Circular RNAs (circRNAs) are a very interesting class of conserved single-stranded RNA molecules derived from exonic or intronic sequences by precursor mRNA back-splicing. Unlike canonical linear RNAs, circRNAs form covalently closed, continuous stable loops without a 5'end cap and 3'end poly(A) tail, and therefore are resistant to exonuclease digestion. The majority of circRNAs are highly abundant, and conserved across different species with a tissue or developmental-stage-specific expression. circRNAs have been shown to play important roles as microRNA sponges, regulators of gene splicing and transcription, RNA-binding protein sponges and protein/peptide translators. Emerging evidence reveals that circRNAs function in various human diseases, particularly cancers, and may function as better predictive biomarkers and therapeutic targets for cancer treatment. In consideration of their potential clinical relevance, circRNAs have become a new research hotspot in the field of tumor pathology. In the present study, the current understanding of the biogenesis, characteristics, databases, research methods, biological functions subcellular distribution, epigenetic regulation, extracellular transport and degradation of circRNAs was discussed. In particular, the multiple databases and methods involved in circRNA research were first summarized, and the recent advances in determining the potential roles of circRNAs in tumor growth, migration and invasion, which render circRNAs better predictive biomarkers, were described. Furthermore, future perspectives for the clinical application of circRNAs in the management of patients with cancer were proposed, which could provide new insights into circRNAs in the future.

Review on circular RNAs and new insights into their roles in cancer.

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide. The incidence rate and mortality rate of breast cancer continue to rise, which leads to a great burden on public health. Circular RNAs (circRNAs), a new class of noncoding RNAs (ncRNAs), have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression. In breast cancer, circRNAs have significant roles in tumorigenesis, recurrence and multidrug resistance that are mediated by various mechanisms. Therefore, circRNAs may serve as promising targets of therapeutic strategies for breast cancer management. This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis, treatment and prognosis evaluation, as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer. Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

Circular RNAs in breast cancer diagnosis, treatment and prognosis

Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs are derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput RNA sequencing and experimental technologies have enabled the extensive identification and characterization of circRNAs, such as novel types of biogenesis, tissue-specific and cell-specific expression patterns, epigenetic regulation, translation potential, localization and metabolism. Increasing evidence has revealed that circRNAs participate in diverse cellular processes, and their dysregulation is involved in the pathogenesis of various diseases, particularly cancer. In this review, we systematically discuss the characterization of circRNAs, databases, challenges for circRNA discovery, new insight into strategies used in circRNA studies and biomedical applications. Although recent studies have advanced the understanding of circRNAs, advanced knowledge and approaches for circRNA annotation, functional characterization and biomedical applications are continuously needed to provide new insights into circRNAs. The emergence of circRNA-based protein translation strategy will be a promising direction in the field of biomedicine. 

New insight into circRNAs: characterization, strategies, and biomedical applications

Chemotherapeutic resistance poses a significant challenge in cancer treatment, resulting in the reduced efficacy of standard chemotherapeutic agents. Abnormal metabolism, particularly increased anaerobic glycolysis, has been identified as a major contributing factor to chemotherapeutic resistance. To address this issue, noninvasive imaging techniques capable of visualizing tumor glycolysis are crucial. However, the currently available methods (such as PET, MRI, and fluorescence) possess limitations in terms of sensitivity, safety, dynamic imaging capability, and autofluorescence. Here, we present the de novo design of a unique afterglow molecular scaffold based on hemicyanine and rhodamine dyes, which holds promise for low-background optical imaging. In contrast to previous designs, this scaffold exhibits responsive "OFF-ON" afterglow signals through spirocyclization, thus enabling simultaneous control of photodynamic effects and luminescence efficacy. This leads to a larger dynamic range, broader detection range, higher signal enhancement ratio, and higher sensitivity. Furthermore, the integration of multiple functionalities simplifies probe design, eliminates the need for spectral overlap, and enhances reliability. Moreover, we have expanded the applications of this afterglow molecular scaffold by developing various probes for different molecular targets. Notably, we developed a water-soluble pH-responsive afterglow nanoprobe for visualizing glycolysis in living mice. This nanoprobe monitors the effects of glycolytic inhibitors or oxidative phosphorylation inhibitors on tumor glycolysis, providing a valuable tool for evaluating the tumor cell sensitivity to these inhibitors. Therefore, the new afterglow molecular scaffold presents a promising approach for understanding tumor metabolism, monitoring chemotherapeutic resistance, and guiding precision medicine in the future.

Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold.

Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication and treatment decision-making. Circular RNAs (circRNAs) represent a class of newly identified long non-coding RNAs. These molecules have been described as key regulators of breast carcinogenesis and progression. Moreover, circRNAs play a role in drug resistance and are associated with clinicopathological features in BC. Accumulating evidence reveals a clinical interest in deregulated circRNAs as diagnostic, prognostic and predictive biomarkers. Furthermore, due to their covalently closed structure, circRNAs are highly stable and easily detectable in body fluids, making them ideal candidates for use as non-invasive biomarkers. Herein, we provide an overview of the biogenesis and pleiotropic functions of circRNAs, and report on their clinical relevance in BC.

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Circular RNAs as Potential Biomarkers in Breast Cancer

Dual inhibition of glucose uptake and energy supply synergistically restrains the growth and metastasis of breast cancer

Objective Cell-free circular RNAs (circRNAs) are stable and abundantly exist in body fluids In this study, we aimed to investigate plasma cell-free circRNAs as a novel class of biomarkers for the diagnosis of breast cancer (BC) Methods Differentially expressed circRNAs from 6 normal and 6 BC plasma samples were detected by microarray Hsa_circ_0008673 was then screened and validated in the plasma of 102 normal and 378 BC samples A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value The correlations between hsa_circ_0008673 expression and demographic characteristics, tumor features, and prognosis were analyzed The effects of hsa_circ_0008673 on BC cell proliferation and metastasis were also measured Results Of the top ten up-regulated (hsa_circ_0008673, hsa_circ_0008500, hsa_circ_0005260, hsa_circ_0003423, hsa_circ_0119881, hsa_circ_0000987, hsa_circ_0007386, hsa_circ_0000091, hsa_circ_0016601, and hsa_circ_0008549) and top ten down-regulated (hsa_circ_0000826, hsa_circ_0072697, hsa_circ_0004587, hsa_circ_0000471, hsa_circ_0007786, hsa_circ_0001417, hsa_circ_0005982, hsa_circ_0001566, hsa_circ_0003823, and hsa_circ_0003823) circRNAs from microarray, hsa_circ_0008673 was the most significantly up-regulated circRNA in BC, and represented a good diagnostic value Hsa_circ_0008673 was remarkably down-regulated after breast mastectomy Hsa_circ_0008673 expression was associated with larger tumor size, distant metastasis, positive estrogen receptor (ER) status, and positive progesterone receptor (PR) status Additionally, hsa_circ_0008673 could serve as a prognostic predicator of overall survival (OS) and disease-specific survival (DSS) Cell assays proved that hsa_circ_0008673 knockdown contributed to inhibition of tumor cell proliferation and migration Conclusion Plasma cell-free hsa_circ_0008673 was up-regulated in BC, which was associated with poorer prognosis and promoted tumor proliferation and metastasis Hsa_circ_0008673 is a promising biomarker for tumor diagnosis and prognostic assessment of BC patients

Identification of plasma hsa_circ_0008673 expression as a potential biomarker and tumor regulator of breast cancer

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Dual inhibition of glucose uptake and energy supply synergistically restrains the growth and metastasis of breast cancer

Identification of plasma hsa_circ_0008673 expression as a potential biomarker and tumor regulator of breast cancer