Overcoming Obscurity: miRNA and Its Biomedical Promise

What is miRNA?

Pop the word ‘DNA’ in any conversation, and it may immediately ring familiar for just about anyone, especially those who are fans of baby-switching teledramas. Deoxyribonucleic acid (DNA), being the repository and mechanism of inheritance for human genetic information, has been placed on a pedestal and marveled at by scientists and non-scientists alike over the last few decades. However, the same cannot really be said about RNA — the versatile, single-stranded cousin of DNA.

Ribonucleic acid (RNA) is primarily different from DNA in that it has a hydroxyl (-OH) group attached to its second carbon. This makes RNA more reactive compared to DNA [1]. Because of this heightened reactivity, RNA is much more dynamic than DNA — it can twist, bend, and even bind with itself, forming loops and structures that seem impossible for the double helix DNA. How this obscure molecule occurs and functions in many different types and forms goes to show that it is more than just ‘bacterial DNA’; it is a revolutionizing entity that plays a crucial role in making life possible, and its applications have greatly contributed to our scientific advancement.

As stated, RNA exists in a variety of forms — messenger RNA (mRNA), ribosomal RNA (rRNA), or even as an enzyme, among others. There are even more obscure RNA forms, one of which is the microRNA or miRNA. miRNA is a class of non-protein-coding RNAs known as non-coding RNAs, which still transcribe genetic information like most RNAs, but the end product is not an amino acid sequence nor protein [3].

miRNA has a characteristic length of approximately 22 nucleotides. Because it is involved in gene expression regulation, more specifically in gene silencing [4], miRNA affects many biological processes such as cell proliferation and apoptosis [5]. To execute its functions, a region of miRNA binds to its target mRNA through complementary base pairing. This binding inhibits mRNA expression through many different mechanisms, all of which are still being debated on — poly-A tail deadenylation, translational inhibition, and mRNA degradation, to name a few [3]. miRNA’s gene regulation function has endowed it with great potential for usage in the biomedical field, and many types of research and studies have already been undertaken to investigate such potential.

What can we use miRNA for?

Two of the most investigated potentials of miRNA are its roles as a disease biomarker and source for drug therapy. miRNA has shown to exhibit great potential as a biomarker as it creates signature miRNA patterns distinct for certain diseases like pancreatic cancer [10]. This is possible because the normal expression levels of miRNA may increase or decrease when an individual has a disease. In cancer, high levels of miRNA expression may indicate the presence of genes that potentially cause cancer [4]. A study by Walayat, et al. (2019) observed that altered miRNAs had been linked to certain conditions like cancer, making it a potential biomarker. Moreover, treating these alterations through the altered miRNAs’ mimics or inhibitors has been presented as potential disease therapy [4]. This then shows the therapeutic potential of miRNA in human disease.

miRNA’s potential for disease diagnostics has also been highlighted in a tumor differentiation study. The study by Hydbring and Badalian-Very (2013) revealed that 48 miRNAs were able to detect tumor tissue origin at 90% accuracy. This is especially relevant for cases when a tumor or cancer origin is hard to discern. A study with a similar undertaking was that of Varadhachary et al. (2011), where results of miRNA profiling of patients with carcinoma of unknown primary were found to be consistent with the clinicopathologic assessment, thus implying that miRNA may be efficient in discerning cancer origin. This would help health professionals give proper and personalized care for cancer patients as their tumors’ primary origins would be correctly diagnosed [7].

Aside from detecting actual diseases, miRNA may also help predict diseases even before they actually take effect [6]. In a study by Boeri et al. (2011), the miRNA expression levels for normal lung tissue, lung tumors, and plasma samples were observed. It was discovered that both the normal lung tissues and plasma samples displayed indications for future cancer development. Specifically, a strong predictive miRNA signature was detected 1–2 years before disease onset in the plasma samples taken from disease-free smokers [8].

The therapeutic implication of miRNA was also investigated by assessing its potential to prevent and treat diseases. For this, two main strategies are applied — one involves blocking signature miRNA expression using substitutes, oligonucleotides, or virus-based constructs, and the other involves altering miRNA expression using drugs that target their transcription and processing [4].

Many studies are being conducted to look into the use of miRNA in treating various diseases, including liver disease. For instance, the expression of microRNA-122 leads to the propagation of hepatitis C virus (HCV). One study by Janssen et al. (2013), used miravirsen, an antisense oligonucleotide that inhibits the function of microRNA-122. Miravirsen was shown to reduce the HCV RNA levels, depending on the dosage [9], and this finding highlights miRNAs potential for disease treatment.

What’s in the future of miRNA?

The obscurity of RNA makes the novel miRNA even more elusive. However, its obscure status may not last long. miRNA was first detected in humans back in the year 2000. Now, over a thousand human miRNAs have already been distinguished and are believed to regulate a considerable fraction of genes in our genomes [4]. As more discoveries trudge towards unlocking the full potential of miRNA, we get more glimpses of the nature of this RNA subclass and how, despite its small size, it holds a grand promise for the advancement of disease diagnostics and therapy. Given that the majority of miRNA research is focused on cancer, it may even provide the long-sought-for cure! The possibilities for miRNA seem endless, so watch out for this RNA subclass that is making its mark on the world.

References

[1] Wan, Y. and Chatterjee, K. (2018, July 13). RNA. Encyclopedia Britannica. https://www.britannica.com/science/RNA

[2] Dhar, M. (2020, October 15). What is RNA? Livescience.Com. https://www.livescience.com/what-is-RNA.html#:%7E:text=Unlike%20DNA%2C%20RNA%20can%20also%20shape-shift%20to%20an,stable%2C%20biologist%20Merlin%20Crossley%20wrote%20in%20The%20Conversation.

[3] Computational Medicine Center at Thomas Jefferson University. (2020, May 6). DNA and RNA. https://cm.jefferson.edu/learn/dna-and-rna/#:%7E:text=There%20are%20two%20differences%20that,uracil%20while%20DNA%20contains%20thymine.

[4] Walayat, A., Yang, M., & Xiao, D. (2019). Therapeutic Implication of miRNA in Human Disease. Antisense Therapy. Published. https://doi.org/10.5772/intechopen.82738

[5] Espinoza-Lewis, R. A., & Wang, D. Z. (2012). MicroRNAs in Heart Development. Current Topics in Developmental Biology, 279–317. https://doi.org/10.1016/b978-0-12-387786-4.00009-9

[6] Hydbring, P., & Badalian-Very, G. (2013). Clinical applications of microRNAs. F1000Research, 2, 136. https://doi.org/10.12688/f1000research.2-136.v1

[7] Varadhachary, G. R., Spector, Y., Abbruzzese, J. L., Rosenwald, S., Wang, H., Aharonov, R., Carlson, H. R., Cohen, D., Karanth, S., Macinskas, J., Lenzi, R., Chajut, A., Edmonston, T. B., & Raber, M. N. (2011). Prospective Gene Signature Study Using microRNA to Identify the Tissue of Origin in Patients with Carcinoma of Unknown Primary. Clinical Cancer Research, 17(12), 4063–4070. https://doi.org/10.1158/1078-0432.ccr-10-2599

[8] Boeri, M., Verri, C., Conte, D., Roz, L., Modena, P., Facchinetti, F., Calabrò, E., Croce, C. M., Pastorino, U., & Sozzi, G. (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proceedings of the National Academy of Sciences, 108(9), 3713–3718. https://doi.org/10.1073/pnas.1100048108

[9] Janssen, H. L., Reesink, H. W., Lawitz, E. J., Zeuzem, S., Rodriguez-Torres, M., Patel, K., van der Meer, A. J., Patick, A. K., Chen, A., Zhou, Y., Persson, R., King, B. D., Kauppinen, S., Levin, A. A., & Hodges, M. R. (2013). Treatment of HCV Infection by Targeting MicroRNA. New England Journal of Medicine, 368(18), 1685–1694. https://doi.org/10.1056/nejmoa1209026

[10] Ali, S., Saleh, H., Sethi, S., Sarkar, F. H., & Philip, P. A. (2012). MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. British Journal of Cancer, 107(8), 1354–1360. https://doi.org/10.1038/bjc.2012.383

Written by: Dionn Marie ‘Yondee’ Pacot