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Causes and consequences of microRNA dysregulation in cancer

Causes and consequences of microRNA dysregulation in cancer. Hulusi Onur Kuzucu - 2007103937. What are miRNA?. 1993, Victor Ambros Small non-protein-coding RNA Undergo several modifications Incorporated into RISC Negative regulators ; inhibit translation , promote degredation.

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Causes and consequences of microRNA dysregulation in cancer

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  1. Causes and consequences of microRNAdysregulation in cancer Hulusi Onur Kuzucu - 2007103937

  2. What are miRNA? • 1993, Victor Ambros • Small non-protein-coding RNA • Undergo several modifications • Incorporated into RISC • Negative regulators; inhibittranslation, promotedegredation

  3. miRNA as Cancer genes • Chronic Lymphocytic Leukaemia (CLL) • Alterations in 13q14, non-protein-codingregion • miR-15a & miR-16-1 • General alterationsof miRNAgenes • Dysregulation of miRNAexpression

  4. miRNA as Tumor suppressors • Heterogeneity • Loss of miR-15a & miR-16-1 in indolent CLLs • Loss of miRNA at 11q23and TP53, leading to aggressive cells • No rigid sequence of genetic events • Mutations affect miRNAfunction

  5. miRNA as Oncogenes • Overexpression of miRNA • miR-155 – 21q23 • Amplification in various BCL • miR-17-92 cluster – C13orf25 • Promote proliferation • Transactivation by MYC • Affects E2F transcription factors • Downregulates PTEN, p21, BIM

  6. miRNA dysregulation by transcription factors • miR-34 family and p53 TS– positive • ERα tumors & miR-221, miR-222 – negative • DysregulatedmiRNA genes, targets and mechanism of action

  7. miRNA in Cancer epigenetics • Methylation of CpG islands, miR-127 • miR-29 & DNMTs

  8. Conclusion • miRNA therapy • Different methods to introduce miRNAs • Use of miR-15a, miR-16-1 and miR-29 on cancer cells, reversal of changes • Focusing on miRNA dysregulation • Identifying miRNAs and their targets • Shifting from conventional chemotherapy to targeted therapies

  9. Thankyou • References: Carlo M. Croce Causes and consequences of microRNA dysregulation in cancer Nature Reviews Genetics: October 2009 Vol 10 No 10 p704 | doi:10.1038/nrg2634 Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with anti-sense complementarity to lin-14. Cell 75, 843–854 (1993). O’Donnell, K. A. et al. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005). Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007). Volinia, S. et al. MicroRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006). Garzon, R. et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111, 3183–3189 (2008). Saito, Y. et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435–443 (2006).

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