensitivity of Colorectal Cancer Cells by Downregulating RAB22A

“…In addition, CNV also results in aberrant expression of genes, including miRNAs (12). Imam and colleagues reported that the 9q21.12 chromosomal region containing miR-204 is frequently lost in ovarian cancers, breast cancers, and pediatric renal tumors (31). We observed no significant changes in the copy numbers of the miR-204 gene between the colorectal cancer and NCT samples, suggesting that CNV may not be a key mechanism leading to the downregulation of miR-204.…”

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…42 miR-204 also regulates expression of an oncogene, neurotrophic receptor tyrosine kinase B, and promotes metastasis in endometrial carcinoma. 43 Imam et al 44 showed that the genomic locus encoding miR-204 is frequently lost in multiple cancers, including breast and ovarian cancers, and pediatric renal tumors. They suggest that miR-204 targets distinct genes involved in tumorigenesis including BDNF.…”

miR-485 Acts as a Tumor Suppressor by Inhibiting Cell Growth and Migration in Breast Carcinoma T47D Cells

“…Recent studies have shown the participation of miRNAs in breast cancer metastasis (Harquail et al, 2012). These studies have shown, for example, that miRlet-7, miR-584, and miR-204 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway, implicating a central role for it in cytoskeletal dynamics (Imam et al, 2012;Fils-Aimé et al, 2013;Hu et al, 2013).…”