RNA is becoming recognized as an integral part of life and useful in vaccines. It can be a message that is transcribed from some pieces of DNA (genes) to become messenger RNA (mRNA). Some can be life savers. The Moderna and Pfizer vaccines for Covid-19 contain mRNA that codes for the spike protein of the SARS-CoV-2 virus that causes Covid-19. This trains immune cells in our body to recognize the virus wherever it appears and to destroy it. The FDA has just approved updated versions of these vaccines.1 The updated mRNA vaccines are approved for individuals 12 years of age and older and are authorized under emergency use for individuals 6 months through 11 years of age. As part of today’s actions, the bivalent Moderna and Pfizer-BioNTech COVID-19 vaccines are no longer authorized for use in the United States.
At the same time, other mRNA molecules are being used to cure cancer, immune-mediated diseases, and rare diseases.2 Many of these diseases occur when a person is unable to produce an important protein, or produces it incorrectly. Even though vaccines are usually thought of as preventions, they can also cure diseases. A vaccine is something that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease. For example, tumors produce specific antigens, much like viruses and pathogenic organisms. Many potential cancer vaccines would stimulate a person’s immune system, causing it to target the tumor antigen (TA). TAs are important in tumor initiation, progression, and metastasis.3 They can include tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). So, mRNA vaccines would deliver genetic information encoding TAs. Moreover, mRNA collected from a patients’ tumor samples can be used to find and target patient-specific TAs.4 The goal is to identify every unique somatic mutation in an individual patient’s tumor sample.5 These cancer vaccines are designed rationally. Therapeutic cancer vaccines should stimulate cell-mediated immune responses that are capable of clearing or reducing the size and metastasis of tumors. So, mRNA vaccines could potentially be used on infectious diseases and cancer. Unlike vaccines based on genetically engineered viruses, mRNA is not infectious. There is no risk of it becoming mutated. Antiviral immunity is not a problem, so it can be given repeatedly. Finally, millions of mRNA vaccines can be produced rapidly and inexpensively. So, researchers are developing mRNA vaccines that may cure many types of cancer. They can be inserted into dendritic cells (DCs) that have been isolated from a patient’s blood. That is, DCs are key activators of a proper immune response. They link the innate and acquired immune systems, causing responses against TAs. There are several clinical trials of mRNA vaccines against a variety of tumors.
Some cancer vaccines use mRNAs that encode a patient’s own specific TAs to activate their immature DCs.6 The DCs are then put back in the patient, thus initiating protective immune responses. With the help of computer-aided design, new, more potent TAs will be discovered and optimum mRNAs will be prepared. That is, the mRNA will not only encode a TA, but also attach untranslated regions to the 5’ and 3’ ends. This maximizes the translation of the mRNA into the desired TA.
The tumor microenvironment (TIME) also presents therapeutic targets. TIME-related RNA or RNA regulators are possible targets for anticancer immunotherapy.7 The complex interplay between cancer cells and the TIME influences the outcome of immunotherapy and anticancer therapy. Combination treatments of immunotherapy and RNA-based targeted therapies are able to overcome tumor immune evasion mechanisms and optimize the clinical benefit of current immunotherapies. Moreover, reprogramming the TIME and reversing immunosuppressive strategies will likely benefit current cancer treatment modalities. Small interfering RNA (siRNA), microRNA (miRNA), and mRNA have useful immunomodulatory effects, indicating their potential for cancer immunotherapy. That is, there are some types of RNA that are transcribed from parts of DNA that don’t code for mRNA and proteins. They are called non-coding DNA (ncDNA). So, some genes code for small pieces of RNA, such as microRNA (miRNA), rather than proteins. They are single-stranded and contain about 22 nucleotides. Many stay within cells, but others (extracellular miRNAs) can circulate throughout the extracellular environment. Both types can bind to mRNA and keep it from being translated into a polypeptide or protein. This is an important part of post-transcriptional regulation of gene expression.
In addition, miRNAs play an important role in chromosome segregation, differentiation of developing cells, metabolism and programmed cell death (apoptosis). Defects in miRNA have been implicated in cancer and diabetes. For example, miRNA-802 is up-regulated in type II diabetes. Also, double-stranded miRNA can bind to complementary portions of DNA, turning off its transcription into mRNA. Another type of RNA, called non-coding RNA-activating (ncRNA-a), can activate transcription by interacting with the Mediator protein complex to stabilize the structure of chromatin.8 The miRNAs are usually encoded within introns.9 That is, human genes exist in sections inside a larger precursor DNA. This precursor contains insertion elements (introns) that are removed. The remaining pieces of DNA are joined to form the gene that codes for a protein or polypeptide.
However, many genes code for miRNAs. They are transcribed from DNA to make a long RNA, called primary RNA, or pri-RNA, which may contain many mi-RNAs. They are partly broken down in the nucleus of the cell to make shorter (about 70 nucleotides) precursor mi-RNAs (pre-mi-RNAs). This is catalyzed by a protein complex called Microprocessor. It contains an RNA hydrolase (RNase III) called Drosha. The pre-mi-RNA is exported out of the nucleus and is hydrolyzed in a reaction catalyzed by another RNase III enzyme called Dicer, producing the mature mi-RNA. The imperfectly complementary miRNA duplexes contain a passenger and guide strand. This binds to an RNA-induced silencing complex (RISC). The RISC is guided to its mRNA target by the miRNA strand. The passenger strand is removed and the guide strand binds to its mRNA target. The RISC complex can silence genes by either inhibiting the initiation of translation or by transporting the complex to cytoplasmic processing bodies (p-bodies) where the mRNA is destroyed.
MicroRNAs play an important role in cellular re-programming. microRNAs can suspend or permanently repress the expression of genes by binding to complementary sequences on target mRNAs. The expression of almost every human gene is controlled by one or more microRNAs. Moreover, interactome hubs, bottleneck proteins and downstream signaling components are regulated by more microRNAs than are other nodes. So, mutations in genes coding for microRNAs are often pathological and can be useful biomarkers for cancer.10 That is, just as some proteins can cause cancer when mutated, some miRNAs can, too. One of them, miRNA-34, interacts with the protein called p53 to prevent cancer.11 It is currently considered to be a master regulator of tumor suppression. The positive feedback regulatory network formed by p53 and miR-34 can inhibit the growth and metastasis of tumor cells and inhibit tumor stem cells.
A fully modified version of miRNA-34, called FMmiR34a was recently shown to be stable and active against several types of cancer cells grown in mice.12 The original form of miRNA34 was not stable in the body and could not be delivered specifically to the target tumor. The FMmiR-34a is much more stable. Specific targeting was achieved through conjugating FM-miR-34a to folate (FM-FolamiR-34a), which inhibited tumor growth leading to complete cures in some mice.
It also appears that the anticancer effects of several antioxidants in green tea, coffee, red wine, soybeans, turmeric and many other foods are partly due to their effects on miRNAs and other ncRNAs.13,14 This is one more reason why a healthy diet avoids red meat and emphasizes the consumption of fruits, vegetables, whole grains, nuts, beans, olive oil and many types of seafood.
1 U.S. Food & Drug Administration. FDA Takes Action on Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants, 11 Sept, 2023.
2 Sanofi. mRNA Technology: Vaccines and Beyond, 27 June, 2023.
3 Jahanafrooz, Z. et al. Comparison of DNA and mRNA vaccines against cancer. Drug Discovery Today, Vol. 25, p. 552-560, 2020.
4 Tureci, O. et al. Targeting the heterogeneity of cancer with individualized neoepitope vaccines. Clinical Cancer Research, Vol. 22, p. 1885–1896, 2016.
5 Pardi, N. et al. mRNA vaccines - a new era in vaccinology. Nature Reviews Drug Discovery, Vol. 17, p. 261-279, 2018.
6 Gu, Y-Z et al. Ex vivo pulsed dendritic cell vaccination against cancer. Acta Pharmacologica Sinica, Vol. 41, p. 959-969, 2020.
7 Pandey, P.R. et al. RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics. [Molecular Cancer] Vol. 21, p. 1-18, 2022.
8 Sun, M. & Kraus, W.L. From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease. [Endocrine Reviews] Volume 36, p. 25-64, 2015.
9 Kim, Y-K. & Kim, V.N.. Processing of intronic microRNAs. [The EMBO Journal] Volume 26, p. 775-783, 2007.
10 Toden, S. & Goel, A. Non-coding RNAs as liquid biopsy biomarkers in cancer. [British Journal of Cancer]. Volume 126, 351-360, 2022.
11 Pan, W. et al. p53/MicroRNA-34 axis in cancer and beyond. [Heliyon], 2023.
12 Abdelaal, A.M. et al. A first-in-class fully modified version of miRNA-34a with outstanding stability, activity, and anti-tumor efficacy. [Oncogene], 2023.
13 Ohishi, T. et al. Involvement of microRNA modifications in anticancer effects of major polyphenols from green tea, coffee, wine, and curry. [Critical Reviews in Food Science and Nutrition] p. 7148-7179, 2022.
14 Huang, Y. et al. Combating cancer with natural products: Non-coding RNA and RNA modification. [Frontiers in Pharmacology] Volume 14, article 1149777, 2023.