MicroRNA-7, a Homeobox D10 Target, Inhibits p21-Activated Kinase 1 and Regulates Its Functions

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 20; pp. 8195 - 8200
• Main Authors: Reddy, Sirigiri Divijendra Natha, Ohshiro, Kazufumi, Rayala, Suresh K., Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States 15.10.2008
• Subjects: 3' Untranslated Regions - physiology; Adaptor Proteins, Signal Transducing - analysis; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement; ErbB Receptors - analysis; Female; Gene Expression Regulation; Homeodomain Proteins - physiology; Humans; Insulin Receptor Substrate Proteins; MicroRNAs - genetics; MicroRNAs - physiology; Neoplasm Invasiveness; p21-Activated Kinases - analysis; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - genetics; p21-Activated Kinases - physiology; Promoter Regions, Genetic; Transcription Factors - physiology
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2103

MicroRNAs are noncoding RNAs that inhibit the expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that microRNA-7 (miR-7) inhibits p21-activated kinase 1 (Pak1) expression, a widely up-regulated signaling kinase in multiple human cancers, by targeting the 3′-untranslated region (UTR) of Pak1 mRNA. We noticed an inverse correlation between the levels of endogenous miR-7 and Pak1 expression in human cancer cells. We discovered that endogenous miR-7 expression is positively regulated by a homeodomain transcription factor, HoxD10, the loss of which leads to an increased invasiveness. HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively up-regulated whereas those of miR-7 and its upstream activator HoxD10 are progressively down-regulated in a cellular model of breast cancer progression from low to highly invasive phenotypes. Furthermore, HoxD10 expression in highly invasive breast cancer cells resulted in an increased miR-7 expression but reduced Pak1 3′-UTR-luciferase activity and reduced Pak1 protein. Finally, we show that miR-7 introduction inhibits the motility, invasiveness, anchorage-independent growth, and tumorigenic potential of highly invasive breast cancer cells. Collectively, these findings establish for the first time that Pak1 is a target of miR-7 and that HoxD10 plays a regulatory role in modifying the expression of miR-7 and, consequently, the functions of the miR-7-Pak1 pathway in human cancer cells. [Cancer Res 2008;68(20):8195–200]