MicroRNAs and Cancer
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1 MicroRNAs and Cancer MicroRNAs are an abundant class of small (20-25 nucleotides) non-protein coding RNAs that function as negative gene regulators. The human genome contains up to 1000 micrornas which constitute approximately 1-5% of the expressed genes. Over half of microrna genes (52.5%) are located in or near fragile sites or cancer-associated genomic regions
2 The discovery of micrornas The founding member of the mirna family, lin-4, was identified in C. elegans through a genetic screen for defects in the temporal control of post-embryonic development (loss of function mutations). 1993
3 Gene structure and microrna gene transcription
4 The biogenesis of micrornas The linear canonical pathway of microrna processing Nature 2010
5 The microrna biogenesis factors
6 Dicer is essential for mouse development morphology brachyury Oct 4 Embryo 7.5
7 RISC formation and function Components: -Argonaute (AGO)-family proteins (AGO1-4) -Gemin 3-4 Helicases
8 Principles of microrna-mrna interactions perfect and contiguous base pairing of mirna nucleotides 2 to 8, representing the seed region (shown in dark red and green bulges or mismatches must be present in the central region of the mirna mrna duplex, precluding the Argonaute (AGO)-mediated endonucleolytic cleavage of mrna. there must be reasonable complementarity to the mirna 3 half to stabilize the interaction
9 Possible mechanisms of the microrna-mediated posttranscriptional gene repression in animal cells
10 P-bodies and stress granules Decapping enzyme complex DCP1-DCP2 Decapping activators RCK/p54, RAP55, EDC3 Deadenylase complex CAF1-CCR4-NOT 5-3 exonuclease XRN1 Other proteins involved in nonsense-mediated mrna decay and other mrna degradation pathways.
11 MicroRNA are subject to genomic regulation
12 MicroRNA are subject to transcriptional and post-trascriptional regulation
13 MicroRNA editing Editing is defined as a post-trascriptional change of RNA sequences by deamination of adenosine (A) to inosine (I), altering the base-pairing and structural properties of the transcript. Editing of mirna transcripts by ADARs (adenosine deaminases acting on RNA) was first described for mir-22 followed by mir-151, mir-197, mir-223, mir- 376a.. Consequences. In primir-142, A-to-I editing inhibits its cleavage by endonuclease Drosha and results in its degradation by ribonuclease Tudor-SN, which preferentially cleaves double-stranded RNA containing inosine-uracil pairs. In prmir-151 editing abolishes its cleavage by Dicer in the cytoplasm. In primir-376 a single A-to-I change redirects the mature mirna to a new target, resulting in altered protein expression in mice. To be established. Predominantly nuclear or cytoplasmic events? Do they occur on the primir or in the premir?
14 Regulation of pri-mirna processing The microprocessor complex Drosha-DGCR8 cleaves the pri-mirna releasing the pre-mirna Some mirnas require additional specificity factors (for example RNA helicases p68 and p72) for efficient cleavage
15 Regulation of pri-mirna processing Interaction of pri-mir-18a with heterogeneous nuclear ribonucleoprotein A1 (hnrnp A1) facilitates cleavage of this specific mirna by Drosha TGF-beta signalling induces SMAD binding to the mir-21 precursor and enhances its efficient processing by Drosha
16 Mirtrons: splicing replaces Drosha cleavage Splicing can replace Drosha processing if the released and debranched intron (mirtron) has the length and haitpin structure of a pre-mirna
17 Lin-28 regulates let-7 processing and precursor stability Lin-28 is a stem-cell-specific regulator of let-7 processing that uses multiple mechanisms
18 Regulation of microrna processing factors a. DGCR8 enhances the protein stability of Drosha b. Drosha cleaves two hairpin structures in the DGCR8 mrna, which is subsequently degradated
19 microrna maturation in the cytoplasm AGO2 mediates pre-mirna cleavage generating the ac-pre-mirna
20 Argonaute proteins: regulators and effectors a b a. Serine 387 phosphorilation of Ago2 by p38 under cellular stress conditions regulates its localization to P-bodies b. Hydroxilation of Pro 700 by the type I collagen prolyl-4- hydroxylase affects the stability of human Ago2
21 RNA expression patterns dictate mirna repressibility in cells
22 RISC-associated factors regulate efficient microrna-mediated repression
23 Pumilio-mediated regulation of p27 silencing by mir-221/mir-222
24 Experimental approaches: MicroRNA identification Cloning and sequecing endogenous small RNAs of bp long (on the basis of characteristics of Dicer cleavage, temporally and spatially regulated expression and, in many cases, evolutionary conservation) Bioinformatic predictions (on the basis of pre-mirna hairpin structures and sequence conservation throughout evolution i.e. mirscan and mirseeker ) microrna Registry (more than 500 in human genome) (
25 Functional characterization of micrornas Approches: Forward Genetic Expression Studies (Reverse Genetic) Bioinformatic predictions: TargetScan (Lewis et al.) miranda (john et al.) DIANA-MicroT (Kiriakidou et al.) PicTar (Krek et al.) Algorithm for predicting vertebrate mirna targets on the basis of different criteria Experimental validation of potential targets (luciferase assay)
26 mir-15 and mir-16 in Chronic Lymphocytic Leukemia Locus 13q14 (30 kb)
27 mir-15 and mir-16 induce apoptosis by targeting BCL2
28 High-throughput tecniques for mirna profiling Solid-phase array-based platform Semiquantitative Requires transcript amplification/labeling Cross-hybridization among mirnas of the same family Flow-based/Liquid-phase array Increse specificity Higher sensitivity Technically demanding Validation by a second tecnique, such as Northern blot or quantitative Realt Time PCR
29 An oligonucleotide microchip for genome-wide microrna profiling in human and mouse tissues
30 MicroRNA expression profiles classify human cancers
31 Cause of abnormal MicroRNA expression 1. Chromosomal abnormality 2. Epigenetic changes 3. Mutations and SNPs 4. Defects in the mirna biogenesis machinery
32 1. MicroRNAs exhibit high frequency genomic alterations in human cancer CGH frequency plots of 227 ovarian cancer (stars indicate mirna genes) acgh data of all genomic loci containing mirnas in ovarian cancer, breast cancer, and melanoma specimens
33 Correlation analysis between DNA copy number alteration and mirna expression
34 2. Methylation of human MicroRNA genes in normal and neoplastic cells The methylation of 9 mirna genes was analyzed by combined bisulfite restriction analysis. The corresponding PCR reactions produced amplicons ranging from 400 to 900 bp, respectively (marked U ).The appearance of smaller restriction fragments ( M ) indicates methylation of the corresponding mirna gene, resistance to digestion indicates the absence of methylation. 5 human cell lines were tested: the human embryonic stem cell line HES7 (HES), primaryhuman fibroblasts (PHF), the HeLa cervical carcinoma cell line (HeLa), the HCT116 colon carcinoma cell line (HCT) and an isogenic DNA methyltransferase-deficient HCT116 cell line (DKO).The CpG-islands of 3 protein-encoding genes, p15, p21 and NPM, were included as controls.
35 3. Functional role of SNPs in mirna sequence: the case of non-small cell lung cancer Lung cancer patients carrying the hsa-mir-196a2 rs CC genotype had a lower survival than the patients carrying TT/CT genotypes, especially among stage I/II patients.
36 4. Post-trascriptional regulation of micrornas mirna expression during mouse development. Red bars represent mature mirna, and blue bars represent primary transcript. mirna expression in primary tumors. There is no correlation between primirna mature expression in the tumor samples.
37 4. Reduced expression of Dicer associated with poor prognosis in lung cancer patients
38 4.Regulation of mirnas by transcription factors E2F1 Regulates mir-106b-25 Expression E2F1 Is a Target of mir-106b and mir-93 mir-106b and mir-93 Repress p21 Overexpression of mir-106b and mir-93 Interfere with TGFb- Dependent G1/S Cell-Cycle Arrest E2F1 is a master regulator of cell cycle that promotes the G1/S transition transactivating a variety of genes involved in chromosomal DNA replication, including its own promoter TGFb is a cytokine playing a major role within the so-called morphogenetic program, a complex system of crosstalk between the epithelial and the stromal compartments that guides gastrointestinal cells toward proliferation, differentiation, or apoptosis
39 MicroRNAs can function as tumor suppressors and oncogenes
40 Mechanisms underlying the global downregulation of mirnas in cancer Cancer cells present global downregulation of mirnas, loss of tumour-suppressor mirnas and specific accumulation of oncogenic mirnas. Transcriptional repression by oncogenic transcription factors (MYC oncoprotein directly contributes to the global transcriptional silencing of mirnas). Changes in mirna biogenesis.
41 Mechanisms of mirna perturbation in cancer
42 Contribution of mirnas to cancer pathways
43 Contribution of mirnas to cancer pathways
44 Contribution of mirnas to cancer pathways
45 Reduced accumulation of mir-143 and mir-145 in Colorectal Neoplasia
46 MicroRNA-21 is an antiapoptotic factor in human glioblastoma
47 Suppression of mir-21 results in caspase activation and increased apoptosis
48 Let-7 influences Ras expression in human cells
49 The 3 UTR of Nras and Kras enable let-7 regulation
50 A microrna polycistron as a potential human oncogene mir cistron is located at 13q31, a genomic locus that is amplified in cases of diffuse large B-cell lymphoma, mantle cell lymphoma, primary cutaneous B- cell lymphoma and several other tumor types.
51 Overexpression of the mir-17-19b cluster accelerates c-myc-induced lymphomagenesis in mice
52 c-myc-regulated micrornas modulate E2F1 expression
53 mir-17-5p and mir-20a regulate E2F1 translational yield
54 Molecular mechanism of microrna-involved cancer pathogenesis
55 MicroRNAs as diagnostic and prognostic tools A microrna expression signature of human tumors
56 MicroRNAs as diagnostic and prognostic tools Clustering of mirna expression in different ALL subtypes
57 MicroRNAs therapeutic tools Re-Expression of mirnas I. Synthetic small RNAs called mirna mimetics (exact sequence of the endogenous mirna) II. DNA vectors (mirnas precursors sequences, degradation) III. Viral vectors Anti-miRNAs I. Antisense oligonucleotides that bind directly to mirnas II. AntagomiR III. mirna sponges Target Protectors (small oligonucleotides with perfect complementary to the seed region and to the 5 and 3 flanking sequences in the 3 UTR of specific mrna target)
58 MicroRNA Silencing in Primates: Towards Development of Novel Therapeutics
59 Antisense oligonucleotides They work by stoichiometric interaction with mature mirnas, either titrating them or binding to mirna precursors and inhibiting the biogenesis of mature mirna 1. 2 O-methyl RNA oligonucleotides, 2 O-methyl group increases stability O-methoxyethyl oligonucleotides (2 -MOEs) 3. 2,4 -methylene bridged nucleic acids ( locked nucleic acid, LNA)
60 In vivo knockdown of mirnas
61 Silencing of micrornas in vivo with antagomirs liver The antagomir is a 2 O-methylated oligonucleotide with a cholesterole molecule linked at its 5 end that improve the cellular uptake of this molecule.
62 Lentivirus-mediated antagomir expression Design of microrna sponge by inserting multiple binding site into the 3 UTR of GFP reporter gene driven by the CMV promoter Sponge with bulged binding sites were designed to protect duplex against endonucleolytic cleavage by AGO2 Design of U6 sponges by subcloning the microrna binding site region into a vector containing a U6
63 In vivo mirna expression
64 In vivo mirna inhibition
65 NATURE PROTOCOLS An integrated biological knowledge and analytic tools aimed at systematically extracting biological meaning from large protein/gene lists
66 PROCEDURE 1) Submit a gene list to DAVID: -Copy and paste a list of gene Ids into Box A - Select the appropriate gene identifier type - Click the Submit List buttom 2) Access DAVID analytic modules
67 RESULTS Functional annotation chart Pathway map viewer. The red star indicates the associations between pathway genes and the user s input genes. Following the pathway flow, IL10 was activated as an upstream immune stimulator. Then, the middle stream gene, HO-1, was involved. IL-1/TNFa/IL-6, as downstream regulator, was finally activated. Thus, the user s genes may be analyzed in a network context.
68 Proposed scheme for the treatment of liver cancer with combined chemotherapy and mirna-based therapy
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