MicroRNA in Cancer Karen Dybkær 2013

Transcription

1 MicroRNA in Cancer Karen Dybkær

2 RNA Ribonucleic acid Types -Coding: messenger RNA (mrna) coding for proteins -Non-coding regulating protein formation Ribosomal RNA (rrna) Transfer RNA (trna) Small nuclear RNA (snrna) app 150 nts Small nucleolar RNA (snorna) Piwi-interacting RNA (pirna) 26-31nts Long noncoding RNA (lncrna) >200 nts RNA interference RNA induced gene silencing Small interfering RNA (sirna) dsrna nts MicroRNA (mirna) nts

3 MicroRNA biogenesis and function MicroRNA genes are first transcribed into primary microrna (pri-microrna), which is further processed to premicrorna. pre-microrna is exported to the cytoplasm, where it is cleaved by the Dicer enzyme into shorter microrna duplex molecules microrna duplex is separated into single strand RNA molecules, from which usually one (guide strand) acts as the final mature microrna, that interacts with the target mrna through RISC If microrna binds partial complementary, translation is inhibited and deadenylation can be speeded up Nature Cell Biology 11, (2009) If microrna binds full complementary, target mrna is degraded.

4 21 25 nucleotide small RNA MicroRNA Background Binds to the 3 -UTR of target mrna. Estimated that 70% of microrna genes may be located within introns and exons of other (protein-coding or non-coding) genes - transcriptionally regulated through the promoters of these genes. Estimated that 30% of microrna genes are located in intergenic regions transcriptionally regulated from independent transcription units. Estimated 50% of microrna genes are associated with CpG islands in the DNA making them prone to epigenetic regulation Homo sapiens mirnas (2555 mirbase 20- junly) MicroRNA function in general seems to be linked to multicellularity: Stem cells don t need functional mirnas for viability, but they fail to differentiate without mirnas. mirnas are essential for vertebrate development. mirnas are involved in differentiation and maintenance of cell identity.

5 MicroRNA in cancer microrna regulate cell proliferation, apoptosis and differentiation processed of importance in cancer initiation and development microrna may function as oncogens or tumor supressors Nature Medicine 11, (2005) Often located in cancer associated genomic regions or in fragile chromosomal areas

6 MicroRNA in cancer Abberant microrna expression in cancer Sequence variation in microrna target sites affects the control and downstream role of microrna function - mutations and SNPs in microrna binding sites of target mrna -3 UTR shortening

7 MicroRNA as diagnostic cancer tools Since microrna expression is often deregulated in cancer, robust quantification may offer new diagnostic tools FEBS leter: Volume 585, Issue 13, 7 July 2011, Pages MicroRNA are more stable than mrna, present in plasma and relatively easy and cheap to detect

8 MicroRNA as cancer therapeutic tools Since microrna functions as onco- or tumor supressor genes regulation of their expression in cancer may offer new therapeutic possibilities

9 Murine models of cancer Why is it smart with murine models of cancer 1. Evaluate new treatments (chemo, Abs) 2. Increase understanding of pathogenesis Which models exists 1. Spontanoues 2. Xenogenic murine models (transplantation of human tumor cells into immunodeficient mice) 3. Immunodeficient mice models - impaired immunesystem (SCID mice fx mutations in scid gene resulting in mice with less or no T and B cells) 4. Genetically engineered mice models - transgene animals: targeted mutations (knock outs), chemically induced mutations (fx ENU), retroviral integrations Transgene models 1. OncomiR addiction

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