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The action of a key player in metastasis

In vitro study shows central role of microRNA molecule miR-200c

Oeiras, 07.04.2015

An international team of researchers at Harvard Medical School ascertained the mechanism through which a microRNA molecule (called miR-200c) promotes metastases. The team published their findings in the journal Oncogene (Nature Publishing Group). Ricardo Perdigão Henriques, an ITQB PhD student co-advised by Manuel Carrondo from the Animal Cell Technology Unit at ITQB/iBET and Judy Lieberman at Harvard University, was the first author.

Metastasis is a complex process. Cancer cells must first detach from the main tumor, travel along the bloodstream, and attach to other organs where they promote the formation of secondary tumors. This process requires transitions between different cellular states, which alter cell motility. While the scientific community knew that miR-200c promoted the formation of metastasis, there was no detailed explanation for how that was done. Surprisingly, researchers found that miR-200c decreases the invasiveness ability of breast cancer cells in vitro.

As a microRNA, miR-200c binds to messenger RNA molecules (mRNA, the protein-coding RNA), decreasing their stability and thus reducing gene expression. Researchers comprehensively identified all mRNA targets of miR-200c in breast cancer cells. As many as 520 targets were identified, of which only a dozen were previously known. By focusing on the most important targets, researchers demonstrated that miR-200c down-regulates genes that repress the formation of epithelial cells.

The transition to an epithelial state is observed in many cancer cells. By binding to the identified targets, miR-200c ultimately destroys the protein complexes that repress epithelial gene expression. Through this mechanism miR-200c activates epithelial gene transcription and induces cells to transition to an epithelial state. While these cells are less prone to separate themselves from the tumor – and are thus less invasive – once detached they will more easily adhere to the epithelium of distant organs, which in the end increases metastases formation.

The central role of miR-200c, and the vast number of cellular pathways it regulates, makes it an extremely important molecule” explains Ricardo Perdigão Henriques, first author of the study, “in fact, even though this is an in vitro study, miR-200c might become a marker for cancer diagnosis or even used as a target for therapy”, he adds.

The study was coordinated by Judy Lieberman from Harvard Medical School/Boston Children's Hospital (USA) and RPH was partially funded by the Portuguese Ministry of Science and Technology (FCT).

Original Article

Oncogene (2015) doi: 10.1038/onc.2015.69.

miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1transcriptional repressor complexes

R Perdigão-Henriques1,2,3, F Petrocca1, G Altschuler4, MP Thomas1, MTN Le1, SM Tan1, W Hide4,5 and J Lieberman1,6

1 Boston Children's Hospital,  USA
2 Animal Cell Technology Unit, ITQB
3 iBET
4 Harvard School of Public
5 University of Sheffield, Sheffield, UK
6 Harvard Medical School, USA

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