Emerging roles of microRNAs as

molecular switches in
carcinogenesis
A Review
Current as in April 2009

March 2010.
N.H.K.S.Senathilake.

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 MiRNA AND SiRNA
Firstdescribed in 1993 (Lee et al. )
As part of a cascade that leads to post-
transcriptional gene silencing in Caenorhabditis.

Small interfering RNAs (siRNAs) - Exogenous.

MicroRNAs (miRNAs) - Exogenous.

Complementary interactions
o Degradation withmRNAs.
of the target mRNA.
o Blocking their translation.

Vast o RNA
network interference
of gene (RNAi).
regulatory systems.

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 RNAi SYSTEMS

RNAi

siRNA-mediated piRNA –based miRNA-based

pathways pathways pathways

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MiRNA BIOGENESIS

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 ONCOGENES, ANTI ONCOGENES AND
CANCER
Anti Proto Onco
Oncogene Gene
Oncogene

Cancer
Mutation Or Mis- Mutation Or Mis-
Regulation(Down Regulation (UP)
)

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 ONCOGENES, ANTIONCOGENES AND
CANCER Cntd…
Activation

Proto- Oncogene Oncogene

01. A mutation within a proto oncogene.

Increased protein activity
Un regulated activity due to Loss of regulatory site of the
protein

02. Miss regulation of proto oncogene.

Increased protein Expression /Activity

03. Gene duplication or chromosomal translocation of proto oncogene.

Increased gene expression (Due to duplication)
Expression in wrong cell type or at wrong times
Expression of a constitutively active hybrid protein(Due to trance location)
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 ONCOMIRS

 Expression of oncogenes and tumorsuppressor

genes.
o Regulated by microRNAs (down regulating them).

 Mutations in such microRNAs (oncomirs) lead to

o Activation of oncogenes or reduce the

function of tumor suppressor Genes.

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 SIX HALLMARK PHENOTYPIC
CHARACTERISTICS
Hanahan and Weinberg
(2000)-Hallmark review.

Progressively
accumulated
genetic and
epigenetic
changes in the
cancer cell
genome proceeds
in a combinatorial
fashion to confer
six hallmark
phenotypic
characteristics
shared by most
cancer cells.
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 01.SELF-SUFFICIENCY IN GROWTH
SIGNALS
RAS is a major intermediate
regulator that participates in the
growth signaling cascade.

Let-7
o A tumor suppressor miRNA
Inhibit translation of RAS gene.

o Frequently down-regulated
in tumors.

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02.INSENSITIVITY TO ANTIGROWTH SIGNALS
AND INCREASED
CAPACITY OF SELF-RENEWAL
 Antigrowth signaling is
occurred mainly through
inactivation of the tumor
suppressor protein Rb.

 TGF-b is a major regulator.

 Recent
findings,
miR-106 Targets Rb
miR-20a Targets TGF-b
miR-124a Targets Rb
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 03. EVADING APOPTOSIS

 IL-6-dependent
survival of multiple
myeloma cells.

 MiR-21 targets tumor

suppressor genes
PTEN
Tropomyosin1(TPM1)

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 04.LIMITLESS REPLICATIVE POTENTIAL
 Senescence
In cell division, Normal cells undero
progressive shortening of telomere sequences
located at the end of the chromosome. At a
certain threshold an irreversible growth arrest is
triggered.

 Adapted mechanisms to escape senescence

Telomere length is maintained by the
enzyme telomerase, human telomere reverse
transcriptase (hTERT).
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 Many
miRNAs were predicted to target the
mRNA that encodes for hTERT.

 miR-138
Is functionally related to the regulation of hTERT
miR-138 expression was found to be down-
regulated in anaplastic thyroid carcinoma cell
lines.

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 05.ANGIOGENESIS

 Provides tumor cells with nutrients.

Vascular endothelial cells are stimulated by
proangiogenic factors secreted by tumor cells
to undergo distinctive phenotypic changes that
finally give rise to new mature blood vessels.

 miR-221 and miR-222 were shown to be

associated with the angiogenesis.

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 06. INVASION AND METASTASIS

 miR-10b
It has been demonstrated that miR-10b
expression levels metastatic breast cancer
were increased by 50-fold when compared
with non metastatic breast cancer.

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THE INTEGRATED CURCUIT AND MiRNA
SWITCHES

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 DEREGULATION MECHANISMS OF
MICRORNA

SWITCHES IN CANCER
How this deregulation is initiated is currently unclear.

 It seems to involve the interplay of multiple mechanisms.

Genomic alterations

Transcriptional regulation of microRNAs

Epigenetic regulation of microRNAs

Polymorphisms and mutations in microRNAs

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 DEREGULATION MECHANISMS OF MICRORNA
SWITCHES IN CANCER Cntd..
1.Genomic alterations.
 Alternations in miRNA gene copy number due to
chromatin remodeling.

2.Transcriptional regulation of microRNA.

 Changes in the expression levels of transcription factors
known for their oncogenic or tumor suppressor function
may have a direct effect on the expression of miRNAs.

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 DEREGULATION MECHANISMS OF
MICRORNA
SWITCHES IN CANCER Cntd..
3.Epigenetic regulation of microRNA.
 Aberrant DNA methylation.

4.Polymorphisms and mutations in microRNAs.

 They may abnormally turn on/off miRNAs that
act as molecular switches in the integrated
circuit of the cancer cell.
 MiRNA target sequences in mRNAs will have
an impact on gene expression.

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EXTERNAL SWITCHES TO THE CELLULAR
CIRCUIT
MicroRNA encoded by oncogenic viruses.
 Up to 15% of human cancers are associated
with a single or multiple viral infections.

 E.g.
EBV has been studied in detail and expresses a
total of 23 miRNAs.

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 MICRORNAS IN MOLECULAR
DIAGNOSIS OF CANCER
 Interactome and switch prediction.
 MiRNA expression databases.
 MiRNA is much more effective for successful
mining of novel tumor biomarkers.
o Highly specific to the type of tumor.

o Extraordinary level of diversity in their expression across human

cancers.

o Provide a large amount of diagnostic, prognostic, and predictive

information.

o Accurate molecular marker Suitable for routine clinical applications.

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 THERAPEUTIC IMPLICATIONS
 Classical methods – Untargeted.
o Chemotherapy.
o Radiation therapy.

 Pharmacological modulation of targeted miRNA

switches.
o RNA interference(RNAi) based therapeutics.
o Antisense drug technology-in vivo delivery of
artificial siRNA in to cell.

o Gene therapy.

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 CONCLUTIONS
In the last two years,
knowledge of the roles of miRNAs in
cancer has expanded significantly.
This will eventually allow for the construction
of the miRNome of normal and cancer cells.

This calls for a revision of the integrated cancer-

cell circuit originally described by Hanahan and
Weinberg (2000) to include not only the
established signaling pathways but also the
‘‘miRNA switches’’ that set them on and off.
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 CONCLUTIONS

Important questions remain to be answered before miRNAs

can be used therapeutically.
o Complexity of miRNA mechanisms.
o Dual roles of miRNAs.
o Additional mechanisms of mRNA activation that
include miRNA binding sequences at gene
promoter regions.

Itremains to be answered whether we can use miRNA

profiling for cancer prognosis and/or selection of
chemotherapy.
oMapping of all human miRNAs and the
availability of complete miRNA microarrays
will
be required to address this question.
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References.
 Georgia sotiropoulou, georgios pampalakis, evi lianidou, and zissimos
mourelatos (2009)emerging roles of micrornas as molecular switches in the
integrated circuit of the cancer cell.

 Massimo Mallardo, Palmiro Poltronieri and Oscar Fernando D'Urso(2008)-

Non-protein coding RNA biomarkers and differential expression in cancers.

 Svetlana A. Shabalina and Eugene V. Koonin(2008)Origins and evolution of

eukaryotic RNA interference

 Ajit Kumar-The silent defense: Micro-RNA directed defense against HIV-1

replication(2007)

 V. Narry Kim1 and Jin-Wu Nam(2006) Genomics of microRNA.

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Thank You.

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