To understand miRNA technology or any other major concept of molecular biology, it is important to understand the central dogma of biology. The central dogma is a theory that states that genetic information flow unidirectionally from DNA to mRNA to eventually protein.
By Umar Bin Adnan
What are microRNAs (miRNAs)?
To be more precise; the DNA is like an instruction manual that contains the information required to synthesize all of the cellular proteins. The mRNA is a transcript extracted from DNA that contains the instructions to synthesize a specific protein. These instructions are then translated into the final protein product through the action of ribosomes. The proteins produced can function in different ways for example, carrying out apoptosis, regulating the cell cycle and transmit inter and intra cellular signals. So where do miRNAs come into all this?
Micro RNAs (miRNAs) are short, noncoding RNA molecules that can have a significant impact on the regulation on the regulation of certain genes. They carry out their function by base pairing complimentary with Messenger RNAs (mRNAs) thus, inhibiting their translation into protein. A single miRNA molecule can inhibit up to a hundred mRNA transcripts and miRNAs may be involved in the regulation of as much as 1/3rd of all protein coding genes. In doing so, miRNAs generate can generate a butterfly effect in which due to the inhibition of specific proteins, entire cellular processes might be affected. These processes might in turn be involved in the progression, prevention or repression of various diseases. There are about 2000 different types of miRNAs currently known and although they are still being studied extensively, they are known to impact various cellular processes by regulating gene expression.
MicroRNAs and Cancer
Studies conducted in the recent past have shown miRNAs to be linked with most if not virtually all types of cancers. miRNAs can be both pro-oncogenic and anti-oncogenic. This is because certain types of miRNAs inhibit the expression of oncogenes while others inhibit the expression of tumor suppressors. Therefore, if miRNAs are not properly regulated, they might result in carcinogenesis by altering the genes responsible for cancer progression. For example, the upregulation of the miRNA miR-1269 causes cancer cell proliferation and suppression of apoptosis (programmed cell death) by targeting the RASSF9 gene. Upregulation of miR-1269 is involved in the formation and progression of gastric cancer.
The miRNA, miR-9 is found to be downregulated in oral squamous cell carcinoma (OSCC) patients. The expression of miR-9 results in G0/G1 cell cycle arrest. Therefore, if miR-9 is downregulated, it will not be able to regulate the cell cycle thereby, causing unregulated proliferation of cells. The low expression of other miRNAs such as miR-192, miR-194, and miR-215 result in the dysregulation of the p53 pathway that allows cancer cells to avoid undergoing apoptosis thus, increasing their proliferation and life span.
Angiogenesis is a process in which the cancer tissue forms blood vessels and is important for development and sustenance of the cancer tissue. It turns out certain miRNAs can regulate angiogenesis. For example, miR29b is reported to have a suppressive effect on angiogenesis, invasion, and metastasis. Therefore, its dysregulation can support angiogenesis and therefore, promote cancerous growth. Hence, it has been linked with hepatocellular carcinoma (HCC).
There are various other miRNAs that have been identified to play a critical role in various cancers and as science progresses more such miRNAs are likely to be detected. The question still remains however, how do these discoveries help in the treatment of cancers?
Using miRNAs as Biomarkers
We have seen the role of miRNAs in oncology and using this information, researchers have proposed using miRNAs as biomarkers of certain cancers. Using miRNAs as biomarkers for cancers has advantages to it. An ideal biomarker, according to Carmen et al. (2020), should be easily accessible, specific and sensitive to the disease and lastly be translatable from research to clinic. MicroRNAs are easily accessible, can be extracted through liquid biopsies from body fluids, have a high specificity for the specific carcinoma and are sensitive as they vary with the disease progression. Lastly, the technology required for detection of nucleic acids such as PCR already exists and the development of newer such technologies is cheap and less complex than those required for detection of protein biomarkers.
Potential biomarkers that have been proposed by researchers include miR-491-5p; the down regulation of which is associated with gastric cancer and are detected through qRT-PCR, miR-223-3p; up regulation is linked with invasive breast cancer and miR-151a-5p and are detected through TaqMan assays and miR-17-5p; upregulated in plasma samples of patients of colorectal cancer (CRC) and are detected through qRT-PCR among various others.
Therapeutic Use of miRNAs for Cancer
MicroRNAs can be an effective target for anti-cancer drugs. In a 2020 review article, Boxue et al. discussed about various potential miRNA drugs which were undergoing in-vivo, in-vitro experiments along with some that were even being tested in clinical trials. These include the frugs miR-634-LNP and Pre-miR-429 used to treat pancreatic cancer undergoing in-vitro tests, Mesomir that targets miR-16 for treatment of malignant pleural mesothelioma and is in the first phase of clinical trials, MRX34 that can be used to treat melanoma by targeting miR-34a currently in the second phase of clinical trials and a mimic of miR-126 that potentially can be used to treat breast cancer currently in the in-vitro phase among other potential drugs.
A common problem that arises in regards to the clinical use of miRNA is its limitations in being delivered to the site of action. One of the reasons is their short half life in blood of a patient. These issues can be overcome however, by using an effective drug delivery system or in other words using nanotechnology to deliver the drug to the site of action. The use of liposomes that are amphiphilic, biocompatible and biodegradable molecules resembling a human cell membrane is a quite popular potential drug delivery system for miRNA drugs. MicroRNA drugs such as miR-21, miR-486, miR-1 and miR-29b are being delivered using liposomes in various experiments. Other nanotechnology delivery systems such as gold, silica and magnetic nanoparticles are also being proposed for delivering the miRNA drug to its site of action effectively.
Future Prospects and Conclusion
The future of miRNA technology looks pretty bright to me after considering all the research that is going into it. The use of miRNAs in cancer research, detection and treatment is being worked on day and night by researchers all around the world. As science develops and newer and newer tools are developed; the use of miRNAs in our battle with cancer will become more apparent and practical than ever before.
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Author: Umar Bin Adnan