Circular RNAs in Cancer: Roles, Mechanisms, and Future Potential

Cancer research is increasingly focused on understanding how RNA molecules influence tumor development, progression, and treatment response. Among these molecules, circular RNAs (circRNAs) have attracted significant attention because of their unique structure and diverse biological functions.

Unlike conventional linear RNA molecules, circRNAs form a covalently closed loop. This structure gives many circRNAs greater resistance to degradation and allows them to interact with microRNAs, proteins, and other molecules involved in gene regulation. Research has linked abnormal circRNA expression and activity with several processes involved in cancer, including cell proliferation, invasion, metastasis, and treatment resistance.

For a vaccine biotechnology company, understanding circular RNA is also important because research into RNA biology extends beyond cancer and into areas such as vaccines, therapeutics, and drug delivery.

But what exactly makes circRNAs relevant to cancer research? And could these molecules eventually become useful biomarkers or therapeutic targets?

Let’s take a closer look.

What Are Circular RNAs?

Circular RNAs are RNA molecules that form a closed-loop structure instead of the typical linear structure found in messenger RNA (mRNA).

They are generally produced through a process called back-splicing, in which a downstream splice donor joins an upstream splice acceptor. This creates a circular RNA molecule with no conventional free 5′ or 3′ ends.

If you want to understand the basic biology first, our guide to what is circular RNA provides a broader explanation of circRNA structure, formation, and function.

The circular structure is one reason circRNAs behave differently from linear RNAs. Many circRNAs are relatively stable because they lack the free ends targeted by certain exonucleases. However, stability varies between individual circRNAs and depends on their sequence, cellular environment, and mechanisms of turnover.

CircRNAs were once considered unusual products or possible errors of RNA splicing. Advances in sequencing and computational analysis have since shown that many are regulated molecules with important biological functions.

Why Are Circular RNAs Important in Cancer?

Research has identified altered circRNA expression across many cancer types. Some circRNAs are found at higher levels in tumors, while others are reduced.

These changes can matter because circRNAs can interact with regulatory molecules and signaling pathways that influence cancer biology.

Research has associated circRNAs with several major processes involved in cancer, including:

Tumor cell proliferation
Apoptosis and cell survival
Cell migration and invasion
Metastasis
Angiogenesis
Cancer stem cell behavior
Immune regulation
Drug resistance
Response to chemotherapy and radiotherapy

However, an important distinction is needed. Finding that a circRNA is associated with a cancer does not automatically prove that it causes tumor development or progression. Researchers increasingly emphasize the need to demonstrate a direct functional relationship between a circRNA and its molecular target.

How Do Circular RNAs Affect Cancer Cells?

Circular RNAs can influence cancer biology through several mechanisms. Their effects depend on the specific circRNA, its abundance, its cellular location, and the molecules with which it interacts.

1. Regulating MicroRNAs

One of the best-known functions attributed to some circRNAs is interaction with microRNAs (miRNAs).

MicroRNAs are small RNA molecules that can regulate gene expression by binding to target RNAs. Some circRNAs contain binding sites for particular miRNAs and can bind them, potentially affecting the availability of those miRNAs to interact with their normal targets.

This has often been described as a microRNA sponge mechanism.

A well-known example is CDR1as, also called ciRS-7, which contains numerous binding sites for miR-7. Its interaction with miR-7 has made it one of the most extensively studied examples of circRNA-mediated miRNA regulation.

However, not every circRNA functions as a miRNA sponge. The biological importance of this mechanism depends on factors such as circRNA abundance, binding affinity, cellular location, and whether the concentrations are sufficient to produce a meaningful regulatory effect.

2. Interacting With Proteins

CircRNAs can also bind RNA-binding proteins and other proteins.

These interactions can influence protein localization, activity, stability, or the formation of molecular complexes. In some cases, circRNAs can act as molecular scaffolds that bring proteins together or affect how they interact.

Because many cancer pathways depend on tightly controlled protein interactions, these functions can potentially affect tumor biology.

3. Influencing Gene Expression and RNA Processing

Some circRNAs can affect gene expression and RNA processing.

Depending on the circRNA and its cellular location, it may interact with transcriptional machinery, RNA-binding proteins, or other regulatory molecules.

CircRNAs can therefore participate in regulatory networks rather than acting through a single mechanism.

4. Producing Peptides or Proteins

Although many circRNAs are described as noncoding, some circRNAs can be translated into peptides or proteins.

Their closed structure does not automatically prevent translation. Certain circRNAs contain internal elements that can support translation under appropriate cellular conditions.

This discovery has expanded the understanding of circRNA biology and raised new questions about how translated circRNAs may contribute to normal physiology and diseases such as cancer.

Circular RNAs and Tumor Growth

Cancer cells must continually grow and survive despite signals that would normally restrict cell division.

Studies have identified circRNAs that can influence pathways involved in cell proliferation and survival. Depending on the specific molecule, a circRNA may promote or suppress these processes.

For example, a circRNA could affect a signaling pathway indirectly by regulating a miRNA or interacting with a protein. Other circRNAs may influence gene expression more directly.

This means there is no single “cancer circRNA pathway.” Instead, different circRNAs can participate in different molecular networks across different cancers.

Circular RNAs and Cancer Metastasis

Metastasis occurs when cancer cells spread from the original tumor to other parts of the body.

For a cancer cell to metastasize, it must complete several steps, including changes in cell adhesion, migration, invasion, survival, and colonization of new tissues.

Research has identified circRNAs associated with several of these processes. Some circRNAs have been shown in experimental models to influence migration and invasion, while altered circRNA expression has also been associated with metastatic disease.

These findings make circRNAs interesting targets for research into how tumors spread.

Still, most findings come from laboratory studies, and additional research is needed to determine which circRNAs have meaningful clinical effects in patients.

Circular RNAs as Cancer Biomarkers

One of the most promising areas of research involving circular RNAs in cancer is their potential use as biomarkers.

A biomarker is a measurable biological feature that can provide information about a disease or a patient’s response to treatment.

CircRNAs have several characteristics that make them interesting candidates:

They can be relatively stable.
Some show tissue-specific or cancer-associated expression patterns.
They can be detected in biological fluids.
Their expression can change during disease development.
Some may remain detectable outside cells.

Researchers have therefore investigated circRNAs as potential diagnostic, prognostic, and predictive biomarkers. Studies have explored their presence in samples such as blood, plasma, saliva, and urine.

Diagnostic Biomarkers

A diagnostic biomarker could potentially help identify the presence of a disease.

If a particular circRNA consistently differs between people with a cancer and healthy individuals, researchers may investigate whether it could contribute to a future diagnostic test.

However, detecting a difference in circRNA levels is only an early step. A clinically useful biomarker must also demonstrate adequate sensitivity, specificity, reproducibility, and performance in well-designed patient studies.

Prognostic Biomarkers

Some circRNA expression patterns have been associated with disease stage, tumor characteristics, or patient outcomes.

This raises the possibility that certain circRNAs could help researchers understand how aggressive a cancer may be.

Again, association does not establish clinical usefulness. Large, well-controlled studies are needed before a biomarker can become part of routine clinical decision-making.

Liquid Biopsy

The detection of circRNAs in body fluids has also contributed to interest in liquid biopsy research.

A liquid biopsy aims to obtain disease-related information from a biological sample such as blood rather than relying entirely on tissue collection.

Because some circRNAs can be relatively stable, researchers are investigating whether they could contribute to non-invasive or minimally invasive cancer monitoring strategies.

Circular RNAs and Treatment Resistance

Cancer treatment resistance is another area where circRNAs are being investigated.

Tumors can become resistant to chemotherapy, targeted therapies, radiation, and other treatments through multiple biological mechanisms. These can include changes in signaling pathways, DNA repair, cell survival, drug transport, and the tumor microenvironment.

Recent research has identified circRNAs associated with resistance-related pathways. Some studies suggest that particular circRNAs may influence signaling networks involved in cancer cell survival and treatment response.

The 2025 Wiley review specifically highlights chemoradiotherapy resistance as an important area where the role of circRNAs remains incompletely understood.

This is an important research direction, but it is still too early to treat circRNA manipulation as an established method for overcoming cancer treatment resistance.

Circular RNAs as Potential Therapeutic Targets

If a circRNA contributes directly to cancer development, researchers may eventually be able to target that molecule therapeutically.

Potential approaches could include:

Reducing the activity or abundance of a disease-promoting circRNA
Restoring or increasing the activity of a tumor-suppressive circRNA
Blocking specific circRNA interactions
Targeting circRNA-associated signaling pathways
Using engineered RNA molecules as therapeutic agents

The basic idea is to interfere with a molecular pathway that contributes to tumor growth or survival.

However, developing a circRNA-based cancer therapy presents major challenges. Researchers need to determine which circRNAs are truly causal, how to target them selectively, how to deliver therapeutic molecules to the correct cells, and how to avoid unwanted effects.

The 2024 Nature Reviews Cancer review emphasizes that functional validation is particularly important. A circRNA needs to be present at biologically meaningful levels and have demonstrated interactions with its proposed targets before it can be considered a strong therapeutic candidate.

Are Circular RNAs Used to Treat Cancer Today?

Not as an established standard cancer treatment.

Circular RNA research has produced promising laboratory findings, but many proposed applications remain in the experimental or preclinical research stage.

This distinction is important because a molecule showing an effect in cultured cells or animal models does not automatically become an effective treatment for people.

Before circRNA-based cancer therapies can become part of routine clinical care, researchers must establish factors such as:

Therapeutic effectiveness
Appropriate dosing
Target specificity
Delivery to the intended tissue
Pharmacokinetics
Safety
Immune effects
Manufacturing consistency
Long-term effects

The clinical translation of circRNA-based therapeutics remains an active area of investigation.

Challenges in Circular RNA Cancer Research

Despite the growing interest in circular RNAs in cancer, several scientific and technical challenges remain.

Identifying True Functional CircRNAs

Thousands of circRNAs can be detected in human cells, but detection alone does not establish biological function.

Researchers need to determine which circRNAs have meaningful effects and which are simply correlated with changes occurring in cancer cells.

Accurate Detection

CircRNAs can be difficult to distinguish from their linear RNA counterparts.

Specialized sequencing and experimental approaches are often required to identify back-splicing junctions and accurately measure specific circRNAs.

Understanding Context

A circRNA may behave differently depending on the cell type, tissue, disease stage, and molecular environment.

A circRNA associated with one cancer cannot automatically be assumed to have the same function in another cancer.

Delivery

For therapeutic applications, researchers need effective ways to deliver RNA-based molecules to the right cells and tissues.

Delivery remains one of the broader challenges in RNA therapeutics, particularly when the intended target is located in a specific tumor or cellular compartment.

Moving From Association to Causation

Many studies report that a circRNA is associated with a particular cancer or clinical outcome.

The next question is whether the circRNA actually contributes to that outcome.

Carefully designed functional studies are needed to establish causality and determine whether targeting the circRNA would produce a meaningful therapeutic effect.

What Does the Future Hold for Circular RNAs in Cancer?

Research into circular RNAs in cancer is moving from basic discovery toward more detailed functional and translational studies.

Future work is likely to focus on identifying which circRNAs have genuine biological effects, understanding their molecular interactions, improving detection methods, and determining whether they can provide useful clinical information.

Potential applications include:

Cancer biomarkers for diagnosis or disease monitoring
Prognostic markers for understanding disease behavior
Predictive biomarkers for treatment response
Therapeutic targets for specific cancer pathways
RNA-based therapeutic approaches
Liquid biopsy applications
Personalized cancer research

The field is promising, but progress will depend on rigorous validation and better understanding of circRNA biology.

Circular RNAs in Cancer and the Broader RNA Research Field

The growing interest in circular RNAs in cancer also demonstrates how much remains to be learned about RNA biology.

CircRNAs were once largely overlooked, but advances in sequencing and molecular biology have revealed a diverse group of RNA molecules with regulatory functions. Their stability, expression patterns, and ability to interact with proteins and other RNAs make them useful subjects for both basic research and therapeutic investigation.

The same broader advances in RNA science are also supporting research into engineered RNA technologies for applications beyond oncology, including vaccine development.

For biotechnology companies working with RNA platforms, understanding how RNA structure, stability, expression, and delivery affect biological activity is increasingly important.

Frequently Asked Questions

What are circular RNAs in cancer?

Circular RNAs in cancer are covalently closed RNA molecules that have been linked to processes such as cell proliferation, metastasis, gene regulation, and treatment resistance. Their roles vary depending on the specific circRNA and cancer type.

Can circular RNA cause cancer?

Some circRNAs have been shown to contribute to cancer-related processes in experimental studies, while others may suppress tumor-related pathways. However, the role of a particular circRNA must be established through functional research rather than assuming that its presence causes cancer.

Can circular RNAs be used to detect cancer?

Researchers are investigating circRNAs as potential diagnostic and prognostic biomarkers. Their stability and detection in biological fluids make them interesting candidates, but most applications still require further clinical validation.

Are circular RNA cancer treatments available?

CircRNA-based cancer therapies are still primarily a research area. Although laboratory and preclinical studies have produced promising findings, circRNA-based treatments are not currently an established standard cancer therapy.

Why are circular RNAs more stable than some linear RNAs?

Many circRNAs lack the free 5′ and 3′ ends that certain exonucleases recognize, which can make them more resistant to degradation. However, stability is not identical for every circRNA and depends on its structure and cellular context.

Do all circular RNAs function as microRNA sponges?

No. Although some circRNAs can bind microRNAs, this is only one of several known or proposed functions. CircRNAs can also interact with proteins, influence RNA processing and gene regulation, and in some cases serve as templates for translation.

Conclusion

Circular RNAs have become an important area of cancer research because they can participate in diverse regulatory processes involved in tumor biology.

Studies have connected specific circRNAs with cancer cell growth, metastasis, treatment resistance, and other disease processes. Their relative stability and detection in biological fluids have also created interest in their potential use as cancer biomarkers.

At the same time, the field is still developing. Not every cancer-associated circRNA is functionally important, and promising laboratory findings do not automatically translate into clinical treatments.

The next stage of research will depend on identifying the circRNAs that have genuine biological effects, understanding their molecular mechanisms, improving detection and delivery technologies, and validating their clinical relevance.

For now, circular RNAs represent a promising research area at the intersection of RNA biology, cancer research, diagnostics, and future therapeutic development.