Význam microRNA (v onkologii) MUDr. Mgr.Marek Mráz Moderní metody analýzy genomu LÉKAŘSKÁ FAKULTA MASARYKOVY UNIVERSITY Interní hematoonkologická klinika LF MU a FN Brno Centrum molekulární biologie a genové terapie  krátké RNA molekuly ~22 nukleotidů  komplementární vazba k cílové mRNA  inhibují translaci a snižují stabilitu mRNA microRNA (miRNA) • Lidské miRNA geny: cca 1000 Stovky evolučně konzervovaných microRNA Mraz et al., 2010 courtesy of F. Slack courtesy of F. Slack miRNAs expression profiles clasify tumors miRNAs are associated with disease prognosis miRNAs are tumor-supressors and proto-oncogenes miRNAs and microRNA binding sites are mutated in cancer miRNAs as drugs and targets in oncology miRNA expression profiles classify cancer microRNA expression can discriminate tumor types Lu et al. Nature 435: 834, 2005 courtesy of G. Calin miRNAs are associated with disease prognosis courtesy of G. Calin miRNAs are tumor-supressors and proto-oncogenes courtesy of S. Hammond courtesy of S. Hammond courtesy of G. Calin Pacienti s funkčním p53 mají ~ 10 násobně vyšší expresi miR-34a (p=0,000001) miR-34a P=0.000001 P=0.00001 a wt TP53 del/mut TP53 control miR- 34a 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 del/mutp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 del/mutp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 individual patients NormalisedmiRNA34aexpression wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 wtp53 Mraz et al., 2009 miR-34a a regulace apoptózy  He et al., NATURE 2007: miR-34a je transkripčně aktivovaná proteinem p53 (studium buněčných linií)  Bommer et al., CURR. BIOL. 2007: miR-34a ovlivňuje BCL2 (studium buněčných linií)  miR-34a je abnormálně exprimována u CLL pacientů s abnormalitou p53 (Mraz et al., 2009; Mraz et al., 2009)  první potvrzení významu miR-34a přímo in vivo u pacientů  je známa úloha BCL2 v patogenezi CLL, možný význam deregulace miR-34a miRNAs and microRNA binding sites are mutated in cancer courtesy of G. Calin Germline abnormalities in miR15-16 are associated with CLL and breast cancer Wojcik et al., 2009 miRNAs as drugs and targets in oncology Calin et al., 2008 Summary MicroRNAs are involved in the regulation of „everything“ MicroRNAs are abnormaly expressed in cancer, which makes them also attractive as prognostic markers Deregulation of microRNAs may be directly responsible for disease pathogenesis (miR-15-16 – deletion 13q14) MicroRNAs are important proto-oncogenes (miR-155, miR-17-92) MicroRNAs can work as tumor supressors (let-7, miR-34a) MicroRNAs represent a potential therapeutic target Thank you for your attention marek.mraz@email.cz