The Emerging Roles of circFOXO3 in Cancer

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs which are mainly formed by reverse splicing of precursor mRNAs. They are relatively stable and resistant to RNase R because of their covalently closed structure without 5’ caps or 3’ poly-adenylated tails. CircRNAs are widely expressed in eukaryotic cells and show tissue, timing, and disease specificity. Recent studies have found that circRNAs play an important role in many diseases. In particular, they affect the proliferation, invasion and prognosis of cancer by regulating gene expression. CircRNA Forkhead box O3 (circFOXO3) is a circRNA confirmed to be abnormally expressed in a variety of cancers, including prostate cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, and breast cancer, etc. At present, the feature of circFOXO3 as a molecular sponge is widely studied to promote or inhibit the development of cancers. However, the diverse functions of circFOXO3 have not been fully understood. Hence, it is important to review the roles of circFOXO3 in cancers. This review has summarized and discussed the roles and molecular mechanism of circFOXO3 and its target genes in these cancers, which can help to enrich our understanding to the functions of circRNAs and carry out subsequent researches on circFOXO3.

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The emerging role of circular RNAs in breast cancer

Bioscience Reports ◽

10.1042/bsr20190621 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 7

Author(s):

Si-ying Zhou ◽

Wei Chen ◽

Su-jin Yang ◽

Zi-han Xu ◽

Jia-hua Hu ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Invasion ◽

Clinical Characteristics ◽

Circular Rnas ◽

Rnase R ◽

New Class ◽

Regulatory Rnas ◽

And Function

AbstractBreast cancer (BCa) is one of the most frequently diagnosed cancers and leading cause of cancer deaths among females worldwide. Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by circular shape resulting from covalently closed continuous loops that are capable of regulating gene expression at transcription or post-transcription levels. With the unique structures, circRNAs are resistant to exonuclease RNase R and maintain stability more easily than linear RNAs. Recently, an increasing number of circRNAs are discovered and reported to show different expression in BCa and these dysregulated circRNAs were correlated with patients’ clinical characteristics and grade in the progression of BCa. CircRNAs participate in the bioprocesses of carcinogenesis of BCa, including cell proliferation, apoptosis, cell cycle, tumorigenesis, vascularization, cell invasion, migration as well as metastasis. Here we concentrated on biogenesis and function of circRNAs, summarized their implications in BCa and discussed their potential as diagnostic and therapeutic targets for BCa.

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Comprehensive analysis of long noncoding RNA expression in circulation of breast cancer patients on neoadjuvant therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12644 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12644-e12644

Author(s):

Boris Krastev ◽

Constanta Timcheva ◽

Spartak Valev ◽

Georgi Zhbantov ◽

Ivaylo Stoykov ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Therapy ◽

Cancer Patients ◽

Expression Analysis ◽

Cancer Biology ◽

Target Genes ◽

Locally Advanced ◽

Breast Cancer Patients ◽

Non Coding Rnas

e12644 Background: Though long considered “nonfunctional”, recent evidence is growing that non-coding RNAs, including long non-coding RNAs (lncRNAs), have an active role in tumor biology, mainly as gene expression regulators. Breast cancer is heterogeneous in nature and locally advanced cases are distinct entity in terms of curability. Being borderline between early and metastatic disease, long-term outcome here strongly depends on the efficacy of systemic therapy. To the best of our knowledge, no study has yet investigated global changes of circulating lncRNAs in this patient population during preoperative (neoadjuvant) treatment. Methods: We conducted a small transcriptomic trial on 10 locally advanced breast cancer patients, assessing lncRNA and messenger RNA (mRNA) expression in plasma samples before (S1) and after (S2) initiation of neoadjuvant therapy. Next-generation sequencing was performed with differential gene expression analysis between S1 and S2 groups. We assessed co-expression between lncRNAs and mRNAs, identifying mRNAs whose transcription was potentially regulated by lncRNAs, i.e. “lncRNA target genes”. In order to elucidate biological roles of these target mRNAs, we performed gene ontology (GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results: 394 lncRNAs and 1085 mRNAs demonstrated statistically significant difference in expression between pretreatment and posttreatment samples. Co-expression analysis revealed positive correlation between 25 lncRNAs and 25 mRNAs located in cis, while potential trans interactions exceeded 105. GO evaluation of lncRNA target genes was significant for 44 terms: 28 for biological process (BP), 9 for cellular component (CC) and 7 for molecular function (MF). The most annotated terms for BP, MF and CC were respectively biosynthetic process, DNA-binding transcription factor activity and nucleus. KEGG analysis showed that 105 of 201 analyzed pathways were statistically significant with most prominent being pathways in cancer and transcriptional misregulation in cancer. Conclusions: Despite limited in size, present study provides broad view on transcriptional landscape in blood circulation, interrogating in vivo dynamics of systemic gene expression during neoadjuvant breast cancer treatment. It demonstrates that substantial number of circulating lncRNAs could be up- or downregulated in the course of therapy and this has the potential to control protein-coding genes that are tightly implicated in cancer biology.

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

Non-Coding RNA ◽

10.3390/ncrna7010002 ◽

2021 ◽

Vol 7 (1) ◽

pp. 2

Author(s):

Debina Sarkar ◽

Sarah D. Diermeier

Keyword(s):

Breast Cancer ◽

Translational Regulation ◽

Closed Loop ◽

Mechanisms Of Action ◽

Circular Rnas ◽

Therapeutic Approaches ◽

Mirna Sponge ◽

Bodily Fluids ◽

Potential Applications ◽

Non Coding Rnas

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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Alterations of Growth and Focal Adhesion Molecules in Human Breast Cancer Cells Exposed to the Random Positioning Machine

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.672098 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jayashree Sahana ◽

Thomas J. Corydon ◽

Markus Wehland ◽

Marcus Krüger ◽

Sascha Kopp ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Target Genes ◽

Interaction Analysis ◽

Expression Patterns ◽

Focal Adhesions ◽

Multicellular Spheroids ◽

Down Regulation ◽

Random Positioning Machine ◽

Mcf 7

In this study, we evaluated changes in focal adhesions (FAs) in two types of breast cancer cell (BCC) lines (differentiated MCF-7 and the triple-negative MDA-MB-231 cell line) exposed to simulated microgravity (s-μg) created by a random positioning machine (RPM) for 24 h. After exposure, the BCC changed their growth behavior and exhibited two phenotypes in RPM samples: one portion of the cells grew as a normal two-dimensional monolayer [adherent (AD) BCC], while the other portion formed three-dimensional (3D) multicellular spheroids (MCS). After 1 h and 30 min (MDA-MB-231) and 1 h 40 min (MCF-7), the MCS adhered completely to the slide flask bottom. After 2 h, MDA-MB-231 MCS cells started to migrate, and after 6 h, a large number of the cells had left the MCS and continued to grow in a scattered pattern, whereas MCF-7 cells were growing as a confluent monolayer after 6 h and 24 h. We investigated the genes associated with the cytoskeleton, the extracellular matrix and FAs. ACTB, TUBB, FN1, FAK1, and PXN gene expression patterns were not significantly changed in MDA-MB-231 cells, but we observed a down-regulation of LAMA3, ITGB1 mRNAs in AD cells and of ITGB1, TLN1 and VCL mRNAs in MDA-MB-231 MCS. RPM-exposed MCF-7 cells revealed a down-regulation in the gene expression of FAK1, PXN, TLN1, VCL and CDH1 in AD cells and PXN, TLN and CDH1 in MCS. An interaction analysis of the examined genes involved in 3D growth and adhesion indicated a central role of fibronectin, vinculin, and E-cadherin. Live cell imaging of eGFP-vinculin in MCF-7 cells confirmed these findings. β-catenin-transfected MCF-7 cells revealed a nuclear expression in 1g and RPM-AD cells. The target genes BCL9, MYC and JUN of the Wnt/β-catenin signaling pathway were differentially expressed in RPM-exposed MCF-7 cells. These findings suggest that vinculin and β-catenin are key mediators of BCC to form MCS during 24 h of RPM-exposure.

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Circular RNAs as microRNA sponges: evidence and controversies

Essays in Biochemistry ◽

10.1042/ebc20200060 ◽

2021 ◽

Author(s):

Morten T. Jarlstad Olesen ◽

Lasse S. Kristensen

Keyword(s):

Gene Regulation ◽

Target Genes ◽

Research Field ◽

Circular Rnas ◽

Transcriptional Level ◽

Additional Layer ◽

Complex Process ◽

Non Coding Rnas ◽

New Research ◽

Microrna Sponges

Abstract Gene expression in eukaryotic cells is a complex process encompassing several layers of regulation at the transcriptional and post-transcriptional levels. At the post-transcriptional level, microRNAs (miRs) are key regulatory molecules that function by binding directly to mRNAs. This generally leads to less efficient translation of the target mRNAs. More recently, an additional layer of gene regulation has been discovered, as other molecules, including circular RNAs (circRNAs), may bind to miRs and thereby function as sponges or decoys resulting in increased expression of the corresponding miR target genes. The circRNAs constitute a large class of mainly non-coding RNAs, which have been extensively studied in recent years, in particular in the cancer research field where many circRNAs have been proposed to function as miR sponges. Here, we briefly describe miR-mediated gene regulation and the extra layer of regulation that is imposed by the circRNAs. We describe techniques and methodologies that are commonly used to investigate potential miR sponging properties of circRNAs and discuss major pitfalls and controversies within this relatively new research field.

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Role of MicroRNAs and Long Non-Coding RNAs in Regulating Angiogenesis in Human Breast Cancer- A Molecular Medicine Perspective

Current Molecular Medicine ◽

10.2174/1566524022666211217114527 ◽

2021 ◽

Vol 22 ◽

Author(s):

Vandana Golhani ◽

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Signaling Pathways ◽

Cancer Therapeutics ◽

Molecular Medicine ◽

Dependent Manner ◽

Protein Coding ◽

Controlled Systems ◽

Expression Of Genes ◽

Non Coding Rnas

: MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are proficient in regulating gene expression post-transcriptionally. Considering the recent trend in exploiting non-coding RNAs (ncRNAs) as cancer therapeutics, the potential use of miRNAs and lncRNAs as biomarkers and novel therapeutic agents against angiogenesis is an important scientific aspect. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein, and are of utmost importance and it governs the expression of genes in a temporal, spatial, and cell context-dependent manner. Angiogenesis is an essential process for organ morphogenesis and growth during development, and it is relevant during the repair of wounded tissue in adults. It is coordinated by an equilibrium of pro-and anti-angiogenic factors; nevertheless, when affected, it promotes several diseases, including breast cancer. Signaling pathways involved here are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Lately, scientific reports are indicating that ncRNAs, such as miRNAs, and lncRNAs, play critical roles in angiogenesis related to breast cancer. The specific roles of various miRNAs and lncRNAs in regulating angiogenesis in breast cancer, with particular focus on the downstream targets and signaling pathways regulated by these ncRNAs with molecular medicine perspective, are highlighted in this write-up.

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Gene expression of indoleamine and tryptophan dioxygenases and three long non-coding RNAs in breast cancer

Experimental and Molecular Pathology ◽

10.1016/j.yexmp.2020.104415 ◽

2020 ◽

Vol 114 ◽

pp. 104415 ◽

Cited By ~ 1

Author(s):

Soudeh Ghafouri-Fard ◽

Zahra Taherian-Esfahani ◽

Sepideh Dashti ◽

Vahid Kholghi Oskooei ◽

Mohammad Taheri ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Non Coding Rnas

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Genome-wide DNA methylome analysis reveals novel epigenetically dysregulated non-coding RNAs in human breast cancer

10.1101/002204 ◽

2014 ◽

Author(s):

Yongsheng Li ◽

Yunpeng Zhang ◽

Shengli Li ◽

Jianping Lu ◽

Juan Chen ◽

...

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Target Genes ◽

Cpg Islands ◽

Aberrant Methylation ◽

Breast Cancers ◽

Human Breast ◽

Protein Coding ◽

Methylome Analysis ◽

Non Coding Rnas

The development of human breast cancer is driven by changes in the genetic and epigenetic landscape of the cell. Despite growing appreciation of the importance of epigenetics in breast cancers, our knowledge of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancers remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers via a sequencing-based comparative methylome analysis, mainly focusing on two most popular ncRNA biotypes, long non-coding RNAs (lncRNAs) and miRNAs. Besides global hypomethylation and extensive CpG islands (CGIs) hypermethylation, we observed widely aberrant methylation in the promoters of ncRNAs, which was higher than that of protein-coding genes. Specifically, intergenic ncRNAs were observed to contribute a large slice of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of ncRNA promoter aberrant methylation in the context of genomic CGIs, where aberrant methylation occurred not only on the CGIs, but also flanking regions and CGI sparse promoters. Integration with transcriptional datasets, we found that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that were able to discriminate between disease phenotypes (AUCs>0.90). Finally, the potential functions for aberrantly methylated ncRNAs were predicted based on similar patterns, adjacency and/or target genes, highlighting that ncRNAs and coding genes coordinately mediated pathways dysregulation in the development and progression of breast cancers. This study presents the aberrant methylation patterns of ncRNAs, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancers.

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Circular RNA Foxo3: A Promising Cancer-Associated Biomarker

Frontiers in Genetics ◽

10.3389/fgene.2021.652995 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tianli Yang ◽

Yang Li ◽

Feng Zhao ◽

Liuhua Zhou ◽

Ruipeng Jia

Keyword(s):

Cancer Diagnosis ◽

Circular Rna ◽

Clinical Applications ◽

Lymphocytic Leukemia ◽

Circular Rnas ◽

Biological Processes ◽

Diagnosis And Prognosis ◽

Forkhead Box ◽

Non Coding Rnas ◽

Downstream Gene Expression

Circular RNAs (circRNAs) are a class of novel non-coding RNAs (ncRNAs). Emerging evidence demonstrates that circRNAs play crucial roles in many biological processes by regulating linear RNA transcription, downstream gene expression and protein or peptide translation. Meanwhile, recent studies have suggested that circRNAs have the potential to be oncogenic or anti-oncogenic and play vital regulatory roles in the initiation and progression of tumors. Circular RNA Forkhead box O3 (circ-Foxo3, hsa_circ_0006404) is encoded by the human FOXO3 gene and is one of the most studied circular RNAs acting as a sponge for potential microRNAs (miRNAs) (Du et al., 2016). Previous studies have reported that circ-Foxo3 is involved in the development and tumorigenesis of a variety of cancers (bladder, gastric, acute lymphocytic leukemia, glioma, etc.). In this review, we summarize the current studies concerning circ-Foxo3 deregulation and the correlative mechanism in various human cancers. We also point out the potential clinical applications of this circRNA as a biomarker for cancer diagnosis and prognosis.

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