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

Abstract

MicroRNAs (miRs) are non-coding RNAs that inhibit expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that miR-7 inhibits p21-activated kinase 1 (Pak1) expression, a widely upregulated signaling kinase in multiple human cancers including breast and gliomas, by targeting the 3′-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, loss of which leads to an increased invasiveness. The HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively upregulated while that of miR-7 and its upstream activator HoxD10 are progressively downregulated 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 expression of miR-7 but a reduced Pak1 3′UTR-luciferase activity as well as 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 play a regulatory role in modifying the expression of miR-7, and consequently, functions of miR7 - Pak1 pathway in human cancer cells.

Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

“…It has been reported that miR-7 has a tumorsuppressor role in various cancers including brain tumors, breast cancer and lung cancer (Kefas et al, 2008;Reddy et al, 2008;Webster et al, 2009), and we herein showed that miR-7 also functions as a tumor suppressor in gastric cancer. Interestingly, in the normal stomach, miR-7 expression is induced during the differentiation of gastric epithelial cells, suggesting a role of miR-7 in the regulation of epithelial cell differentiation.…”

“…We found the expression level of miR-7 to significantly decrease in gastric tumors in an inflammation-dependent manner. It has been shown that miR-7 has a tumor-suppressor role in several cancers, including glioblastoma, breast cancer and lung cancer (Kefas et al, 2008;Reddy et al, 2008;Webster et al, 2009;Jiang et al, 2010;Saydam et al, 2011). In this manuscript, we demonstrate that miR-7 is induced during the differentiation of normal gastric epithelial cells, and it also has a tumor-suppressor role in the stomach.…”

“…EGFR is one of the important miR-7 target genes, and is at least partially responsible for its tumor-suppressor role (Kefas et al, 2008). Moreover, p21-activated kinase 1, Raf1, and the insulin-like growth factor 1 receptor have also been identified as miR-7 target genes that are upregulated in cancer cells (Reddy et al, 2008;Webster et al, 2009;Jiang et al, 2010). Although most of these gene products contribute to cancer cell proliferation, we believe that miR-7 inhibits expression of other factors that have a role in the maintenance of the undifferentiated status of epithelial cells.…”

The microRNA network and tumor metastasis

“…In addition, it still positively regulates miR-7 (Reddy et al, 2008), which was found to control epidermal growth factor receptor signaling and promote photoreceptor differentiation, inducing cell cycle arrest and cell death in some cancer cell lines (Kefas et al, 2008;Webster et al, 2009). miRNA expression profiling revealed that miR-7 was involved in tumor aggressiveness, invasion and metastasis in urothelial carcinomas and breast cancer (Foekens et al, 2008;Veerla et al, 2009).…”

“…miRNA expression profiling revealed that miR-7 was involved in tumor aggressiveness, invasion and metastasis in urothelial carcinomas and breast cancer (Foekens et al, 2008;Veerla et al, 2009). Reddy et al (2008) found that miR-7 inhibited p21-activated kinase 1 (Pak1) that has the potential to promote tumor invasion and metastasis. Accordingly, the HoxD10/miR-7/Pak1 and BRMS1/Twist/miR-10b/HOXD10/RHOC pathways form a cascade effect for tumor metastasis (Figure 2).…”