Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer

Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches.

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Non-Coding RNAs in Breast Cancer: Intracellular and Intercellular Communication

Non-Coding RNA ◽

10.3390/ncrna4040040 ◽

2018 ◽

Vol 4 (4) ◽

pp. 40 ◽

Cited By ~ 25

Author(s):

Carolyn Klinge

Keyword(s):

Breast Cancer ◽

Intercellular Communication ◽

Intracellular Signaling ◽

Colorectal Neoplasia ◽

Breast Tumors ◽

Estrogen Receptor Α ◽

Circular Rnas ◽

Intercellular Signaling ◽

Protein Coding ◽

Non Coding Rnas

Non-coding RNAs (ncRNAs) are regulators of intracellular and intercellular signaling in breast cancer. ncRNAs modulate intracellular signaling to control diverse cellular processes, including levels and activity of estrogen receptor α (ERα), proliferation, invasion, migration, apoptosis, and stemness. In addition, ncRNAs can be packaged into exosomes to provide intercellular communication by the transmission of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) to cells locally or systemically. This review provides an overview of the biogenesis and roles of ncRNAs: small nucleolar RNA (snRNA), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), miRNAs, and lncRNAs in breast cancer. Since more is known about the miRNAs and lncRNAs that are expressed in breast tumors, their established targets as oncogenic drivers and tumor suppressors will be reviewed. The focus is on miRNAs and lncRNAs identified in breast tumors, since a number of ncRNAs identified in breast cancer cells are not dysregulated in breast tumors. The identity and putative function of selected lncRNAs increased: nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), steroid receptor RNA activator 1 (SRA1), colon cancer associated transcript 2 (CCAT2), colorectal neoplasia differentially expressed (CRNDE), myocardial infarction associated transcript (MIAT), and long intergenic non-protein coding RNA, Regulator of Reprogramming (LINC-ROR); and decreased levels of maternally-expressed 3 (MEG3) in breast tumors have been observed as well. miRNAs and lncRNAs are considered targets of therapeutic intervention in breast cancer, but further work is needed to bring the promise of regulating their activities to clinical use.

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Advances in the Identification of Circular RNAs and Research Into circRNAs in Human Diseases

Frontiers in Genetics ◽

10.3389/fgene.2021.665233 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shihu Jiao ◽

Song Wu ◽

Shan Huang ◽

Mingyang Liu ◽

Bo Gao

Keyword(s):

Neurological Disorders ◽

Closed Loop ◽

Significant Proportion ◽

Human Diseases ◽

Circular Rnas ◽

The Status ◽

Research Questions ◽

Non Coding Rnas ◽

Microrna Sponges

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a closed-loop structure that are mainly produced by variable processing of precursor mRNAs (pre-mRNAs). They are widely present in all eukaryotes and are very stable. Currently, circRNA studies have become a hotspot in RNA research. It has been reported that circRNAs constitute a significant proportion of transcript expression, and some are significantly more abundantly expressed than other transcripts. CircRNAs have regulatory roles in gene expression and critical biological functions in the development of organisms, such as acting as microRNA sponges or as endogenous RNAs and biomarkers. As such, they may have useful functions in the diagnosis and treatment of diseases. CircRNAs have been found to play an important role in the development of several diseases, including atherosclerosis, neurological disorders, diabetes, and cancer. In this paper, we review the status of circRNA research, describe circRNA-related databases and the identification of circRNAs, discuss the role of circRNAs in human diseases such as colon cancer, atherosclerosis, and gastric cancer, and identify remaining research questions related to circRNAs.

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Circular RNAs and Hepatocellular Carcinoma: New Epigenetic Players With Diagnostic and Prognostic Roles

Frontiers in Oncology ◽

10.3389/fonc.2021.653717 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kedeerya Aishanjiang ◽

Xin-dong Wei ◽

Yi Fu ◽

Xinjie Lin ◽

Yujie Ma ◽

...

Keyword(s):

Gastric Cancer ◽

Hepatocellular Carcinoma ◽

Closed Loop ◽

Therapeutic Potential ◽

Therapeutic Targets ◽

Circular Rnas ◽

Diagnosis And Prognosis ◽

Physiological Processes ◽

Non Coding Rnas ◽

Novel Targets

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Due to the lack of potent diagnosis and prognosis biomarkers and effective therapeutic targets, the overall prognosis of survival is poor in HCC patients. Circular RNAs (circRNAs) are a class of novel endogenous non-coding RNAs with covalently closed loop structures and implicated in diverse physiological processes and pathological diseases. Recent studies have demonstrated the involvement of circRNAs in HCC diagnosis, prognosis, development, and drug resistance, suggesting that circRNAs may be a class of novel targets for improving HCC diagnosis, prognosis, and treatments. In fact, some artificial circRNAs have been engineered and showed their therapeutic potential in treating HCV infection and gastric cancer. In this review, we introduce the potential of circRNAs as biomarkers for HCC diagnosis and prognosis, as therapeutic targets for HCC treatments and discuss the challenges in circRNA research and chances of circRNA application.

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Circular RNAs in Hepatocellular Carcinoma: Emerging Functions to Clinical Significances

Frontiers in Oncology ◽

10.3389/fonc.2021.667428 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yucheng Zhang ◽

Yali Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Closed Loop ◽

Early Stage ◽

Circular Rnas ◽

High Morbidity ◽

Future Perspectives ◽

Diagnostic Biomarkers ◽

Diagnosis And Prognosis ◽

Highly Sensitive ◽

Non Coding Rnas

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and carries high morbidity and mortality. Diagnosing HCC at an early stage is challenging. Therefore, finding new, highly sensitive and specific diagnostic biomarkers for the diagnosis and prognosis of HCC patients is extremely important. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed loop structures. They are characterized by remarkable stability, long half-life, abundance and evolutionary conservation. Recent studies have shown that many circRNAs are expressed aberrantly in HCC tissues and have important regulatory roles during the development and progression of HCC. Hence, circRNAs are promising biomarkers for the diagnosis and prognosis of HCC. This review: (i) summarizes the biogenesis, categories, and functions of circRNAs; (ii) focuses on current progress of dysregulated expression of circRNAs in HCC with regard to regulation of the tumor hallmarks, “stemness” of cancer cells, and immunotherapy; (iii) highlights circRNAs as potential biomarkers and therapeutic targets for HCC; and (iv) discusses some of the challenges, questions and future perspectives of circRNAs research in HCC.

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An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms22084234 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4234

Author(s):

Francesca Baldini ◽

Matilde Calderoni ◽

Laura Vergani ◽

Paola Modesto ◽

Tullio Florio ◽

...

Keyword(s):

Recent Progress ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Biological Functions ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Definitive Therapy ◽

Sporadic Cases ◽

Non Coding Rnas

Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.

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Potential Clinical Applications of Exosomal Circular RNAs: More than Diagnosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.769832 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kearabetsoe Matseliso Molibeli ◽

Rong Hu ◽

Yuze Liu ◽

Dehui Xiong ◽

Lijun Tang

Keyword(s):

Rna Binding ◽

Neurological Diseases ◽

Cell Communication ◽

Clinical Applications ◽

Circular Rnas ◽

Control Gene Expression ◽

Genome Wide ◽

Potential Applications ◽

Non Coding Rnas ◽

Regulatory Functions

Exosomes are small vesicles derived from cells used as cell-to-cell communication goods in numerous diseases including tumorigenesis, neurological diseases, cardiovascular diseases and other diseases. Circular RNAs (circRNAs) are an innovative constituent of non-coding endogenous RNAs generated through backsplicing, catalyzed by RNA polymerase Ⅱ. These non-coding RNAs have been suggested to control gene expression through miRNA sponging, RNA-binding protein regulation and translational capabilities. Genome-wide RNA sequence analyses observed that circRNAs were stably improved in exosomes in association to parental cells. Little attention has been dedicated to exosomal circRNAs (exo-circRNAs). However, research has demonstrated that exo-circRNAs may have important regulatory functions because of their stability in cells and within exosomes. If well understood, the precise roles and mechanisms of exo-circRNAs might surge the impending clinical applications of these molecules as markers in the identification, prediction and treatment of various diseases. In this review, we outline recent findings regarding exo-circRNAs which includes their functions and highlights their potential applications and therapeutic targets in human diseases.

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Circular RNAs: Their Role in the Pathogenesis and Orchestration of Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.647736 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiao He ◽

Tao Xu ◽

Weijie Hu ◽

Yufang Tan ◽

Dawei Wang ◽

...

Keyword(s):

Breast Cancer ◽

Target Gene ◽

Evolutionary Conservation ◽

Therapeutic Strategies ◽

Circular Rnas ◽

Therapeutic Resistance ◽

Transcriptional Level ◽

Metastatic Progression ◽

Single Chain ◽

Non Coding Rnas

As one of the most frequently occurring malignancies in women, breast cancer (BC) is still an enormous threat to women all over the world. The high mortality rates in BC patients are associated with BC recurrence, metastatic progression to distant organs, and therapeutic resistance. Circular RNAs (circRNAs), belonging to the non-coding RNAs (ncRNAs), are connected end to end to form covalently closed single-chain circular molecules. CircRNAs are widely found in different species and a variety of human cells, with the features of diversity, evolutionary conservation, stability, and specificity. CircRNAs are emerging important participators in multiple diseases, including cardiovascular disease, inflammation, and cancer. Recent studies have shown that circRNAs are involved in BC progress by regulating gene expression at the transcriptional or post-transcriptional level via binding to miRNAs then inhibiting their function, suggesting that circRNAs may be potential targets for early diagnosis, treatment, and prognosis of BC. Herein, in this article, we have reviewed and summarized the current studies about the biogenesis, features, and functions of circRNAs. More importantly, we emphatically elucidate the pivotal functions and mechanisms of circRNAs in BC growth, metastasis, diagnosis, and drug resistance. Deciphering the complex networks, especially the circRNA-miRNA target gene axis, will endow huge potentials in developing therapeutic strategies for combating BC.

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Circular RNAs Sparkle in the Diagnosis and Theranostics of Hepatocellular Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.628655 ◽

2021 ◽

Vol 11 ◽

Author(s):

Menglan Wang ◽

Minjie Wu ◽

Tian Xie ◽

Jianxiang Chen

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Diagnosis ◽

Potential Application ◽

Body Fluid ◽

Closed Loop ◽

High Specificity ◽

Host Gene ◽

Circular Rnas ◽

Scientific Interest ◽

Non Coding Rnas

Exonic circular RNAs (circRNAs) are a novel subgroup of non-coding RNAs, which are generated by a back-splicing mechanism of the exons or introns. Unlike the linear RNA, circRNA forms a covalently closed loop, and it normally appears more abundant than the linear products of its host gene. Due to the relatively high specificity and stability of circular RNAs in tissues and body fluid, circular RNAs have attracted widely scientific interest for its potential application in cancer diagnosis and as a guide for preclinical therapy, especially for hard-to-treat cancers with high heterogeneity, such as hepatocellular carcinoma (HCC). Thus, we summarize the updated knowledge of circular RNAs, including the mechanism of the generation of endogenous circular RNAs and their regulatory, diagnostic, and therapeutic roles in HCC.

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Vitamin D and non-coding RNAs: new insights into the regulation of breast cancer

Current Molecular Medicine ◽

10.2174/1566524020666200712182137 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mohammad Karim Shahrzad ◽

Reyhaneh Gharehgozlou ◽

Sara Fadaei ◽

Parastoo Hajian ◽

Hamid Reza Mirzaei

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Cancer Therapy ◽

Circular Rnas ◽

Cancer Etiology ◽

Life Threatening ◽

Non Coding Rnas ◽

Incident Rate ◽

Serious Disease

: Breast cancer, a life-threatening serious disease with high incident rate among women, is responsible for thousands of cancer-associated death worldwide. Numerous investigations have been evaluated the possible mechanisms related to this malignancy. Among of them, non-coding RNAs (ncRNAs) i.e., microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have recently attracted attentions of researchers. In addition to recent studies for evaluating the role of ncRNAs in breast cancer etiology, some investigations have revealed that vitamin D has regulatory and therapeutic roles in breast cancer. Moreover, an important link between vitamin D and ncRNAs in cancer therapy has been highlighted. Herein, we aimed to discuss the available data on mentioned link in breast cancer.

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Comprehensive Transcriptomic Analysis Reveals Dysregulated Competing Endogenous RNA Network in Endocrine Resistant Breast Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2020.600487 ◽

2020 ◽

Vol 10 ◽

Author(s):

Liang Gao ◽

Kunwei Shen ◽

Ni Yin ◽

Min Jiang

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Endocrine Therapy ◽

Breast Cancer Cells ◽

Regulatory Networks ◽

Endocrine Resistance ◽

Differentially Expressed ◽

Circular Rnas ◽

Competing Endogenous Rna ◽

Non Coding Rnas

BackgroundTamoxifen and fulvestrant, both approved for endocrine therapy, have remarkably increased the prognosis of hormone receptor-positive breast cancer patients. However, acquired resistance to endocrine therapy greatly reduces its clinical efficacy. Accumulating evidence suggests a pivotal role of non-coding RNAs (ncRNAs) in breast cancer endocrine resistance, but the specific functions of ncRNAs in tamoxifen and fulvestrant resistance remain largely unknown.MethodsMicroarray analysis was performed for endocrine therapy sensitive (MCF-7), tamoxifen-resistant (LCC2), and dual tamoxifen and fulvestrant-resistant (LCC9) breast cancer cells. Gene ontology and pathway analysis were conducted for functional prediction of the unannotated differentially expressed ncRNAs. Competing endogenous RNA regulatory networks were constructed.ResultsWe discovered a total of 3,129 long non-coding RNAs (lncRNAs), 13,556 circular RNAs (circRNAs), 132 microRNAs, and 3358 mRNAs that were significantly differentially expressed. We constructed co-expression networks for lncRNA-mRNA, circRNA-mRNA, and microRNA-mRNA. In addition, we established lncRNA-microRNA-mRNA and circRNA-microRNA-mRNA regulatory networks to depict ncRNA crosstalk and transcriptomic regulation of endocrine resistance.ConclusionsOur study delineates a comprehensive profiling of ncRNAs in tamoxifen and fulvestrant resistant breast cancer cells, which enriches our understanding of endocrine resistance and sheds new light on identifying novel endocrine resistance biomarkers and potential therapeutic targets to overcome endocrine resistance.

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