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      Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies

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          Abstract

          Multiple members of the let-7 family of miRNAs are often repressed in human cancers 1, 2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3, 4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs 58, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis.

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          Most cited references 43

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          Reprogramming of human somatic cells to pluripotency with defined factors.

          Pluripotency pertains to the cells of early embryos that can generate all of the tissues in the organism. Embryonic stem cells are embryo-derived cell lines that retain pluripotency and represent invaluable tools for research into the mechanisms of tissue formation. Recently, murine fibroblasts have been reprogrammed directly to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) to yield induced pluripotent stem (iPS) cells. Using these same factors, we have derived iPS cells from fetal, neonatal and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. These data demonstrate that defined factors can reprogramme human cells to pluripotency, and establish a method whereby patient-specific cells might be established in culture.
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            Selective blockade of microRNA processing by Lin28.

            MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked posttranscriptionally in embryonic stem cells, embryonal carcinoma cells, and primary tumors. Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.
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              Impaired microRNA processing enhances cellular transformation and tumorigenesis.

              MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers. However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nature genetics
                1061-4036
                1546-1718
                7 May 2009
                31 May 2009
                July 2009
                1 January 2010
                : 41
                : 7
                : 843-848
                Affiliations
                [1 ]Stem Cell Program, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
                [2 ]Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA.
                [3 ]Howard Hughes Medical Institute, Boston, MA 02115, USA.
                [4 ]Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
                [5 ]Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [7 ]Massachusetts General Hospital, Vincent Center for Reproductive Biology, Thier 913, 55 Fruit Street, Boston, Massachusetts
                [8 ]Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
                [9 ]Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, IRCSS Foundation, Milan 20133, Italy
                [10 ]BCLC Group [HCC Translational Research Lab, Liver Unit, and Department of Pathology], IDIBAPS, CIBERehd, Hospital Clínic, Barcelona 08036, Catalonia, Spain
                [11 ]Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
                [12 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA, USA
                [13 ]St Jude Children's Research Hospital, Memphis, TN
                [14 ]Division of Haematology, The Institute for Medical and Veterinary Science, Adelaide, South Australia 5000, Australia
                [15 ]Department of Pathology, University of British Columbia, and the Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3.
                [16 ]Department of Pathology, Our Lady's Children's Hospital Crumlin, and Department of Pathology, Trinity College Dublin, Dublin, Ireland
                Author notes
                [* ]To Whom Correspondence should be Addressed: George Daley, Phone:(617) 919-2013, Fax:(617) 730-0222, E-mail: george.daley@ 123456childrens.harvard.edu

                Author Contributions

                S.R.V. and G.Q.D. conceived experiments and wrote the manuscript. S.R.V., J.T.P., W.E., Y.H., T.N., S.T., M.O., J.L. L.A.P., V.L.L, S.P.S., P.S.T., C.H.M., R.B., M.A., J.T., M.M., T.P.H., J.M.L., J.R, C.G.M., T.R.G. and P.H.S. executed experiments, contributed reagents, analyzed array data, and edited the manuscript.

                Article
                nihpa115931
                10.1038/ng.392
                2757943
                19483683
                Funding
                Funded by: National Institute of Child Health & Human Development : NICHD
                Funded by: Office of the Director : NIH
                Award ID: R01 HD052701-02 ||HD
                Funded by: National Institute of Child Health & Human Development : NICHD
                Funded by: Office of the Director : NIH
                Award ID: R01 HD052701 ||HD
                Funded by: National Institute of Child Health & Human Development : NICHD
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000256-01 ||OD
                Categories
                Article

                Genetics

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