We have previously examined the impact of miRNAs in the
development of cancers from several perspectives. In this new White Paper we
take a recent finding regarding melanoma and a specific miRNA and then use it
as a baseline to examine miRNAs in a broader context, focusing specifically on
melanoma. The interest here is twofold; first, as a potential therapeutic target
and second as a potential prognostic marker.
miRNAs have been examined for the past twenty years but just
the last decade have they been understood specifically as elements in cancer
control. Even more so, only in the past five years has their full impact been
understood and the ability to manipulate certain miRNA paths controlled.
This section details many of the elements of miRNA as
regards to cancer and metastatic control as well as the therapeutic control via
miRNAs. What is of most significant interest is that miRNAs have such a
pervasive set of control paths via activating oncogenes and suppressing genes
which control metastatic growth. The miRNAs are not just control elements in
select paths but appear to be control elements in the day to day paths of
cellular homeostasis. This makes modeling of pathways significantly more
complex.
It is critical to understand that as we have seen genomic
models built around proteins, genes and pathways, we have also not seen the
clear presence of miRNAs as integral parts of this process. One need just look
at the many papers on pathway dynamics and almost to each one there is a total
absence of miRNAs. We had proposed about five years ago that we look at miRNAs
as noise, as at best epigenetic accidents which result in loss of expression. Now
however it may be argued that they play as significant a role as the well-known
pathways, albeit not yet fully understood.
Let us recall that the miRNA functions in a manner shown
below:
The specific focus here is on miRNA-26a[1].
There are many databases now with a great deal of information regarding the
miRNAs and we refer to them as in course.
We begin by examining a recent paper regarding miR-26a. As
we shall discuss later this miRNA is found to be aberrant in multiple cancers
and in the case of melanoma the disruption associated with several pathways is
somewhat clearly understood. In a recent paper by Reuland et al the authors
make the following observations[2]:
Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription–PCR (qRT-PCR) experiments as a miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested.
In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control.
The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′ untranslated region (3′UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target.
Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription–PCR (qRT-PCR) experiments as a miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested.
In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control.
The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′ untranslated region (3′UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target.
The observations focus on several key areas:
1. The impact of
miRNAs on melanoma metastasis. As we will discuss there have been many previous
studies implicating many miRNAs in this area. Thus seems to expand the results.
2. There appears to
be a therapeutic approach to the issue by increasing the miRNA26a to further
reduce by binding to the SODD facilitator product. There again have been
several studies along this line recently. SODD is an interesting controlling
gene/protein complex and the control via miR-26a is of significance.
3. There may be a
prognostic indicator here as well. Again there has been a great deal of work in
this field.
First we examine
both the miRNA26a and SODD respectively and then we examine the issues
discussed above in some detail. This represents just another of many studies
regarding the use of miRNAs for the potential control of melanoma.
Before continuing it is useful to examine some of the
additional comments the authors of the referred to article have made to the
trade press relating to the release of the paper. Now one trade press article
states[3]:
A University of Colorado Cancer Center study in this month's edition of the Journal of Investigative Dermatology describes a new target and potential treatment for melanoma, the most dangerous form of skin cancer. MicroRNA can decide which genes in a cell's DNA are expressed and which stay silent. Melanoma tends to lack microRNA-26a, which makes the gene SODD go silent.
A University of Colorado Cancer Center study in this month's edition of the Journal of Investigative Dermatology describes a new target and potential treatment for melanoma, the most dangerous form of skin cancer. MicroRNA can decide which genes in a cell's DNA are expressed and which stay silent. Melanoma tends to lack microRNA-26a, which makes the gene SODD go silent.
"It's a double negative," says Yiqun Shellman,
PhD, investigator at the CU Cancer Center, associate professor at the CU School
of Medicine, and the study's co-senior author. "miR-26a works to stop the
growth of cancer. You turn off this thing that should stop growth, and you have
growth." When Shellman, David Norris and colleagues reintroduced
microRNA-26a to melanoma cell lines that lacked it, they saw a marked decrease
in cancer cell survival. MicroRNA-26a killed melanoma cells while leaving
healthy cells unharmed. In fact, the discovery started back a couple steps. First the group compared microRNA expression in healthy
cells to that of microRNA expression in melanoma cells. "We hoped the
difference between microRNA expression in healthy and melanoma cells would show
which ones were contributing to tumorgenesis," Shellman says. The microRNA most consistently different between healthy
and cancerous cells was 26a. The discovery of how it works and what exactly it
does was serendipitous. "We started by testing the effect of microRNA-26a
on known gene targets to see if it was effecting the expression of logical,
cancer-causing pathways, but none of them seemed affected in melanoma,"
Shellman says. "We were
working with the SODD gene in an unrelated project, and SODD has a putative but
not high-scored binding site for miR-26a, and thought, why not test it? Sure
enough, it turned out to be the target – microRNA-26a downregulates this
gene." Shellman hopes this robust finding in cell cultures will help pave
the way for future work with microRNA-26a as a therapeutic target in animal
models and eventually a human trial. "The first
step is to further pinpoint the genetic signatures of the patients likely to
benefit from microRNA-26a replacement therapy," Shellman says, noting that
only some and not all melanoma cells were killed by miRNA replacement.
"Maybe it's simply the downregulation of microRNA-26a itself, or maybe we
can use SODD expression as the biomarker," Shellman says. Once Shellman and colleagues discover the characteristics
of a melanoma susceptible to microRNA-26a treatment, they hope funding will
allow the lab to follow the promising therapy up the evolution from cells to
humans.
As can be seen from the conversation above, there still may exist some questions of the details of the process. What is critical, however, is the fact that the miRNA plays such a prominent role, that one may target the miRNA, and that a pathway is a fundamental part of the development of a putative therapeutic. But fundamentally the last sentence above does diminish the ultimate enthusiasm.
The critical observations made here is the relationship
between the controlling proteins, their related mRNA and the interference
coming from miRNA. This has not been explored in significant detail until of
late.
Another trade press review states as follows[4]:
Researchers from the University of Colorado Cancer Center say that they have discovered a new, more targeted way of treating melanoma, the most deadly form of skin cancer
Researchers from the University of Colorado Cancer Center say that they have discovered a new, more targeted way of treating melanoma, the most deadly form of skin cancer
The findings, described in a recent edition of the
Journal of Investigative Dermatology, describe how small pieces of genetic
material known as MicroRNA can choose the genes in a DNA cell that are either
expressed or kept silent. With melanoma in particular, the researchers
discovered a deficiency of microRNA-26a that usually silences the gene SODD. “It’s a double negative,” explained the study’s co-senior
author Yiqun Shellman, an investigator at
the University of Colorado Cancer Center and associate
professor at the University of Colorado School of Medicine, in a prepared
statement. “MiR-26a works to stop the growth of cancer. You turn off this thing
that should stop growth, and you have growth.”
In the study, melanoma cell lines that lacked microRNA-26a were reintroduced to the cell in a lab. As a result, there was a reduction in cancer cell survival and the microRNA-26a eliminated melanoma cells while leaving healthy cells alive. The team of investigators was able to compare the expression of microRNA in healthy cells to the expression of microRNA in melanoma cells. “We hoped the difference between microRNA expression in healthy and melanoma cells would show which ones were contributing to tumorgenesis,” continued Shellman in the statement. The researchers saw that the expression of micro-RNA-26 was consistently different between healthy and cancerous cells. Some, but not all, of the melanoma cells were eliminated by the replacement introduction of mRNA. “The first step is to further pinpoint the genetic signatures of the patients likely to benefit from microRNA-26a replacement therapy,” noted Shellman in the statement. “Maybe it’s simply the downregulation of microRNA-26a itself, or maybe we can use SODD expression as the biomarker.” Moving forward, Shellman believes that her team’s discovery of the role of MicroRNA in the development of carcinoma in cell cultures may eventually help develop new therapeutic techniques that could be used in real cancer patients.
In the study, melanoma cell lines that lacked microRNA-26a were reintroduced to the cell in a lab. As a result, there was a reduction in cancer cell survival and the microRNA-26a eliminated melanoma cells while leaving healthy cells alive. The team of investigators was able to compare the expression of microRNA in healthy cells to the expression of microRNA in melanoma cells. “We hoped the difference between microRNA expression in healthy and melanoma cells would show which ones were contributing to tumorgenesis,” continued Shellman in the statement. The researchers saw that the expression of micro-RNA-26 was consistently different between healthy and cancerous cells. Some, but not all, of the melanoma cells were eliminated by the replacement introduction of mRNA. “The first step is to further pinpoint the genetic signatures of the patients likely to benefit from microRNA-26a replacement therapy,” noted Shellman in the statement. “Maybe it’s simply the downregulation of microRNA-26a itself, or maybe we can use SODD expression as the biomarker.” Moving forward, Shellman believes that her team’s discovery of the role of MicroRNA in the development of carcinoma in cell cultures may eventually help develop new therapeutic techniques that could be used in real cancer patients.
This above statement is a simple reiteration of some of the
prior work. Again it is clear that although experimentally observed, one is
still quite a way from clinical reality.
Other researchers have examined miRNAs and
melanoma as well. For example the work of Segura et al (2012) state:
Melanoma incidence and associated mortality continue to
increase worldwide. The lack of treatments with durable responses for stage IV
melanoma may be due, at least in part, to an incomplete understanding of the
molecular mechanisms that regulate tumor initiation and/or progression to
metastasis. Recent evidence supports miRNA dysregulation in melanoma impacting
several well-known pathways such as the PI3K/AKT or RAS/MAPK pathways, but also
underexplored cellular processes like protein glycosylation and immune
modulation. There is also increasing evidence that miRNA can improve
patient prognostic classification over the classical staging system and provide
new therapeutic opportunities. The integration of this recently acquired
knowledge with known molecular alterations in protein coding genes
characteristic of these tumors (i.e., BRAF and NRAS mutations, CDKN2A
inactivation) is critical for a complete understanding of melanoma
pathogenesis. Here, we compile the evidence of the functional roles of
miRNAs in melanomagenesis and progression, and of their clinical utility as
biomarkers, prognostic tools and potential therapeutic targets.
Characterization of miRNA alterations in melanoma may provide new angles for
therapeutic intervention, help to decipher mechanisms of drug resistance, and
improve patient classification for disease surveillance and clinical benefit.
The above work readily complements the work upon which we
have focused this analysis. Additional melanoma analyses has been done by Zehavi et al. Zehavi
et al state[5]:
We show that the expression of miRNAs from a large
cluster on human chromosome 14q32 is significantly down-regulated in melanoma
cell lines, benign nevi and melanoma samples relative to normal melanocytes.
This miRNA cluster resides within a parentally imprinted chromosomal region
known to be important in development and differentiation. In some melanoma cell
lines, a chromosomal deletion or loss-of-heterozygosity was observed in the
cis-acting regulatory region of this cluster. In several cell lines we were able to re-express two
maternally induced genes and several miRNAs from the cluster with a combination
of de-methylating agents and histone deacetylase inhibitors, suggesting that
epigenetic modifications take part in their silencing. Stable over-expression of mir-376a and mir-376c, two
miRNAs from this cluster that could be re-expressed following epigenetic
manipulation, led to modest growth retardation and to a significant decrease in
migration in-vitro. Bioinformatic analysis predicted that both miRNAs could
potentially target the 3'UTR of IGF1R. Indeed, stable expression of mir-376a and mir-376c in
melanoma cells led to a decrease in IGF1R mRNA and protein, and a luciferase
reporter assay indicated that the 3'UTR of IGF1R is a target of both mir-376a
and mir-376c. Our work is the first to show that the large miRNA cluster
Note in the above the selection and determination of other
miRNAs as well. It is not expected that any single miRNA will be considered the
sole controlling element. In fact one may anticipate a progression as the tumor
develops. The setting off of miRNAs as the tumor stage changes would be an
interesting by-product of this analysis.
Another quite useful analysis of miRNAs and melanoma has
been done by Taveira da Cruz and Jasiulionis. In their work the two authors
state:
miRNAs are non-coding RNAs that bind to mRNA targets and
disturb their stability and/or translation, thus acting in gene
posttranscriptional regulation. It is predicted that over 30% of mRNAs are
regulated by miRNAs. Therefore these molecules are considered
essential in the processing of many biological responses, such as cell
proliferation, apoptosis, and stress responsiveness. As miRNAs participate of virtually all
cellular pathways, their deregulation is critical to cancer development.
Consequently, loss or gain of miRNAs function may contribute to tumor
progression. Little is known about the regulation of
miRNAs and understanding the events that lead to changes in their expression
may provide new perspectives for cancer treatment. Among distinct types of
cancer, melanoma has special implications. It is characterized as a complex
disease, originated from a malignant transformation of melanocytes.
Despite being rare, its metastatic form is usually incurable, which makes melanoma the major death cause of all skin cancers. Some molecular pathways are frequently disrupted in melanoma, and miRNAs probably have a decisive role on these alterations. Therefore, this review aims to discuss new findings about miRNAs in melanoma fields, underlying epigenetic processes, and also to argue possibilities of using miRNAs in melanoma diagnosis and therapy.
Despite being rare, its metastatic form is usually incurable, which makes melanoma the major death cause of all skin cancers. Some molecular pathways are frequently disrupted in melanoma, and miRNAs probably have a decisive role on these alterations. Therefore, this review aims to discuss new findings about miRNAs in melanoma fields, underlying epigenetic processes, and also to argue possibilities of using miRNAs in melanoma diagnosis and therapy.
The conclusions drawn from the above paper are considerable.
After just a few years there is now a well-accepted understanding of how miRNAs
function and that they play critical roles in pathways. However, and this is a
very significant however, we do not understand what precipitates them nor do we
fully understand their relationship in pathway analysis. What is clear is that
they are found in a multiple set of cancers, that that are pathway control
elements, but the complex interactions we would anticipate are still unknown.
miRNAs are small (19-25 nucleotide single strand RNA) which
have been created off intron sections of the DNA of a cell through pol II or
pol III. They then operate on mRNA from exons which have escaped from the
nucleus and are putatively maturing to proteins in the cytoplasm. Some of the
proteins may be beneficial and some may not. The miRNAs seem to be secondary,
and in some cases primary, pathway control elements. miRNAs contain RNA
nucleotides, U, A, C, G. Thus simply stated if any possible combination is
available there could be 422 such miRNAs or about one trillion,
equal to the national debt each year! This is a simplistic statement but it
does provide a metric. We have discovered just more than a 1,000 miRNAs to
data, with variants on some. Therefore a great deal more can be determined.
To demonstrate the recent occurrence of miRNA, it was not
until the 6th edition of Watson’s Biology of the Gene in 2008 that
we see a Chapter on controlling RNAs with miRNA (See Chapter 18). In addition
even some of the recent literature lends miRNAs a place as a curiosity. In fact
the more they are understood the more powerful they become.
In the classic review paper by Esquela-Kerscher, A. and F,
Slack, they present an excellent discussion on miRNAs. First we present the
overall construct. miRNAs are produced like all RNA and then pass through the
Drosha/Pasha complex and emerge from the nucleus as a double RNA with a loop.
Dicer cuts the loop creating single strand short RNAs which are the miRNA.
Now from the paper we have the more detailed description
where we show how miRNA can interfere with RNA translation by either inhibiting
it or by slicing the RNA and in turn also inhibiting it. We depict that below
We rely upon that here, They state:
The biogenesis of microRNAs.
MicroRNA (miRNA) genes are generally transcribed by RNA
Polymerase II (Pol II) in the nucleus to form large pri-miRNA transcripts,
which are capped (7MGpppG) and
polyadenylated (AAAAA). These pri-miRNA transcripts are processed by the RNase
III enzyme Drosha and its co-factor, Pasha, to release the ~70-nucleotide
pre-miRNA precursor product. (Note that the human let-7a-1
miRNA is shown here as an example of a pre-miRNA hairpin sequence. The
mature miRNA sequence is shown in red.) RAN–GTP and exportin 5 transport the pre-miRNA into the
cytoplasm. Subsequently, another RNase III enzyme, Dicer, processes the
pre-miRNA to generate a transient ~22- nucleotide miRNA:miRNA* duplex. This duplex is then loaded into the miRNA-associated
multiprotein RNA-induced silencing complex (miRISC) (light blue), which
includes the Argonaute proteins, and the mature single-stranded miRNA (red) is
preferentially retained in this complex. The mature miRNA then binds to
complementary sites in the mRNA target to negatively regulate gene expression
in one of two ways that depend on the degree of complementarity between the
miRNA and its target. miRNAs that bind to mRNA targets with imperfect
complementarity block target gene expression at the level of protein
translation owever, recent evidence indicates that miRNAs might also
affect mRNA stability (not shown). Complementary sites for miRNAs using this
mechanism are generally found in the 3′ untranslated regions (3’ UTRs) of the
target mRNA genes. miRNAs that bind to their mRNA targets with perfect (or
nearly perfect) complementarity induce target-mRNA cleavage (lower right).
miRNAs using this mechanism bind to miRNA complementary sites that are generally
found in the coding sequence or open reading frame (ORF) of the mRNA target.
They further detail it as follows:
MicroRNAs can function as tumour suppressors
and oncogenes. a. In normal tissues, proper microRNA (miRNA)
transcription, processing and binding to complementary sequences on the target
mRNA results in the repression of target-gene expression through a block in
protein translation or altered mRNA stability. The overall result is normal
rates of cellular growth, proliferation, differentiation and cell death. b. The reduction or deletion of a miRNA that
functions as a tumour suppressor leads to tumour formation. c. A reduction in or elimination of mature miRNA
levels can occur because of defects at any stage of miRNA biogenesis (indicated
by question marks) and ultimately leads to the inappropriate expression of the
miRNA-target oncoprotein (purple squares). The overall outcome might involve
increased proliferation, invasiveness or angiogenesis, decreased levels of
apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading
to tumour formation. The amplification or overexpression of a miRNA
that has an oncogenic role would also result in tumour formation. In this
situation, increased amounts of a miRNA, which might be produced at
inappropriate times or in the wrong tissues, would eliminate the expression of
a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur
because of amplification of the miRNA gene, a constitutively active promoter,
increased efficiency in miRNA processing or increased stability of the miRNA
(indicated by question marks). ORF, open reading frame.
We depict these three cases shown as follows. First, miRNA acting in a normal manner. This is below:
Notice above the miRNA is assumed to be a normal part of the
control mechanism of the control of the conversion of the mRNA into a protein.
It block the conversion.
Second, we now consider the second case. Here we have an
oncogene which is not blocked by the miRNA and it results in many oncoproteins
as shown below.
Third and finally in case 2 we have a massive explosion of
miRNAs acting as onco activators as shown below.
These methods demonstrate in a somewhat simple manner how
the miRNA functions in the case of certain cancers. It also demonstrates how
the miRNA can become a target for therapeutics.
Much of what we know about miRNAs and their functions has
evolved in the past five years to a decade at most. In fact in the past decade
one has seen a great opening to RNAs in general. Before that it could be said
that RNAs were the poor cousin in the process, the glory given the DNA and then
the pathway dynamics dominated by proteins. We now appear to have opened a door
on control mechanisms at the RNA level, dominated by miRNA and their control of
mRNA before it becomes a protein. Thus RNA is somewhat exciting, and the miRNA
have presented an added level of complexity to our modeling of complex cellular
dynamics.
Based upon the analysis herein:
The most significant result from the explosion of miRNA
effects is that what we have seen as now classic pathways may have significant
undercurrent resulting from the miRNAs. Are miRNAs dominant control elements,
is so where do they impact the most. We have seen many of the miRNA discoveries
as just incidental to studying pathways. In our prior analysis we assumed them
to be just noise. Now we can no longer accept such a proposition. In fact they
seem to play significant if not dominant roles.
The use of miRNAs as therapeutic targets is of significant
interest. We have discussed some of the results and we have tried to place
miRNAs in context of a broad therapeutic approach. The true reason is the
simplicity of the miRNA structure. It is not a complex protein of hundreds of
nucleic acids folded in a complex manner. The miRNA is just some 22 nucleotides
on a sugar backbone.
We have been trained to ignore the introns. It was the trash
heap of evolution, perhaps of some use in the past. However since miRNAs are
intro sourced, we now have a new window on the importance of introns.
We have looked at such proteins as PTEN, p53, and others as
the control element. We looked at kinases and receptors and instigating ligands
as part of that process. When we examine miRNA we see control coming from
within. What instigates the processing and release of miRNAs. What are the
feedback loops, if any, between the surface changes on receptors and the
activation of miRNAs.
One of the problems we have in many cancers is both
diagnosis and prognosis. In melanoma unfortunately prognosis may often be dire,
but not always. In addition diagnosis of pigmented lesions is often
problematic. Take a simple melanoma in situ, where it is diagnosed based on
upward movement of the melanocyte. Are there differences in the MIS? Namely is
each MIS identical, just losing its stability, say through loss of E-cadherin,
and if not are there simple miRNAs which can be targeted and profiled.
There are many more observations which will evolve as we
better understand miRNAs. Since we are at the beginning of understanding them
we must keep in mind the ever changing field of play, and thus any analysis
must include miRNAs as significant participants.
1.
Barbar, I., F. Slack,
MicroRNAs in Cancer, Clin Onco, 2007.Bartel,, D., MicroRNAs: Target Recognition
and Regulatory Functions, Cell, V 136 Jan 23, 2009, p 215.
2.
Bennett, D., How to Make a
Melanoma: What Do We Know of the Primary Clonal Events, Pig Cell Mel Res V 21
pp 27-38, 2008.
3.
Bousquet , M.,
MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA, Haematologica
| 2012; 97(11)
4.
Calin, G., C., Croce,
MicroRNA signatures in human cancers, NATURE REVIEWS | CANCER VOLUME 6 |
NOVEMBER 2006 | 857.
5.
Chario, A., et al, The
NF-κB-independent functions of IKK subunits in immunity and cancer, Trends in
Cell Biology Volume 19, Issue 8,
August 2009, Pages 404–413.
6.
Dang X, et al, MicroRNA-26a
regulates tumorigenic properties of EZH2 in human lung carcinoma cells, Cancer
Genet. 2012 Mar;205(3):113-23. doi: 10.1016/j.cancergen.2012.01.002.
7.
Esquela-Kerscher, A. and F,
Slack, Oncomirs —
microRNAs with a role in cancer, NATURE REVIEWS | CANCER VOLUME 6 | APRIL 2006
| 259.
8.
Holst, L, et al, The
microRNA molecular signature of atypic and common acquired melanocytic nevi:
differential expression of miR-125b and let-7c, Experimental Dermatology, 2010,
p 278.
9.
Huse, J. et al, The
PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and
facilitates gliomagenesis in vivo, Genes Dev. 2009 23: 1327-1337.
10.
Kaczkowski, B,
Computational Cancer Biology: From Carcinogenesis to Metastasis, PhD Thesis University
of Copenhagen, April 2012.
11.
Kota, J., et al,
Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer
Model, Cell 137, 1005–1017, June 12, 2009.
12.
Luo, C., microRNAs Involved
in the Aggressiveness of Malignant Melanoma, PhD Thesis Heidelberg, Dec 2011.
13.
Pritchard, C., et al,
MicroRNA profiling: approaches and considerations, Nature Reviews, 358 , MAY
2012, VOLUME 13.
14.
Reuland , S. et al, MicroRNA-26a Is
Strongly Downregulated in Melanoma and Induces Cell Death through Repression of
Silencer of Death Domains (SODD), Journal
of Investigative Dermatology , (29 November 2012) | doi:10.1038/jid.2012.400.
15.
Reuland, S., et al, MicroRNA-26a
Is Strongly Downregulated in Melanoma and Induces Cell Death through Repression
of Silencer of Death Domains (SODD), Journal
of Investigative Dermatology , (29 November 2012) | doi:10.1038/jid.2012.400.
16.
Schuster, C., et al,
MicroRNA expression profiling of specific cells in complex archival tissue
stained by immunohistochemistry, Laboratory Investigation (2011) 91, 157–165.
17.
Segura, M., et al, Melanoma
MicroRNA Signature Predicts Post-Recurrence Survival, Clin Cancer Res Published
OnlineFirst February 23, 2010.
18.
Segura, M., et al, MicroRNA
and cutaneous melanoma: from discovery to prognosis and therapy, Carcinogenesis
(2012) doi: 10.1093/carcin/bgs205 First published online: June 12, 2012 http://carcin.oxfordjournals.org/content/early/2012/08/30/carcin.bgs205.abstract
.
19.
Taveira da Cruz , A., M. Galvonas
Jasiulionis, miRNAs and Melanoma: How Are They Connected? Dermatology
Research and Practice, Volume 2012, Article ID 528345, 12 pages
doi:10.1155/2012/528345.
20.
Trang, P., et al, MicroRNAs
as potential cancer therapeutics, Oncogene, V 27 2009.
21.
Tschopp, J., et al, Apoptosis:
Silencing the death receptors, Current Biology Volume 9, Issue 10, 20 May 1999,
Pages R381–R384.
22.
Viatour, P., et al,
Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation,
Trends in Biochemical Sciences Volume 30, Issue 1,
January 2005, Pages 43–52.
23.
Watson, J., et al,
Molecular Biology of the Gene, 6th Edition, Pearson (New York) 2008.
24.
Zehavi, et al, Silencing of
a large microRNA cluster on human chromosome 14q32 in melanoma: biological
effects of mir-376a and mir-376c on insulin growth factor 1 receptor, Molecular
Cancer 2012, 11:44 Page 8 of 15, http://www.molecular-cancer.com/content/11/1/44.
25.
Zhu, Y., MicroRNA-26a/b and
their host genes cooperate to inhibit the G1/S transition by activating the pRb
protein, Nucleic Acids Research, 2011, 1–11.
Posts
