Fengmei et al. contributed in a significant way towards the
preliminary phases of a potentially novel and effective cancer treatment
strategy with their paper titled MicroRNA-21
Down-regulates Rb1 Expression by Targeting PDCD4 in Retinoblastoma. This
outcome may not have even been the initial goal of the research project, but a
human health application of their findings could lead the way for cancer
treatment through modulation of MicroRNA in cancerous retinoblastoma cells.
Retinoblastoma is a cancer of the eye, more specifically the
retina. The retina is home to the rods and cones, the parts of the eye that
detect light, concentrated by other ocular structures, and deliver the sensory
information to the brain for processing. The brain utilizes this information
and creates an image that we perceive based upon top-down processing. Our sense
of sight is essentially continuous, so it is clearly a process that happens in
an extremely brief period of time, relying exclusively on the retina for
detection of light. Unfortunately, retinoblastoma is the most common form of
eye cancer in children, and can also occur in adults, which is a less frequent
event.
Retinoblastoma is caused by mutations in both alleles of the tumor
suppressing Rb1 gene. This cancer progresses, like most cancers, through the
formation of a tumor. The mutated DNA from each cancer cell within the tumor is
passed on to the daughter cells, causing a snowball effect that leads to
challenging treatment if not identified in the preliminary stages. The cells
that make up this tumor are termed “cancerous” due to their abnormally fast
mitotic activity, which can cause a host of other negative effects on the body
such as tumors invading various other tissues and impeding organ function. One
safeguard to cancer that the body has naturally programmed into its genetic
information is a group of tumor suppressor genes. These genes function to
protect cells from exhibiting a cancerous phenotype. Regulation of many cancer
suppressor genes is controlled by various MicroRNAs. In this study, Fengmei et
al. examined mainly MicroRNA regulation of PDCD4, a tumor suppressor gene, in
retinoblastoma cells.
MicroRNA, or more commonly referred to as miRNA, was first
discovered in 1993. We are now aware of over 2,500 different miRNAs in humans!
They are a diverse group of RNA that often have a unique hairpin structure.
Since the initial discovery of these units, we have come to learn that miRNAs
are involved in many cellular processes, mainly revolving around regulatory mechanisms
and post-transcriptional modifications. With this knowledge in mind, Fengmei
and his team set out first to examine expression levels of multiple miRNAs that
could be related to retinoblastoma progression in three different
retinoblastoma cell lines: Weri-Rb1,
Y79 and RB 355. This preliminary work revealed prominence of the eventual focal
point of this study: miR-21.
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The next step of the experimentation, after miR-21 was recognized
as the study target, was to identify the tumor suppressor genes that miR-21
regulated. This was done using TargetScan, a program that predicts a specific
miRNA’s targets. PDCD4 was one result that stuck out to the researchers because
it is known to be involved in many other types of cancer. The PDCD4 genetic
sequence was compared to miR-21 and it was confirmed that their sequences were
compatible. With all of this information compiled, Fengmei and his partners
were ready to delve deeper into the question they were investigating: Does
miR-21 effect tumor suppressor genes in retinoblastoma cells and how might this
effect progression of the cancer.
With the scope of their research narrowing, the final phase of the
project culminated with an extensive analysis of the relationship between
miR-21, PDCD4 mRNA, and PDCD4 protein levels in two different retinoblastoma
cell lines, Weri-Rb1 and Y79. This process was carried out through techniques
such as quantitative PCR and Western blotting and aimed to determine how miR-21
might effect tumor suppression in retinoblastoma cells. It turned out that in
the Weri-Rb1 line, as miR-21 levels increased, the level of PDCD4 mRNA did not
change much, but the level of PDCD4 protein expressed decreased. This leads one
to believe that the miR-21 is acting upon the PDCD4 post-transcriptionally and
causes less protein the more that is present in the cell. In the Y79 cells,
similar results were shown excluding the PDCD4 mRNA levels. In this line of
cells, the mRNA levels corresponded to the protein levels, leading one to think
that maybe miR-21 worked pre-transcriptionally in this cell line.
Although scientists do not know
of the exact mechanism that miR-21 employs to carry out its function of
subduing tumor suppressor gene material, it is clear and confirmed that it
causes a decrease in the ability of retinoblastoma cells to combat the progression
of the cancer. Information on how a negative thing, like cancer, occurs can
contribute to helping those with the malady. In this instance, now that
scientists know that miR-21 disables cellular cancer fighting mechanisms, it’s
possible that a drug or treatment could be developed to destroy that miRNA in
retinoblastoma cells, which could stop those cells in their tracks and
eradicate patients of these crippling tumors. This kind of forward-thinking may
be ambitious because it takes time to develop complex cancer therapy drugs;
however, the sooner information like this is available to pharmacists, the
sooner it will be helping people.
Refs:
Fengmei, Shen et al. MicroRNA-21 Down-regulates Rb1
Expression by Targeting PDCD4 in Retinoblastoma. Journal of Cancer, 2014; 5(9): 804–812.
Almeida MI, Reis RM, Calin GA. MicroRNA history:
discovery, recent applications, and next frontiers. Mutation
research 2011; 717: 1–8.
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