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| MicroRNA: A new Twist on invasion and metastasis
The microRNA miR-10b indirectly regulates RhoC expression to promote tumor cell invasion and metastasis, documenting a novel role for microRNAs in regulating migration and motility, and exposing their involvement at several different stages of tumor formation and progression. MicroRNA molecules (miRNAs) regulate many diverse cellular processes, including development, apoptosis and tumor formation. Several reports have shown that miRNAs can act as oncogenes or tumor suppressors to facilitate or repress tumorigenesis. However, a role for miRNAs in the later stages of malignancy — invasion of cancer cells into the surrounding stroma and metastasis to distant sites — has not yet been found. In Nature, Weinberg and colleagues document a novel function for the miRNA miR-10b in promoting invasion and metastasis by regulating the expression of the pro-metastatic small GTPase RhoC.
Work from previous studies enabled the identification of several miRNAs that were substantially upregulated in breast cancer cells compared to primary human mammary epithelial cells. The expression of one of the miRNAs, miR-10b, was limited to metastatic cells, indicating a potential role for miR-10b in regulating metastasis. Indeed, mammary fat pad implantation of cells that overexpressed miR-10b resulted in tumors that invaded the surrounding stroma and frequently metastasized to the lungs. Like their protein-coding genetic counterparts, the expression of miRNA molecules can be modulated by the activity of transcription factors. The transcription factor Twist is upregulated in metastatic cells, hinting at a potential relationship between Twist activity and miR-10b expression. Chromatin immunoprecipitation experiments found that Twist could bind to the miR-10b promoter. Inhibition of miR-10b in cells that overexpress Twist significantly reduced cell motility, confirming miR-10b as a Twist-regulated gene that relays the pro-metastatic effects of Twist activity. How, then, does miR-10b promote migration and invasion? In silico and in vitro experiments found that miR-10b could bind to and inhibit translation of homeobox D10 (HOXD10) mRNA. HOXD10 is known to repress several pro-metastatic genes, including RhoC. A linear miR-10b–HOXD10–RhoC regulatory pathway unfolded upon the observation that miR-10b inhibited expression of HOXD10 and promoted expression of RhoC, and that depletion of RhoC limited miR-10b-mediated invasion and motility. Furthermore, exogenous co-expression of miR-10b in combination with a HOXD10 construct that was resistant to miR-10b-mediated silencing almost completely inhibited migration. Together, these data define a novel pro-metastatic pathway in which Twist facilitates expression of miR-10b, preventing translation of HOXD10. The absence of HOXD10 potentiates the expression of RhoC, as well as several other pro-migration genes, and promotes invasion and metastasis. The authors suggest that other genetic targets of miR-10b could have additional roles in promoting malignant progression, hinting at the complex regulatory events that underlie tumorigenesis and metastasis. Future studies into the role of miRNAs in regulating these diverse cellular processes will ultimately yield a better understanding of the events that foster the development of a metastatic tumor from a cancer cell. Emily J. Chenette Reference | |
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