The role of circular RNAs in gastric cancer drug resistance

Cancer News: Gastric cancer, one of the most prevalent cancers affecting the digestive system, continues to pose a significant challenge globally. Current treatment strategies, including surgery, chemotherapy, and targeted therapies, have improved survival rates. However, one of the key barriers to long-term success is drug resistance, a phenomenon where cancer cells gradually become immune to the effects of anticancer drugs. Recently, research has identified a new player in this arena: circular RNAs (circRNAs).


The role of circular RNAs in gastric cancer drug resistance

Understanding Gastric Cancer and Drug Resistance
Gastric cancer primarily develops in the lining of the stomach and is often detected at an advanced stage, making it difficult to treat. Although chemotherapy is commonly used to combat the disease, gastric cancer cells can evolve, becoming less responsive to treatment over time. This reduction in drug sensitivity is referred to as drug resistance. Several mechanisms contribute to this, including changes in cell structure, DNA repair pathways, and the cells' ability to undergo programmed cell death (apoptosis).
 
Recent findings have shown that non-coding RNAs, particularly circRNAs, play a crucial role in this process. CircRNAs, unlike linear RNAs, have a circular structure that makes them more stable and long-lasting within the cell. They have been found to regulate various biological functions in gastric cancer cells, including proliferation, migration, invasion, and resistance to chemotherapy drugs.
 
The Role of CircRNAs in Drug Resistance
CircRNAs have gained attention for their unique role in enhancing drug resistance in gastric cancer. This Cancer News report highlights the significant findings from research conducted by scientists at institutions like Jiangsu University and Anhui Medical University, who have extensively studied circRNAs in this context. Their work has provided new insights into how circRNAs contribute to the development of drug resistance in gastric cancer cells.
 
Impact on Cell Invasion and Migration
One of the key ways circRNAs influence drug resistance is by affecting the invasion and migration of cancer cells. Tumor cells that can invade surrounding tissues and spread to other parts of the body are more likely to resist chemotherapy. For instance, circ0063526 has been found to enhance resistance to the chemotherapy drug cisplatin by promoting cell migration and invasion. Studies suggest that when circ0063526 is knocked down, cancer cells become less resistant to cisplatin, highlighting the potential of targeting this circRNA to overcome drug resistance.
 
CircRNAs and Cancer Cell Proliferation
Uncontrolled cell proliferation is a hallmark of cancer, and circRNAs also play a role in this process. CircDLG1, for example, has been shown to promote the proliferation of gastric cancer cells and their resistance to anti-PD-1 therapy, a type of immunotherapy. By sponging specific microRNAs, circRNAs like circDLG1 increase the expr ession of proteins that drive cancer cell growth, ultimately making the cells less sensitive to treatment. Targeting these circRNAs could offer a new approach to inhibiting cancer growth and improving the effectiveness of chemotherapy.
 
Autophagy and Chemoresistance
Autophagy, the process by which cells break down and recycle their own components, can also contribute to drug resistance in cancer. CircRNAs have been found to regulate autophagy in gastric cancer cells. For example, circCUL2 has been shown to promote autophagy in gastric cancer cells, leading to increased resistance to cisplatin. By targeting circRNAs that influence autophagy, researchers may be able to reduce the ability of cancer cells to resist treatment.
 
CircRNAs and Apoptosis
Apoptosis, or programmed cell death, is a critical mechanism that helps eliminate damaged or abnormal cells, including cancer cells. Many anticancer drugs work by inducing apoptosis in cancer cells. However, circRNAs can interfere with this process, making it harder for drugs to kill cancer cells. CircUBAP2, for instance, has been shown to promote apoptosis in gastric cancer cells, enhancing their sensitivity to cisplatin. By targeting circRNAs involved in apoptosis, researchers could improve the effectiveness of chemotherapy drugs and reduce drug resistance.
 
DNA Repair and Cancer Stem Cells
CircRNAs also play a role in DNA repair, which allows cancer cells to survive despite damage caused by chemotherapy. In gastric cancer cells, circAKT3 has been found to enhance DNA repair and promote resistance to cisplatin. Additionally, circRNAs can influence the behavior of cancer stem cells, which are believed to be responsible for tumor recurrence and resistance to treatment. CircFAM73A, for example, promotes the properties of cancer stem cells, making them more resistant to chemotherapy.
 
Future Directions: Targeting CircRNAs for Better Therapies
The growing understanding of how circRNAs contribute to drug resistance in gastric cancer opens up new possibilities for treatment. By targeting specific circRNAs, it may be possible to reverse drug resistance and enhance the effectiveness of chemotherapy. Several approaches could be explored, including the use of small interfering RNAs (siRNAs) or gene editing techniques to knock down oncogenic circRNAs or enhance the expression of circRNAs that promote drug sensitivity.
 
However, there are still challenges to be addressed. For one, more research is needed to fully understand the molecular mechanisms by which circRNAs influence drug resistance. Additionally, the safety and efficacy of circRNA-based therapies must be rigorously evaluated in clinical trials. Nevertheless, the potential of targeting circRNAs for cancer therapy is promising, and ongoing research is likely to yield new insights in the coming years.
 
Conclusion
Gastric cancer remains a formidable challenge, particularly due to the development of drug resistance. The discovery of circRNAs as key regulators of drug resistance offers new hope for overcoming this obstacle. By targeting circRNAs that influence cell invasion, proliferation, autophagy, apoptosis, DNA repair, and cancer stem cell behavior, researchers may be able to develop more effective therapies for gastric cancer. This article provides a glimpse into the future of cancer treatment, where circRNA-based therapies could play a pivotal role in improving patient outcomes.
 
The study findings were published in the peer-reviewed journal: Frontiers in Pharmacology.
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1435264/full
 
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