Recent genome encodes proteins and 98% of it

Recent
advances in sequencing technologies have revealed new secrets of the genome.  Interestingly, it is now evident that only
2% of human genome encodes
proteins and 98% of it is actively transcribed into RNA molecules that lost
their protein coding capacity and called non coding RNAs.  MiRNAs as the most widely described non-coding RNAs
are a class of small
molecules with 19-24 nucleotides in length that play important roles in many
biological pathways. Lin-4 was the first miRNA which was identified by victor
Ambros and colleagues in C. elegance in 1993 and since then miRNAs have been
examined in many studies considerably. According to the miRBase (http://www.mirbase.org),
a miRNA database, until now, more than 2500 miRNAs in humans and approximately
1915 in mice have been recognized and the list is growing. The vast majority of
miRNA genes are located within the introns or exons of protein coding
genes(about 70%) and small part them are in the intergenic areas(30%). miRNAs have critical roles in
post transcriptional regulation of gene expression and based on complementary
sequence between them and 3-untranslated region (3’UTR) of the target messenger
RNA (mRNA), downregulate the gene expression by mRNA cleavage or translational
repression (Bartel,
2009).

 

   The
biogenesis of these short single strand RNAs occurs by a well characterized
mechanisms which is depicted in figure 1. Firstly, in the nucleus, miRNA genes
are transcribed by RNA polymerase II (pol II) to form along primary transcript called
primary miRNA (pri-miRNA). Then, pri-miRNA is processed by
Drosha complex in the nucleus, producing a
transcript about 70 nucleotides, called precursor miRNA (pre-miRNA). At this
point, protein exportin 5 transfers the pre-miRNA from nucleus to the cytoplasm
where it converts to a mature miRNA duplex of about 20-22 nucleotides by Dicer complex.
After strand separation, the passenger strand is removed and degraded but the
other strand is incorporated into RNA-induced silencing complex (RISC) and
guide it to the target mRNAs for regulation of gene expression at post
transcriptional level via inhibition of translation or degradation of target
transcripts. Computational analyses show that each miRNA may be able to target more than 100 different
transcripts and adjust the expression of them. Indeed, over 60% of human
protein-coding genes are regulated by miRNAs, implicating that they can act as
key regulators of many biological events including proliferation, development,
differentiation, apoptosis and metabolism. Therefore, it is not surprising that
their aberrant expression contributes tovarious diseases such as cancer.

3.
MicroRNA and cancer

The first evidence for the involvement of
miRNAs in cancer was reported by Calin and colleagues in 2002, who discovered a
cluster of two microRNAs, miR-15 and miR-16, at critical region 13q14,
frequently deleted in chronic lymphocytic leukemia (CLL). Since then, a great
number of dysregulated miRNAs have been discovered in many cancers. MiRNAs can
act as oncogene or tumor suppressor which respectively up regulation and down
regulation of them can be related to the initiation and progression of
different malignancies by affecting several cancer related process including proliferation,
apoptosis, invasion and angiogenesis. The most dysregulated miRNAs in cancer
has been summarized in Table1.

Although the aberrant expression of miRNAs in
cancer is a proven fact, the exact causes of its have not yet been fully determined.
For this reason, many
researchers around the world have focused their attention on uncovering of
these mechanisms. Until now, several possible causes have been presented.one of
them is chromosomal abnormalities, like miR-15 and miR-16, as previously
mentioned are located in a frequently deleted genomic region in CLL. In
addition to structural genetic alteration, miRNAs expression can be also affected by altered activity of the enzymes involved in
the biogenesis of microRNAs,
like Drosha and Dicer. For instance, down regulation of Drosha and Dicer
complex has been reported in 39% of ovarian cancer patients. Indeed, it seems
that decreased expression of level of Drosha and Dicer complex promotes
cellular transformation and tumourgenesis in vivo. MicroRNA expression can be
also modulated by other miRNAs. For example, mouse miR-709 located in the nucleus preventing from pri-miR-15a/16-1
processing into pre-miR-15a/16-1 by directly binding to
recognition site on pri-miR-15a/16-1. Epigenetic changes are another causes of deregulated
microRNA expression in cancer which is well reported in various literatures.
For example, epigenetic repression of tumor suppressor miR-129-2in endometrial
cancer causes the over expression of the SOX4, an oncogene belonging to the
SRY-related high mobility group box family. Notably, miRNAs can also regulate
the expression of enzymes responsible for epigenetic control
which is complicated the scenario connecting microRNAs
and epigenetics. For instance, it has been determined that miR-143 directly
targets DNA methyltranferase 3A DNMT3A in colorectal cancer. Eventually,
deregulated miRNA expression in cancer can be created as a result of altered
transcription factor activity. For example, miR-34a, as commonly deleted miRNA
in human cancers, is directly transactivated by p53. Furthermore, as expected in
significant number of ovarian cancer patients with p53 mutation, due to the loss
of p53 function decreased expression of the miR-34 family was observed.

Over the recent years, the extensive miRNA
profiling studies have demonstrated that there are significantly differences
between miRNA profiles in cancer cells compared with those in normal cells,
suggesting that they have great potential utility as clinical biomarkers and
can also significantly help to the early detection of cancer. For example, in
ductal adenocarcinoma prior to any phenotypic changes in ducts overexpression
of miR-205 and miR-21 has been reported, implicating that aberrant miRNA
expression is an early event in the development of cancer that can derive a
benefit for early diagnosis of cancers.

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