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AACR: MicroRNAs in Cancer

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At the annual meeting of the American Association for Cancer Research in Chicago this week, Rockefeller University's Sohail Tavazoie discussed his work on determining the role of miRNAs in metastasis. Tavazoie wondered if miRNAs could suppress metastasis, and whether characterization of such miRNAs could provide insight into cancer's cellular pathways. In their analysis of lung and bone metastases, Tavazoie and his team identified eight miRNAs that were silenced. In addition, the patients in whom these miRNAs were silenced had worse disease outcomes than the patients in which the miRNAs were expressed. Further, the team caused the miRNAs to be over-expressed in mouse models of metastasis, and found that they drastically reduced metastases.

Tavazoie then proposed that these miRNAs work by targeting genes responsible for migration and invasion. Though all eight of the miRNAs were associated with at least one kind of cancer, Tavazoie and his team focused on miR-126, as they found it was implicated in cervical, gastric, colon, lung, and liver cancers. The team developed a loss-of-function model with miR-126 knocked down, and determined that this led to a significant enhancement of metastasis in the lung, brain, and other organs. However, they also found that silencing of miR-126 didn't lead to a significant increase in the proliferation of cancer cells, and so theorized that miR-126 works to suppress metastasis by modulating the ability of cancer cells to recruit endothelial cells. To show this, they identified all eight genes up-regulated in metastasis when miR-126 is knocked down, and further winnowed that list to three genes when they determined that endothelial recruitment was significantly reduced in their absence. Further tests showed that those three genes recruit endothelial cells to tumors to form metastases. Tavazoie concluded that these genes could all serve as targets for therapeutics in the suppression of metastasis.

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