MicroRNA-661, a c/EBPα Target, Inhibits Metastatic Tumor Antigen 1 and Regulates Its Functions

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 14; pp. 5639 - 5642
• Main Authors: Reddy, Sirigiri Divijendra Natha, Pakala, Suresh B., Ohshiro, Kazufumi, Rayala, Suresh K., Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2009
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Tumors; Gene silencing; Target; RNA interference; Tumor associated antigen; Targeting; Micro RNA; Advanced stage; Inhibitor; Malignant tumor; Metastasis; Cancer; C/EBP transcription factor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-0898

MicroRNAs (miR) have been identified as posttranscriptional modifiers of target gene regulation and control the expression of gene products important in cancer progression. Here, we show that miR-661 inhibits the expression of metastatic tumor antigen 1 (MTA1), a widely up-regulated gene product in human cancer, by targeting the 3′ untranslated region (UTR) of MTA1 mRNA. We found that endogenous miR-661 expression was positively regulated by the c/EBPα transcription factor, which is down-regulated during cancer progression. c/EBPα directly interacted with the miR-661 chromatin and bound to miR-661 putative promoter that contains a c/EBPα-consensus motif. In addition, we found that the level of MTA1 protein was progressively up-regulated, whereas that of miR-661 and its activator, c/EBPα, were down-regulated in a breast cancer progression model consisting of MCF-10A cell lines whose phenotypes ranged from noninvasive to highly invasive. c/EBPα expression in breast cancer cells resulted in increased miR-661 expression and reduced MTA1 3′UTR-luciferase activity and MTA1 protein level. We also provide evidence that the introduction of miR-661 inhibited the motility, invasiveness, anchorage-independent growth, and tumorigenicity of invasive breast cancer cells. We believe our findings show for the first time that c/EBPα regulates the level of miR-661 and in turn modifies the functions of the miR661-MTA1 pathway in human cancer cells. Based on these findings, we suggest that miR-661 be further investigated for therapeutic use in down-regulating the expression of MTA1 in cancer cells. [Cancer Res 2009;69(14):5639–42]