microrna & carcinogenesis - seoul national...
TRANSCRIPT
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2009 June MGEL W/S
성 현 아
MicroRNA & Carcinogenesis
2009 June MGEL W/S성 현 아
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Presentation Summary
• MicroRNA, Discovery and Biogenesis
• MicroRNA & Carcinogenesis
• MiRNA and Breast Cancer
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How few genes there were !There weren't that many more than a fruit fly or
a unicellular organism, yeast.
Saccharomyces cerevisiae~ 6,000 genes
Drosophila melanogaster~ 14,000 genes
Homo sapisens~ 19,000 genes
24 March 2000 3 April 200129 May 1997
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What makes human to be human?
"Junk" RNA May Have Played Role in Vertebrate Evolution
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Right about when vertebrates split off fro
m other animals, there was an explosion o
f these microRNAs in their DNA.
The complexity didn't come from the numb
er of genes an animal has.
The complexity comes from how similar g
enes are used.
This is where microRNAs come in because
they affect how an animal (or plant) uses it
s genes.
MicroRNAs Control How Genes are Used.
Evidence that Vertebrate Complexity Comes from non-codingRNA
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Non coding RNA
• A non-coding RNA (ncRNA) is any RNA molecule that is not translated into a protein
• tRNA / rRNA
• snRNA/miRNA/gRNA/piRNA/siRNA/tmRNA
• small RNA(sRNA), non-messenger RNA (nmRNA), small non-messenger RNA (snmRNA), or functional RNA (fRNA)
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• lin-4 is essential for the normal temporal control of diverse postembryonic developmental events in C. elegans
• lin-4 downregulates LIN-14
larval stage (L1)
• lin-4 does not encode a protein
• Two small lin-4 transcripts of approximately 22 and 61 ntsequences complementary to a repeated sequence element in the 3′ UTR of lin-14 mRNA
• lin-4 regulates lin-14translation via an antisense RNA-RNA interaction.
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The Biogenesis of miRNA & Assembly into miRISC
Txn. Of pri-miRNA(RNA pol II) pri-miRNAs pre-miRNA(Drosha)
Transport into cytoplasm small RNA duplexes(Dicer)
miRISC(RNA-induced silencing complex) target mRNA sequence
target miRNA silencing
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Possible Mechanisms of miRISC-Mediated Repression : post-transcriptional gene regulation
Usually via either translational repression or direct mRNA cleavage
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MicroRNA(miRNA)
• Endogenous 22-nt non-coding RNAs (22-24nts)
• Protein level regulation in a sequence-specific manner
• Developmental timing in worms, cell death and fat metabolism in flies,
and leaf development and floral patterning in plants(Evolutionary conserved)
• In mammals, including cell growth and apoptosis, hematopoietic lineage differentiation, insulin secretion, brain morphogenesis, and muscle cell differentiation and proliferation
• From 450 to 1000 miRNAs in the human genome
• Most human protein-coding genes influenced
• A single miRNA may bind to as many as 200 target genes
• Half of the known miRNA mapped to fragile sites in the genome, providing the first clue to their role in cancer
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At least 10% of the protein coding mRNAs might be conserved targets of miRNA
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Expression and function of micro RNAs in immune cells during normal or disease state Esmerina Tili1, Jean-Jacques Michaille1, 2, George Adrian Calin 3
Int J Med Sci 2008; 5:73-79
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microRNA and Human Disease
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Potential mechanisms of aberrant miRNA regulation
Mutation/SNP in the 3’ UTR target mRNA
(poly-miRTS)miRNAs located near fragile sites
epigenetic changes Roughly 20,000 poly-miRTS catalogued in databases such
as PolymiRTS(http://compbio.utmem.edu/miRSNP/)
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Method to determine miRNA expression levels
• High-throughput tech. for hundreds of miRNAs in a large number of samples(commonly used )
• Bead-based flow-cytometric tech.
• miRAGE : a genome-wide miRNAanalysis with serial analysis of gene expression (SAGE)
• qRT PCR
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miRNA & Carcinogenesis
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How miRNA contribute to oncogenesis ?
1> Function either as tumor suppressors or oncogenes
2> The genomic abnormalities found to influence the activity of miRNA : frequently located near fragile sites
3> Epigenetic changes such as alterations in CpG methylation patterns
4> SNP and/or mutations in the miRNA themselves
5> Differences in the expression levels or affinities of any protein involved in miRNA Transcription and Processing
: Drosha, Dicer, Argonaut etc.
6> the role of polymorphisms in the sites of target mRNAs 3’ UTR
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miRNAs as cancer players: miRNA , frequently located near fragile sites
Calin G. A. et.al. PNAS 2004;101:2999-3004
© 2004 by National Academy of Sciences
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A model of miRNA involvement in cancer by modulation of expression of tumor suppressor genes and oncogenes
Carlos Caldas et al. Sizing up miRNAs as cancer genes, Nature Medicine 11, 712 – 714 (2005)
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miRNA-expression profiles classify human cancers.
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• 217 miRNA, 334 samples including multiple human cancers
• A general downregulation of miRNAs in tumours compared with normal tissues
• Classifying poorly differentiated tumours using miRNA expression profiles
• A. Most of miRNA (129 out of 217, P<0.05) had lower expression levels in human tumour samples
• B. Normal lungs and lung adenocarcinomas of K-RasLA1 mice
• C. HL-60 cells, treated with all-trans retinoic acid or vehicle
• Highlightening the potential of miRNA profiling in cancer diagnosis
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• miR15 and miR16 are deleted or down-regulated in the majority
(≈68%) of CLL cases.
• miR15 and miR16 are located at chromosome 13q14, a region
deleted in more than half of B-CLL
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• Genome wide expression profiling of miRNAs in human B-CLL
using microarray
• 41 samples from 38 pts. with CLL and 6 normal samples
( 1 lymph node, 2 tonsillar CD5+ B cells, 3 blood MNC)
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Top 25 miRNAs differentially expressed in CLL cells vs. CD5+ cells
Calin G. A. et.al. PNAS 2004;101:11755-11760
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miRNAs differentially expressed bet. the two main CLL clusters
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miRNA signatures associaed with prognosis in B-CLL
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• 1st Set – 94 pts. of CLL cells
2nd Set - 50 pts. of CLL cells
to validate the predictive
power of the miRNA signature
• Northern blotting
miRNA-microchip
procedures( 368 probes,
corresponding to 245 human
and mouse miRNA genes)
Prognostic Factor
ZAP-70 >20% ZAP-70 <20%
IgVh status unmutated
Group 1(36pts) Group3(10pts)
IgVh status mutated
Group 2(10pts) Group 4(47pts)
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• Group1
Poor prognosis
(unmutated IgVh& high ZAP-20)
• 13 miRNAassociated with prognostic factors
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Relationship bet. the level of expression of miRNA and the time from diagnosis to initial therapy
• 94 pts
• 9 miRNAs, all members of the 13-member prognostic signature
• Short interval(40±39 months)/ longer interval (88±42 months)
• miRNA expression can be included in the markers with prognostic significance in CLL
• Germ-line or somatic mutations were found in 5 of 42 sequenced miRNAsin 11 of 75 pts. with CLL, but no such mutations were found in 160 subjects without cancer
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tool.
• 104 pairs of primary lung cancer and corresponding normal tissue
• 43 miRNAs differentially expressed in lung cancer vs. normal tissue thru microarray
• 6 miRNAs differentially expressed in adenocarcinoma and squamous cell carcinoma
• Correlation bet. miRNA expression profiles and prognosis of lung adenocarcinoma pts
• Validation using an independent set of adenocarcinoma
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• Using real-time RT-PCR, miRNA expression profiling in 112 NSCLC pts. divided into the training and testing sets
• a five-miRNA signature for the prediction of treatment outcome of NSCLC in the training set
• Validation by the testing set and an independent cohort
• Patients with high-risk scores in their miRNA signatures had poor overall and disease-free survivals compared to the low-risk-score pts.
This miRNA signature is an independent predictor of the
cancer relapse and survival of NSCLC patients.
2008 Jan08
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Calin and Croce Nature Reviews Cancer 6, 857–866 (November 2006)
miRNA-expression profiles classify human cancers.
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Common miRNA genes differentially expressed in various cancers, suggesting common altered regulatory pathways ?
• miR-21 ; directly target the tumor suppressor PTEN in cholangiocarcinoma cells (Meng et al. 2006, Gastroenterology)
• mrR-21 ; knockdown in cultured glioblastoma cells triggers apoptosis by a caspase-dependent mechanism (Chan, J. A. et al. 2005, Cancer Res)
miR-21 as an anti-apoptotic and pro-survival factor
• Let-7 miRNA family ; Ras regulation(Voorhoeve, P. M. et al ,Cell, 2006)
• miR-372 and miR-373 ; facilitate the proliferation and transformation of cells
• miR-155 transgenic mouse in B-cells ; polyclonal pre-leukaemic pre-B-cell proliferation followed by B-cell malignancy(early event in oncogenesis that needs additional genetic alterations for the development of the fully malignant phenotype) (Costinean, S. et al. PNAS, 2006)
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A new form of cancer predisposition?
• Abnormalities of miRNAs in the germline, an inherited predisposing event(blue person)• The overexpression of target oncogenes (red protein) in the case of miRNA deletion• The downregulation of target tumour-suppressor genes in the case of miRNA amplification (purple protein)
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Short Summary• miRNAs located in genomic regions amplified in cancers function as
oncogenes, whereas miRNAs located in portions of chromosomes deleted in cancers function as tumour suppressors.
• Abnormal expression of miRNAs has been found in both solid and
haematopoietic tumours by various genome-wide techniques.
• The abnormally expressed miRNAs targeting essential protein-coding genes involved in tumorigenesis, such as the Ras by let-7 family members, the BCL2 anti-apoptotic gene by the miR-15a–miR-16-1 cluster,
• miRNA expression fingerprints correlate with clinical and biological
characteristics of tumors, including tissue type, differentiation, aggression and response to therapy.
• Germline sequence abnormalities in miRNA genes and targeted sequences in mRNAs .
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miRNA & Breast Cancer
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Numbers of publications on the relationship of Breast Cancer & miRNAs since 2005
87
9
0
20
40
60
80
100
Orginal Ariticale
Review
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Numbers of publications according to research objective
16
5
45
37
0
10
20
30
40
50 Human BC Expression Profile
miRNA/target polymorphism
Functional Analysis
Genomic Localization
Method
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miRNA expression profiles in Breast Cancer Pts. Tissue
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• 76 breast cancers and 34 normal samples
• Deregulated expression of 29 miRNAs by microarray analysis
• A minimum predictive gene set of 15 candidates able to separate normal from cancer tissue
• The correlations bet. miRNA expression and standard pathologic features of breast cancers including lymph node status, vascular invasion, metastasis, ER, PR, and p53 status with the exception of ERBB2 expression
• Only a small set of 15 miRNA correctly predict the nature of the sample analyzed (i.e., tumor or normal breast tissue) with 100% accuracy.
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Iorio, M. V. et al. Cancer Res 2005;65:7065-7070
Figure 1. Cluster analysis and PAM prediction in breast cancer and normal breast tissues
Deregulated expression of 29 miRNAs by microarray analysis
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Deregulated expression of 29 miRNAs in tumor breast tissue
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miRNA name Median expression ANOVA* P SVM prediction strength
PAM score Chromosome map
Cancer Normal Cancer Normal
mir-009-1 1.36 1.01 0.0091 8.05 0.011 –0.102 1q22
mir-010b 1.11 1.70 0.0449 8.70 –0.032 0.299 2q31
mir-021 1.67 1.08 0.0047 10.20 0.025 –0.235 17q23.2
mir-034 1.67 1.09 0.0106 8.05 0.011 –0.106 1p36.22
mir-102 (mir-29b) 1.36 1.14 >0.10 8.92 0.000 –0.004 1q32.2-32.3
mir-123 (mir-126) 0.92 1.13 0.0940 9.13 –0.015 0.138 9q34
mir-125a 1.20 1.73 0.0033 8.99 –0.040 0.381 19q13.4
mir-125b-1 1.30 2.87 0.0265 14.78 –0.096 0.915 11q24.1
mir-125b-2 1.26 2.63 0.0233 17.62 –0.106 1.006 21q11.2
mir-140-as 0.93 1.10 0.0695 11.01 –0.005 0.050 16q22.1
mir-145 1.52 3.61 0.0040 12.93 –0.158 1.502 5q32-33
mir-155 (BIC) 1.75 1.37 0.0012 10.92 0.003 –0.030 21q21
mir-194 0.96 1.09 >0.10 11.12 –0.025 0.234 1q41
mir-204 0.78 0.89 0.0022 8.10 –0.015 0.144 9q21.1
mir-213 3.72 2.47 0.0108 9.44 0.023 –0.220 1q31.3-q32.1
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Differentially expressed miRNAs associated With biopathologic features of breast cancers
ER and PR
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lymph node status, vascular invasion, metastasis, p53 status
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What mRNA could be targeted by these targets?
• miR-10b targets ; FLT1(v-crk homologue), the growth factor BDNF, and the transducing factor SHC1
• miR-125b target ; YES, ETS1, TEL, and AKT3; the growth factor receptor FGFR2; mitogen-activated signal transduction pathway VTS58635, MAP3K10, MAP3K11, and MAPK14.
• miR-145 target ; cell cycle promoters such as cyclinsD2 and L1; and MAPK transduction proteins such as MAP3K3 and MAP4K4
• miR-21 target ; the TGF-beta gene
• miR-155 ; tumor suppressor genes SOCS1 and APC,
and the kinase WEE1, which blocks the activity of Cdc2
and prevents entry into mitosis. HIF1A.
Now, using PITA algorithms
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Correlation analysis between DNA copy number alteration
and miRNA expression
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miRNA & BC metastasis
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miR-10b is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion.
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miR-10b induces tumour invasion.
Stromal Invasion
Muscular Invasion
Vascular Invasion
Ki-67 Ki-67MECA-32 MECA-32
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miR-10b induces distant metastasis
Clusters of metastatic cells
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miR-10b expression level is associated with the metastasis outcome in breast cancer patients
a. miR-10b expression level is associated with the metastasis outcome in breast cancer patients.
b. miR-10b suppresses HOXD10, leading to induction of RHOC.
HOXD10 : preveously reported to be progressively lost in BC showing increasing degree of malignancy(metastasis supression)
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Clinical association of miR-335 and miR-126 with metastasis-free survival
20 primary breast tumor samplesmiR-335 and miR-126; metastasis suppressor miRNAs in human breast cancer
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miRNA signatures classify breast cancer subtype
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Expression profiling of 453 miRNAsperfomed in 29 early-stage breast cancer specimens
NA™ miChip array pl
atforms (Exiqon versi
on 7, containing 453
miRNA sequences)
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• the genome-wide expression profiling of miRNAs in primary BC
• microarray containing 435 mature human miRNA oligonucleotide probes
• 9 miRNAs(miR-21, miR-365, miR-181b, let-7f, miR-155, miR-29b, miR-181d, miR-98, and miR-29c) up-regulated greater than 2 fold in BC compared with NAT
• 7 miRNAs (hsa-miR-497, hsa-miR-31, hsa-miR-355, hsa-miR-320, rno-mir-140, hsa-miR-127 and hsa-miR-30a-3p) down-regulated greater than 2 fold.
RNA. 2008 November; 14(11): 2348–2360.
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miR-21, serve as a molecular prognostic marker for BC and disease progression
• TaqMan RT PCR in 113 BC tumors
• High level expression of miR-21
: with advanced clinical stage (P = 0.006), lymph node metastasis (P = 0.007), shortened survival of the patients (HR=5.476, P < 0.001)
Multivariate Cox regression analysis revealed this miR-21 (HR=4.133,P = 0.001) to be independent of disease stage (HR=2.226, P = 0.013) and histological grade (HR=3.681, P = 0.033)
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Cancer Treatment Reviews 25 (2009) 328-334
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MiRNA Polymorphisms & Breast Cancer
Prasun J Mishraet al Pharmacogenomics, Mar 2009
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• 3 important aspects in analyzing miRNA target site mutation/polymorpism
• (i) functional: testing SNP-mediated differential miRNA targeting
• (ii) genetic: testing association of the SNP with a disease or quantitative trait and
• (iii) mechanistic: testing a mechanism by which the differential miRNA activity can lead to disease
• Recommend for the convincing evidence for all three components by
• (i) providing experimental (in vivo if possible) validation of SNP-mediated differential miRNA targeting
• (ii) minimizing or eliminating the confounding effects of population stratification
• (iii) explicitly testing an underlying mechanism by which the poly-miRTS could contribute to disease pathogenesis.
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7
• Case-control study using a familial study population
• Study population : 1223 German breast cancer families(BRACA1/2 mutation negative) and 1495 unrelated German controls
• Sample : genomic DNA from peripheral blood lymphocytes collected during the years 1997–2007 by 7 centers of the German Consortium for Hereditary Breast and Ovarian Cancer
• SNP selection : 11 putative functional SNPs in miRNA target sites located in genes involved in cancer and breast cancer
• Genotyping : TaqMan allelic discrimination. Primers and TaqMan probes, 5 ng of genomic DNA per assay
• Conclusions : a variant in the ESR1 affecting a putative miRNA-binding site of miR-453 was significantly associated with familial breast cancer risk, especially in premenopausal and high-risk women
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11 putative functional SNPs in miRNA target sites located in genes involved in cancer and breast cancer
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Genotype frequencies polymorphisms in breast cancer-related genes in the German study population
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Genotype frequencies of ESR1 polymorphism rs2747648 in the German study population
according age stratification and high-risk families
From the in silico analysis, C variant allele of miR-453 is stronger than T allele T allele the binding of miR-453 miRNA-mediated ESR1-repression ESR1 an increased breast cancer risk
: protective effect observed for the C allele is biologically reasonable.
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• 42 pts. w/ familial breast cancer
• 23 of pts were BRCA1 mutation, 8 had BRCA2 mutation, 7 were non carriers of BRCA1/2
• 17 selected miRNA gene predicted to regulate key BC genes 7 novel genetic variants
• miR-30c-1 and miR-17 vatiantsin noncarriers of BRCA1/2
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7 Novel genetic variants in selected miRNA genes in BC
17 miRNA genesPrecursur seq.
Genomic seq. PCR/ Sequencing
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Sequence variations in the pri-miRNAcan translate into structural alterations
C(-48.1kcal/mol, more stable)T(-43.0kcal/mol, less stable)
conformational change in the predicted secondary structure(RNAHYbrid) altered exp.of mature miRNA
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Effects of miR-17 on the luciferase reporter gene bearing 3’UTR segment from BRCA1
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miRNA, as a new, novel, CANCER BIOMARKER ?
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http://www.hammerstockblog.com/
miRNA being evaluated as therapeutic targets as well as diagnostic targets
Designed to Differentiate
bet. pancreatic cancer and
pancreatitis
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Why miRNA better than mRNA as a diagnostic tool?
• Remarkably, the number of miRNAs analyzed was far smaller than the number of mRNA transcripts (≈200 miRNAs vs. ≈15000 mRNAs).
• More useful because of their regulatory role and their functions in modulating cellular differentiation.
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Research Fields on miRNA,as a Breast Cancer Biomarker
• SUSCEPTIBILITY MARKER for BC miRNA gene variation/genomic alteration of miRNA genes – polymorphism in miRNA target gene/miRNA related gene– copy number variation in miRNA gene in breast cancer
• DIAGNOSTIC MARKER to BC- Deregulation of miRNA biogenesis related genes in breast cancer- Differential miRNA expression associated with biopathologic features of breast cancer[receptor status, TNM stages, vascular invasion status… etc.]
• PROGNOSTIC MARKER to BC– miRNA profiling / response to therapeutics / disease outcome
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Small RNAs Are Raising Big Expectations
Karyn Hede Vol.101 Issue 12 June 16. 2009