User:FarhanaMazumder2023/Circular RNA

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Circular RNA pathogenesis in Heart, Renal, Liver, autoimmune disease, and Cancer development:

Heart disease

Recent studies have shown that circRNA is associated with heart failure and heart disease. circFOXO3, Titin genes, circSLC8A1-1 and circAmotl1 play an important role in cardiac function through upregulation or inhibition relevant to heart disease. Overexpression of circFOXO3 and its downregulation binds to the transcription factors E2F1, HIF1α and protein ID1, FAK, causing cardiomyopathy induced by DOX. Titin gene derived circRNA induces cardiotoxicity in cardiomyocytes. circSLC8A1-1 overexpression causes sponging of the cardiac hypertrophy regulator miR-133 and leads to heart failure. Apart from circRNA-mediated cardiac disease, some circRNAs have played a role in cardiac damage repair. For example, circAmotl1 overexpression increases cardiomyocyte longevity through binding and translocation of AKT that regulates cardiac repair. Circular RNA CDR1 has an important role during infection in the myocardium. Cardiac dysfunction occurs post myocardial infection due to CircNfix downregulation. Since various types of circular RNA are related to heart disease, it can be used as a potential biomarker and therapeutic target. For example, postoperative atrial fibrillation has been observed in some patients after cardiac surgery where circRNA_025016 is used as a biomarker. Although the relevance of circular RNA overexpression and downregulation to heart disease has been found from various research studies, it is still unclear. Therefore, further research is needed to trace disease progression in different stages of cardiac dysfunction using circular RNA as a biomarker and can be used for gene delivery purposes in cells.

Renal disease

Various studies have demonstrated that circular RNA acts as a prognostic agent and biomarker in kidney diseases including renal cell carcinoma, acute kidney injury, diabetic nephropathy, and lupus nephritis. Renal chronicity is associated with miR-150, which is negatively regulated by circHLA-C, in patients with lupus nephritis. There is also evidence that circular RNA is involved in acute kidney injury. In these circumstances circular RNA proves to be a novel biomarker and is also used for targeted therapy of kidney disease because its pseudogene can alter DNA composition.

Liver disease

Evidence found that circular RNA plays a role in chronic liver disease and homeostasis regulation leading to liver fibrosis and autoimmune disease by an epigenetic mechanism.

Cancer

Circular RNA has both positive and negative functions in cancer. For example, ciRS-7 was found to be an oncogene in colorectal cancer tissue that regulates the disease. Overexpression of this ciRS-7 leads to deregulated gene expression leading to malignant phenotypic features. On the other hand, some CircRNAs show positive effects such as circ-ITCH which regulates lung cancer associated with oncogenic sponges miR7 and miR214 and overexpression of circ-ITCH inhibits cell proliferation in lung cancer. From different research studies it has been found that F-circM-9, F-circPR and F-circEA, FcircEA-2 are involved in the development of leukemia and cancer. In osteosarcoma cell circ-0016347 induces tumor and downregulation of caspase-1 target. Another circular RNA hsa_circRNA_002178 leads to breast cancer when it overexpresses and down-regulates COL1A1 protein function. In contrast, silencing of hsa_circRNA_002178 reduced IL-6 and TNF-α production, which inhibited tumor growth and inflammation. Some viruses such as Epstein Barr virus and human papillomavirus can encode circular RNAs such as circEBNA_W1_C1 (EBV) and circE7 (HPV) that play a role in oncogenesis in infected individuals. As circRNAs involved in cancer development or regulation process so that it has the potential to use as a biomarker in cancer surveillance and identification process. Circular RNA has the advantage of stability, tissue specificity and it can be found in the blood, saliva, urine, cerebrospinal fluid, and human body fluid secretion that has abundance in exosomes are good to use as cancer biomarker agent.

Autoimmune disease

Circular RNA has a function in autoimmune disease progression acting as a miRNA sponge which regulates DNA methylation, adaptive immune activation, and costimulatory molecule secretion.

Circular RNA in immune response:

Circular RNA plays a significant role in immune regulation and induction of T cell responses. circRNA100783 is involved in immunity and senescence of CD8+ T cells. circRNA-003780 and circRNA-010056 also have major roles for macrophage differentiation and polarization.

Circular RNA acts as a very active immune agent when it combines with soluble protein antigens and induces adaptive immunity that does not require a specific route of administration.  Plasma circular RNA and combined circRNa have higher efficiency in diagnosis than tissue specific treatment and single circular RNA. Treatment with circular RNA activates the differentiation and maturation of dendritic cells which then secrete a large number of different cytokines and chemokines by expressing the genes for IL-1β, IL-6 and TNFa. After immunization with circular RNA that encodes the antigen sequence, CD8+ mediator T cell responses to the target antigen are enhanced. Circular RNA has the very advantageous properties of stability and long shelf life, so it is useful for use as biomarkers and plasmids to express genes of interest.

CircRNA Myogenesis regulation:

Circular RNA plays an important role in myogenesis mechanisms such as circRBFOX2, circLMO7 acts as a negative regulator and CircSVIL acts as a positive regulator.

circRBFOX2 regulates miR-206 expression and induces myoblast proliferation in a negative effect on the myogenesis process. circLMO7 is involved in overexpression of HDAC4 and downregulates MEF2A expression by upregulating miR-378a-3p leading to myoblast differentiation.

CircSVIL a positive regulator induces miR-203 activity that is the inhibitor of myoblast production and differentiation. circFUT10 is involved in inhibition of myoblast proliferation but enhances differentiation through enhancement of SRF expression.

circSNX29 sponges miR-744 and circFGFR2 sponges miR-133a-5p and miR-29b-1-5p that promote myoblast differentiation. circSNX29 activates Wnt pathways by enhancing Wnt5a and CaMKIId expression which are involved in myogenesis regulation.