Francis Crick’s central dogma is a foundational concept in molecular biology. Genetic information usually flows in one direction – from the DNA to RNA, and then to ribosomes in the cells for protein synthesis, regulatory functions, and various other core biological processes.
Even cancer cells do not deviate from the central dogma, despite being mutated forms of healthy cells. They continue to use and exploit various RNA molecules to multiply, expand, and evade the detection of the body’s defense mechanisms.
RNA’s role as the messenger is of special interest to cancer researchers. Drugs that selectively “shoot the messengers” could result in safer and more effective treatments. In recent years, one class of RNA in particular has attracted attention as potential targets – circular RNAs (circRNA).
What are Circular RNAs?
RNA molecules in the body typically have a linear, single-stranded structure comprising a chain of nucleotides. Messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA) are all examples. In contrast, circRNAs have a unique closed-loop structure.
The circular structure gives circRNA greater stability and longevity than linear RNA molecules. They have a half-life of up to 48 hours, compared to the 10-hour average typical for linear RNAs.
And unlike linear RNAs, circRNAs do not have a direct role in protein synthesis – they are non-coding RNAs. When they were discovered in viruses in the 1970s, circRNA were considered to be largely unimportant byproducts or anomalies with limited function, if any, in key biological processes.
The Role and Functions of CircRNA in the Body
New research using techniques like next-gen RNA sequencing indicates that circRNAs are far more commonly expressed than previously thought, with a more direct impact on gene regulation. Thousands of circRNA strands have been identified in various tissues, across mammals, plants, bacteria, and viruses.
Three main mechanisms of circRNA action on gene expression have been identified so far:
(1.) As “miRNA Sponges”
MicroRNAs (miRNAs) are a type of non-coding molecules that control gene expression by directly binding to the mRNA inside a cell’s cytoplasm. CircRNAs can absorb the miRNA, like a “sponge,” preventing them from activating the messenger RNA molecules.
(2.) Binding with Proteins
CircRNAs can also bind to various other proteins that target RNA molecules, reducing their impact on cell cycle progression and proliferation. They can even bind with multiple RNA-binding proteins (RBPs) and form large protein complexes.
(3.) Competing With mRNAs
The process of generating new circRNA molecules takes place at the same sites that are used to create mRNA strands. This means that as more circRNA molecules are created, the production of mRNA falls. The interaction between circRNA and proteins can also affect mRNA genesis.
The Link Between CircRNA and Cancers
An increase in the expression of circRNA has been linked to the onset and evolution of several different types of cancers. Dr. Mark Anton, founder of OC Breast Surgery and a leading expert in the field with 33 years of experience, had this to say on the subject:
“As a breast cancer surgeon, I have followed research on circular RNAs (circRNAs) closely. CircRNAs are non-coding RNAs that regulate gene expression and play an important role in cancer development and progression. In breast cancer, certain circRNAs have been shown to promote tumor growth, metastasis, and drug resistance.”
The mouth is another part of the body where abnormally high expression of circRNA molecules could be a sign of the presence of malignancies. Dr. Ryan Doyle, a senior dentist with 18 years of experience, concurs – “as a dentist, I have followed research on circRNAs and their role in oral cancers. CircRNAs regulate gene expression in cells and appear dysregulated in many cancers, including oral cancers.”
MiR-7 is an important non-coding RNA molecule that helps suppress various types of tumors. By acting as an miRNA sponge, circRNAs can reduce the expression of this vital molecule in cells. This in turn allows the over-expression of other mutated oncogenes that promote cancer cell growth and migration.
Similarly, circRNAs can promote the uncontrolled growth of cancer cells by binding key proteins. Other notable ways in which they benefit cancer cells include:
- By promoting the formation of new blood vessels in tumors (angiogenesis)
- By influencing critical signaling pathways that promote cancer cell growth
- By increasing the resistance of cancer cells against chemotherapy
Besides cancers, these RNA molecules have also been linked to several other diseases including Alzheimer’s, cardiovascular disorders like myocardial infarction, as well as type-2 diabetes and obesity. Dr. Anton, who also heads a weight loss clinic, has some experience in this regard:
“My clinic conducted early research on circRNAs in weight loss and found they regulate fat burning and appetite control. By analyzing blood samples, we identified circRNAs involved in metabolism that were under-active in obese patients. Supplementing with synthesized circRNA molecules revved up their metabolic rate and reduced hunger, enabling 15-20% weight loss over 3-6 months.”
The Potential Role of CircRNAs in Cancer Treatment
There are two main ways in which we can exploit the links between circRNA over-expression and tumor growth. First, an increase in the expression of circRNA molecules could prove useful in the early detection of cancers, even before the tumors start manifesting.
Dr. Anton highlights recent research that found a high rate of circRNA in exosomes, tiny vesicles secreted by cells. “We could analyze a patient’s blood or urine to look for circRNAs associated with breast cancer cells. If found, it may indicate the presence of tumors even before symptoms arise or at early, more treatable stages.”
The same also holds for certain oral cancers, according to Dr. Doyle.
“For example, circRNAs are abundant in saliva,” he said. “By analyzing a patient’s saliva, we may detect circRNAs associated with oral cancers even before symptoms appear. This could allow for earlier diagnosis and intervention.”
Even more exciting is the potential for the development of drugs that target circRNA. Since these molecules actively promote cancer growth and migration, blocking them using small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) could help treat breast and oral cancers with greater efficiency.
“If we can stop circRNAs that drive breast cancer, it may slow or stop tumor growth. Targeting circRNAs precisely may lead to better treatments with fewer side effects,” says Dr. Thomas Jeneby, a San Antonio-based plastic surgeon who has performed 9,000+ surgical interventions over two decades.
This sentiment is echoed by Dr. Anton as well, who summarized the current situation.
“CircRNAs represent the future of precision medicine,” he said. “They provide new tools to understand diseases, detect them earlier, and develop customized treatments. While more research is needed, circRNAs may help overcome diseases like cancer and obesity in the coming decades.”
