Wednesday, March 11, 2015

MicroRNA and Metastasis in Retinoblastoma

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.                           
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.

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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