Department of Microbiology and ImmunobiologyDana Farber Cancer Institute
Dana Building, Room 1420B
450 Brookline Avenue
Boston, MA 02215
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MicroRNAs are non-coding, endogenous, ~21-nucleotide-long RNAs that play key roles in numerous cellular processes such as maintenance of embryonic and somatic stem cells; differentiation and development of cells, tissues, organs, and organ systems; and a wide spectrum of cell-specific functions. It is not surprising, therefore, that microRNA dysregulation is associated with numerous diseases, especially cancers. Research in the Novina laboratory focuses on (1) the fundamental biology of microRNAs and (2) their altered function in cancers. Our work combines hypothesis-driven, discovery-driven, and computation-driven approaches to identify microRNAs, their target mRNAs, and the effectors and regulators of microRNA activities.
To understand the molecular details of microRNAs function, we developed the first cell-free, microRNA-directed translational repression reactions (Mol. Cell 2006, PNAS 2008). Using this cell-free system, we can selectively add or remove microRNAs, mRNAs, or proteins from the repression reactions to define the roles for each constituent in microRNA function. Additionally, the effects of particular modifications to microRNAs, mRNAs, or proteins can be studied in a controlled setting. To complement in vitro approaches to microRNA function, we engineered cells in which a robustly-expressed, endogenous microRNA (miR-21) inhibits translation of a reporter mRNA. We have used genetic screening approaches to identify factors that mediate or regulate microRNA function. We also use confocal microscopy and FRET-based approaches to visualize microRNA-containing repressive complexes in the cells.
MicroRNA expression is frequently altered during cancer initiation and progression. Detecting which microRNAs are altered can help identify not only the presence of cancer and the type of cancer but also can help determine the prognosis and likelihood of responding to particular therapies. Determining the basis of altered microRNA expression and function can also provide fundamental insights into the mechanisms of oncogenesis. We recently used microRNA expression profiling of human chronic lymphocytic leukemia (CLL) patient samples to discern an activated B cell-like phenotype in CLL cells (PLoSONE, 2011). Generally, CLL cells are not thought to represent activated B cells. However, microRNA expression profiling identified certain microRNA changes in CLL cells characteristic of B cells stimulated by B cell activators. For example, our data indicate up-regulation of miR-29c and down-regulation of miR-223 in activated donor B cells and in CLL patient cells. Importantly, up-regulation of miR-29c and down-regulation of miR-223 are associated with increased time to first treatment, a poor prognostic indicator for CLL. These data imply that miR-29c and miR-223 might be targets for therapeutic inhibition and reconstitution, respectively.
We also study microRNA dyregulation in melanomas. Metastatic melanomas are often refractory to treatment and are frequently lethal. Collaborating with Levi Garraway’s laboratory (DFCI, Broad), we generated large datasets of SNP, mRNA, and microRNA expression profiles from 55 human melanoma patient samples. In one project, we identified two populations of melanomas: (1) highly-invasive melanomas expressing low levels of miR-211 and (2) non-invasive melanomas expressing higher levels of miR-211. The gene for miR-211 is contained in intron 6 of a putative melanoma tumor suppressor gene called melastatin. Melastatin has long been considered a melanoma tumor suppressor because when melanomas become invasive and metastasize, melastatin is strongly reduced and melanoma patients with low levels of melastatin have a poor prognosis. However, the way that melastatin suppresses tumor formation has been a mystery. Because both melastatin and miR-211 are strongly reduced in human melanomas when compared to normal human melanocytes, we hypothesized that miR-211 might be responsible for increasing melanoma metastasis. Collaborating with David Fisher’s laboratory (MGH), we found that increasing miR-211 but not melastatin in human melanoma patient cells reduced melanoma invasive potential in vitro and melanoma metastasis in mouse xenograft models, suggesting that miR-211 (and not its host gene melastatin) functions as melanoma tumor suppressor and is a potential target for treatment of metastatic melanomas. This report was the first demonstration that a microRNA can assume the tumor suppressor function of its host gene (Mol. Cell 2010).
Last Update: 8/22/2013