MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions.

Abstract

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.

• Authors: Sirigiri Divijendra Natha Reddy, Kazufumi Ohshiro, Suresh K Rayala, Rakesh Kumar
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 20 Pg. 8195-200 (Oct 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18922890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3' Untranslated Regions
• Adaptor Proteins, Signal Transducing
• Homeodomain Proteins
• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• MicroRNAs
• Transcription Factors
• HOXD10 protein, human
• ErbB Receptors
• PAK1 protein, human
• p21-Activated Kinases

Topics

• 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, physiology)
• Neoplasm Invasiveness
• Promoter Regions, Genetic
• Transcription Factors (physiology)
• p21-Activated Kinases (analysis, antagonists & inhibitors, genetics, physiology)