266 results on '"Burton B. Yang"'
Search Results
2. Aggravated Ulcerative Colitis via circNlgn-Mediated Suppression of Nuclear Actin Polymerization
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William W. Du, Chi Zhou, Hui Yang, Shuoyang Wen, Yu Chen, Eric X. Chen, Xiuwei H. Yang, Feiya Li, Kevin Y. Du, Hui Yuan, Ting Ye, Javeria Qadir, and Burton B. Yang
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Science - Abstract
Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.
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- 2024
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3. A Novel Circular RNA circITGa9 Predominantly Generated in Human Heart Disease Induces Cardiac Remodeling and Fibrosis
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Feiya Li, William W. Du, Xiangmin Li, Jindong Xu, Nan Wu, Faryal Mehwish Awan, Yang Yang, Fariborz Asghari Alashti, Sheng Wang, and Burton B. Yang
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Science - Abstract
Recent studies have highlighted the pivotal roles of circular RNAs (circRNAs) in cardiovascular diseases. Through high-throughput circRNA sequencing of both normal myocardial tissues and hypertrophic patients, we unveiled 32,034 previously undiscovered circRNAs with distinct cardiac expression patterns. Notably, circITGa9, a circRNA derived from integrin-α9, exhibited substantial up-regulation in cardiac hypertrophy patients. This elevation was validated across extensive sample pools from cardiac patients and donors. In vivo experiments revealed heightened cardiac fibrosis in mice subjected to transverse aortic constriction (TAC) after circITGa9 injection. We identified circITGa9 binding proteins through circRNA precipitation followed by liquid chromatography tandem-mass spectrometry. Furthermore, circRNA pull-down/precipitation assays demonstrated that increased circITGa9 expression facilitated binding with tropomyosin 3 (TPM3). Specific binding sites between circITGa9 and TPM3 were identified through computational algorithms and further validated by site-directed mutagenesis. We further showed that circITGa9 induced actin polymerization, characteristic of tissue fibrosis. Finally, we developed approaches that improved cardiac function and decreased fibrosis by delivering small interfering RNA targeting circITGa9 or blocking oligo inhibiting the interaction of circITGa9 and TPM3 into TAC mice, which is amenable for further preclinical and translational development. We conclude that elevated circITGa9 levels drive cardiac remodeling and fibrosis. By pinpointing circITGa9 as a therapeutic target, we open doors to innovative interventions for mitigating cardiac remodeling and fibrosis.
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- 2024
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4. Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies
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Ying Wei, Sonia Erfani, David Schweer, Rafael de Gouvea, Javeria Qadir, Junfeng Shi, Kai Cheng, Dabao Wu, Rolf Craven, Yadi Wu, Thibault Olivier, Lauren A. Baldwin, Binhua Zhou, Ying Zhou, Weidong Zhao, Burton B. Yang, Frederick R. Ueland, and Xiuwei H. Yang
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ovarian cancer ,receptor tyrosine kinases ,EGFR ,ERBB2 ,MET ,VEGFR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide. Receptor tyrosine kinases (RTKs) have long been sought as therapeutic targets for EOC, as they are frequently hyperactivated in primary tumors and drive disease relapse, progression, and metastasis. More recently, these oncogenic drivers have been implicated in EOC response to poly(ADP-ribose) polymerase (PARP) inhibitors and epigenome-interfering agents. This evidence revives RTKs as promising targets for therapeutic intervention of EOC. This review summarizes recent studies on the role of RTKs in EOC malignancy and the use of their inhibitors for clinical treatment. Our focus is on the ERBB family, c-Met, and VEGFR, as they are linked to drug resistance and targetable using commercially available drugs. The importance of these RTKs and their inhibitors is highlighted by their impact on signal transduction and intratumoral heterogeneity in EOC and successful use as maintenance therapy in the clinic through suppression of the VEGF/VEGFR axis. Finally, the therapeutic potential of RTK inhibitors is discussed in the context of combinatorial targeting via co-inhibiting proliferative and anti-apoptotic pathways, epigenomic/transcriptional programs, and harnessing the efficacy of PARP inhibitors and programmed cell death 1/ligand 1 immune checkpoint therapies.
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- 2023
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5. Nuclear Actin Polymerization Regulates Cell Epithelial‐Mesenchymal Transition
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William W. Du, Javeria Qadir, Kevin Y. Du, Yu Chen, Nan Wu, and Burton B. Yang
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actin polymerization ,epithelial‐mesenchymal transition ,nuclear actin ,transcription factor ,wound healing ,Science - Abstract
Abstract Current studies on actin function primarily rely on cytoplasmic actin due to the absence of cellular models specifically expressing nuclear actin. Here, cell models capable of expressing varying levels of nuclear F/G‐actin are generated and a significant role of nuclear actin in the regulation of epithelial‐mesenchymal transition (EMT) is uncovered. Through immunoprecipitation and mass spectrometry analyses, distinct binding partners for nuclear F‐actin (β‐catenin, SMAD2, and SMAD3) and nuclear G‐actin (MYBBP1A, NKRF, and MYPOP) are investigated, which respectively modulate EMT‐promoting and EMT‐repressing transcriptional events. While nuclear F‐actin promotes EMT with enhanced cell migration, survival, and elongated mesenchymal morphology, nuclear G‐actin represses EMT and related cell activities. Mechanistically, nuclear F‐actin enhances β‐catenin, SMAD2, and SMAD3 expression and stability in the nuclei, while nuclear G‐actin increases MYBBP1A, NKRF, and MYPOP expression and stability in the nuclei. The association between nuclear F/G‐actin and N‐cadherin/E‐cadherin in the cell lines (in vitro), and increased nuclear actin polymerization in the wound healing cells (in vivo) affirm a significant role of nuclear actin in EMT regulation. With evidence of nuclear actin polymerization and EMT during development, and irregularities in disease states such as cancer and fibrosis, targeting nuclear actin dynamics to trigger dysregulated EMT warrants ongoing study.
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- 2023
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6. An Improved Model for Circular RNA Overexpression: Using the Actin Intron Reveals High Circularization Efficiency
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Feiya Li, Juanjuan Lyu, Yang Yang, Qiwei Yang, Cristian Santos, and Burton B. Yang
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actin intron ,circRNA ,circular RNA ,overexpression ,splicing factor ,T4 intron ,Genetics ,QH426-470 - Abstract
Abstract Traditionally, the group 1 intron of the T4 td gene is used to generate a foreign circular sequence. However, the T4 system has been shown to be fairly inefficient in expressing circular RNA (circRNA). Here, a new method is developed to express circular sequences with high circularization efficiency to strengthen the confidence for future circRNA functional studies. CircRNA expression plasmids, constructed with different lengths derived from the actin intron (15‐nt, 30‐nt, 60‐nt, 100‐nt, 180‐nt) and T4 intron, are introduced into human and mouse cell lines 293T and B16. Junction detection and sequencing are used to determine successful circularization of introns and their expression efficiencies. An actin intron with a medium length (60‐nt–100‐nt) shows significantly increased efficiency of circularization, whereas intron‐100‐nt shows the best efficiency in most conditions. RNA pull‐down assays are designed to precipitate the splicing factors that are bound to the introns and intron/exon junction. The precipitated proteins are analyzed by mass spectrometry (MS), aiming to identify the possible underlying mechanism behind the high circularization efficiency. This expression system has been validated using different circRNAs, and such method shows potential in contributing to the expanding field of circRNA studies.
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- 2023
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7. The circular RNA circNlgnmediates doxorubicin-inducedcardiac remodeling and fibrosis
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Jindong Xu, William W. Du, Nan Wu, Feiya Li, Xiangmin Li, Yizhen Xie, Sheng Wang, and Burton B. Yang
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Non-coding RNAs ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Doxorubicin is a chemotherapeutic medication commonly used to treat many types of cancers, but it has side effects including vomiting, rash, hair loss, and bone marrow suppression. The most dangerous side effects are cardiomyopathy, cardiofibrosis, and heart failure, as doxorubicin generates cytotoxicity and stops DNA replication. There is no treatment to block these side effects. We have developed a transgenic mouse line overexpressing the circular RNA circNlgn and shown that circNlgn is a mediator of doxorubicin-induced cardiofibrosis. Increased expression of circNlgn decreased cardiac function and induced cardiofibrosis by upregulating Gadd45b, Sema4C, and RAD50 and activating p38 and pJNK in circNlgn transgenic heart. Silencing circNlgn decreased the effects of doxorubicin on cardiac cell activities and prevented doxorubicin-induced expression of fibrosis-associated molecules. The protein (Nlgn173) translated by circNlgn could bind and activate H2AX, producing γH2AX, resulting in upregulation of IL-1b, IL-2Rb, IL-6, EGR1, and EGR3. We showed that silencing these molecules in the signaling pathway prevented doxorubicin-induced cardiomyocyte apoptosis, increased cardiomyocyte viability, decreased cardiac fibroblast proliferation, and inhibited collagen production. This mechanism may hold therapeutic implications for mitigating the side effects of doxorubicin therapy in cancer patients.
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- 2022
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8. Promotion of tumor progression by exosome transmission of circular RNA circSKA3
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William W. Du, Xiangmin Li, Jian Ma, Ling Fang, Nan Wu, Feiya Li, Preet Dhaliwal, Weining Yang, Albert J. Yee, and Burton B. Yang
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circular RNA ,circSKA3 ,SKA3 ,integrin beat 1 ,invadopodia ,heterogenecity ,Therapeutics. Pharmacology ,RM1-950 - Abstract
We performed in vitro and in vivo experiments to investigate the role of the circular RNA circSKA3 in tumor development. We examined the effects of circSKA3 on mediating breast cancer metastasis. In vitro, we found that the circular RNA circSKA3 was transferred between breast cancer cells, which were decreased by inhibiting exosome secretion. In vivo, circSKA3-containing exosomes potentiated tumor development and invasion that were inhibited by blocking exosome transmission. The ascites isolated from tumor-bearing mice or breast cancer patients showed high levels of circSKA3 and integrin β1. Single-cell culture and single-cell PCR showed that circSKA3 was heterogeneously expressed, the cells expressing higher levels of circSKA3 had a higher potential to form large colonies. This property was similar to c-myc, but circSKA3 expression had no correlation with c-myc levels. The effects of circSKA3 on cell migration and invasion appeared to predominate c-myc functions. By releasing circSKA3-containing exosomes to cancer cells expressing lower levels of circSKA3, the large colonies could regulate the activities of small colonies, enhancing the tumor-forming capacity of the entire population. Thus, we provide evidence that the transmission of circular RNAs in tumor-derived exosomes may allow for the maintenance of advantageous invasive sub-clones in breast cancer.
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- 2022
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9. Mapping CircRNA–miRNA–mRNA regulatory axis identifies hsa_circ_0080942 and hsa_circ_0080135 as a potential theranostic agents for SARS-CoV-2 infection
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Hassan Ayaz, Nouman Aslam, Faryal Mehwish Awan, Rabea Basri, Bisma Rauff, Badr Alzahrani, Muhammad Arif, Aqsa Ikram, Ayesha Obaid, Anam Naz, Sadiq Noor Khan, Burton B. Yang, and Azhar Nazir
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Medicine ,Science - Abstract
Non-coding RNAs (ncRNAs) can control the flux of genetic information; affect RNA stability and play crucial roles in mediating epigenetic modifications. A number of studies have highlighted the potential roles of both virus-encoded and host-encoded ncRNAs in viral infections, transmission and therapeutics. However, the role of an emerging type of non-coding transcript, circular RNA (circRNA) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has not been fully elucidated so far. Moreover, the potential pathogenic role of circRNA-miRNA-mRNA regulatory axis has not been fully explored as yet. The current study aimed to holistically map the regulatory networks driven by SARS-CoV-2 related circRNAs, miRNAs and mRNAs to uncover plausible interactions and interplay amongst them in order to explore possible therapeutic options in SARS-CoV-2 infection. Patient datasets were analyzed systematically in a unified approach to explore circRNA, miRNA, and mRNA expression profiles. CircRNA-miRNA-mRNA network was constructed based on cytokine storm related circRNAs forming a total of 165 circRNA-miRNA-mRNA pairs. This study implies the potential regulatory role of the obtained circRNA-miRNA-mRNA network and proposes that two differentially expressed circRNAs hsa_circ_0080942 and hsa_circ_0080135 might serve as a potential theranostic agents for SARS-CoV-2 infection. Collectively, the results shed light on the functional role of circRNAs as ceRNAs to sponge miRNA and regulate mRNA expression during SARS-CoV-2 infection.
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- 2023
10. Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases
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Rabea Basri, Faryal Mehwish Awan, Burton B. Yang, Usman Ayub Awan, Ayesha Obaid, Anam Naz, Aqsa Ikram, Suliman Khan, Ijaz ul Haq, Sadiq Noor Khan, and Muslim Bin Aqeel
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circRNAs ,autophagy ,neurodegeneration ,nervous system ,therapeutics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich’s ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.
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- 2023
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11. Design and use of a back splicing junction probe for pulldown of circular RNA-binding proteins in cell lines
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Feiya Li, Nan Wu, Qiwei Yang, William W. Du, Javeria Qadir, and Burton B. Yang
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RNAseq ,Molecular biology ,Molecular/Chemical probes ,Science (General) ,Q1-390 - Abstract
Summary: Due to the unique structure of circular RNAs, it is challenging to use traditional pulldown approaches. Here, we describe the design and use of a probe that spans the back splicing junction (BSJ), enabling interaction with circular RNAs. The probe repeats four times, allowing efficient and specific pulldown of circular RNAs and their binding partners. This protocol describes the steps for mouse cardiac fibroblast (MCF) cells; we have also verified the protocol in other cell types.For complete details on the use and execution of this protocol, please refer to Wu et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
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- 2022
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12. Targeting circular RNAs as a therapeutic approach: current strategies and challenges
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Alina T. He, Jinglei Liu, Feiya Li, and Burton B. Yang
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Medicine ,Biology (General) ,QH301-705.5 - Abstract
Abstract Significant progress has been made in circular RNA (circRNA) research in recent years. Increasing evidence suggests that circRNAs play important roles in many cellular processes, and their dysregulation is implicated in the pathogenesis of various diseases. CircRNAs are highly stable and usually expressed in a tissue- or cell type-specific manner. Therefore, they are currently being explored as potential therapeutic targets. Gain-of-function and loss-of-function approaches are typically performed using circRNA expression plasmids and RNA interference-based strategies, respectively. These strategies have limitations that can be mitigated using nanoparticle and exosome delivery systems. Furthermore, recent developments show that the cre-lox system can be used to knockdown circRNAs in a cell-specific manner. While still in the early stages of development, the CRISPR/Cas13 system has shown promise in knocking down circRNAs with high specificity and efficiency. In this review, we describe circRNA properties and functions and highlight their significance in disease. We summarize strategies that can be used to overexpress or knockdown circRNAs as a therapeutic approach. Lastly, we discuss major challenges and propose future directions for the development of circRNA-based therapeutics.
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- 2021
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13. Rapid Development of Targeting circRNAs in Cardiovascular Diseases
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Chao Zhang, Si Tong Huo, Zhiyong Wu, Lina Chen, Chang Wen, Honghao Chen, William W. Du, Nan Wu, Daogang Guan, Sen Lian, and Burton B. Yang
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Circular RNAs (circRNAs) are circularized, single-stranded RNAs that are covalently linked. With their abundance in tissues and developmental stage-specific expression, circRNAs participate in a variety of physiological and pathological processes. In this review, we discuss the development of circRNAs used as biomarkers and therapeutic targets for cardiovascular diseases (CVDs), focusing on recent discoveries and applications of exosomal circRNAs that highlight opportunities and challenges. Some studies have identified a spectrum of circRNAs that are differentially expressed in CVDs, while other studies further manipulated specific circRNA expression and showed an ameliorated pathogenic state such as ischemic injury, hypertrophy, and cardiac fibrosis. Studies and applications of circRNAs are being rapidly developed. We expect to see clinical use of circRNAs as biomarkers and targets for disease treatment in the near future.
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- 2020
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14. Overexpression of lncRNA EPB41L4A-AS1 Induces Metabolic Reprogramming in Trophoblast Cells and Placenta Tissue of Miscarriage
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Yuanchang Zhu, Qing Liu, Meijian Liao, Lianghui Diao, Tonghua Wu, Weijie Liao, Ziqiang Wang, Bing Li, Shikuan Zhang, Songmao Wang, Weidong Xie, Yuyang Jiang, Naihan Xu, Yong Zeng, Burton B. Yang, and Yaou Zhang
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment. Keywords: lncRNA EPB41L4A-AS1, HIF-1α, VDAC1, recurrent miscarriage, metabolic reprogramming
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- 2019
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15. Non-Coding RNAs in Invadopodia: New Insights Into Cancer Metastasis
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Feiya Li and Burton B. Yang
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invadopodia ,noncoding RNA ,ncRNA ,cancer metastasis ,circular RNA ,circRNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Invadopodia are actin-rich structures and their formation is implicated in cancer invasion and metastasis. Growing evidence has shown that noncoding RNAs (ncRNAs) play important roles in pathological conditions, including tumorigenesis and metastasis. Although this is still a new area of research, ncRNAs appear to be promising biomarkers and therapeutic targets for cancer metastasis. However, understanding the roles of ncRNAs in invadopodia is still in the early stages and far from clinical application. In this mini-review, we summarize the roles of ncRNAs in invadopodia functions and discuss them in a therapeutic context. The current challenges and gaps in this field are also raised, and we provide some open questions to facilitate new ideas in targeting invadopodia in anticancer therapy.
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- 2021
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16. LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2Research in context
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Meijian Liao, Weijie Liao, Naihan Xu, Bing Li, Fuhai Liu, Shikuan Zhang, Yanzhi Wang, Songmao Wang, Yuanchang Zhu, Deheng Chen, Weidong Xie, Yuyang Jiang, Liu Cao, Burton B. Yang, and Yaou Zhang
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. Methods: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. Findings: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. Interpretation: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer. Keywords: EPB41L4A-AS1, HDAC2, Glycolysis, Glutaminolysis, Cancer metabolism
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- 2019
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17. The pro-metastasis effect of circANKS1B in breast cancer
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Kaixuan Zeng, Bangshun He, Burton B. Yang, Tao Xu, Xiaoxiang Chen, Mu Xu, Xiangxiang Liu, Huiling Sun, Yuqin Pan, and Shukui Wang
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CircRNA ,Breast cancer ,Prognosis ,Metastasis ,EMT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer. Methods CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer. Results CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to-mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-β1 expression, resulting in activating TGF-β1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1. Conclusions Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis.
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- 2018
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18. Metabolic regulation of Ganoderma lucidum extracts in high sugar and fat diet-induced obese mice by regulating the gut-brain axis
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Chen Diling, Guo Yinrui, Qi Longkai, Tang Xiaocui, Liu Yadi, Feng Jiaxin, Zhu Xiangxiang, Zeng Miao, Shuai Ou, Wang Dongdong, Xie Yizhen, Burton B. Yang, and Wu Qingping
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Gut-liver axis ,Gut-brain axis ,Metabolic regulation ,Prebiotics ,Ganoderma lucidum ,Nutrition. Foods and food supply ,TX341-641 - Abstract
In this study, an obese mouse model was developed by administering a high sugar and fat diet for 60 days, followed by administration of a special dietary supplement of Ganoderma lucidum extract for another 35 days. Then, the changes in histopathology of the liver, adipose, colon, intestines, spleen, renal and brain tissues; metabolism and transcription; and gut microbiota were monitored. The results showed that alcohol extracts of the G. lucidum fruit body could reduce body weight; change the serum levels of lipid; ameliorate the damage to the gut microbiota, colon, liver, brain and other organs induced by the high sugar and fat diet; and activate the leptin regulatory pathways in the hypothalamus to improve metabolism. These findings indicate that administration of the alcohol extracts of the G. lucidum fruit body has beneficial effects on the microbiome-gut-liver and microbiome-gut-brain axes, and activates leptin-mediated signaling to improve metabolic regulation.
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- 2020
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19. A novel prognostic prediction tool for postoperative recurrence in patients with stage II/III colon cancer
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Jian Ma and Burton B. Yang
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2019
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20. Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents
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Guoxiao Lai, Yinrui Guo, Diling Chen, Xiaocui Tang, Ou Shuai, Tianqiao Yong, Dongdong Wang, Chun Xiao, Gailian Zhou, Yizhen Xie, Burton B. Yang, and Qingping Wu
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DNA methylation ,Ganoderma lucidum ,aging ,Alzheimer’s disease ,active ingredients ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Age-related changes in methylation are involved in the occurrence and development of tumors, autoimmune disease, and nervous system disorders, including Alzheimer’s disease (AD), in elderly individuals; hence, modulation of these methylation changes may be an effective strategy to delay the progression of AD pathology. In this study, the AD model rats were used to screen the main active extracts from the mushroom, Ganoderma lucidum, for anti-aging properties, and their effects on DNA methylation were evaluated. The results of evaluation of rats treated with 100 mg/kg/day of D-galactose to induce accelerated aging showed that alcohol extracts of G. lucidum contained the main active anti-aging extract. The effects on DNA methylation of these G. lucidum extracts were then evaluated using SAMP8 and APP/PS1 AD model mice by whole genome bisulfite sequencing, and some methylation regulators including Histone H3, DNMT3A, and DNMT3B in brain tissues were up-regulated after treatment with alcohol extracts from G. lucidum. Molecular docking analysis was carried out to screen for molecules regulated by specific components, including ganoderic acid Mk, ganoderic acid C6, and lucidone A, which may be active ingredients of G. lucidum, including the methylation regulators of Histone H3, MYT, DNMT3A, and DNMT3B. Auxiliary tests also demonstrated that G. lucidum alcohol extracts could improve learning and memory function, ameliorate neuronal apoptosis and brain atrophy, and down-regulate the expression of the AD intracellular marker, Aβ1-42. We concluded that alcohol extracts from G. lucidum, including ganoderic acid and lucidone A, are the main extracts involved in delaying AD progression.
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- 2019
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21. Correction: Versican G3 Domain Modulates Breast Cancer Cell Apoptosis: A Mechanism for Breast Cancer Cell Response to Chemotherapy and EGFR Therapy.
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William Weidong Du, Burton B. Yang, Bing L. Yang, Zhaoqun Deng, Ling Fang, Sze Wan Shan, Zina Jeyapalan, Yaou Zhang, Arun Seth, and Albert J. Yee
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Medicine ,Science - Published
- 2012
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22. An active ingredient isolated from Ganoderma lucidum promotes burn wound healing via TRPV1/SMAD signaling
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Chunwei Jiao, Hao Yun, Huijia Liang, Xiaodong Lian, Shunxian Li, Jiaming Chen, Javeria Qadir, Burton B. Yang, and Yizhen Xie
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Aging ,Cell Biology - Published
- 2022
23. Circular RNA translation: novel protein isoforms and clinical significance
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Shuo-yang Wen, Javeria Qadir, and Burton B. Yang
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Gene Expression Regulation ,Protein Biosynthesis ,Humans ,Protein Isoforms ,RNA ,Molecular Medicine ,RNA, Circular ,Internal Ribosome Entry Sites ,Molecular Biology - Abstract
In recent years, significant attention has focused on circular RNA (circRNA) translation to determine its clinical significance. Cap-independent translation of circRNAs driven by an internal ribosome entry site (IRES) or an N6-methyladenosine (m
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- 2022
24. Supplementary Figure Legend from The Role of Versican in Modulating Breast Cancer Cell Self-renewal
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Albert J. Yee, Burton B. Yang, Yaou Zhang, Arun Seth, Bing L. Yang, Wang Sheng, Xiangling Yang, Ling Fang, and William Weidong Du
- Abstract
PDF file - 85K
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- 2023
25. Supplementary Figures 1 - 8, Tables 1 - 2 from mda-7/IL-24 Expression Inhibits Breast Cancer through Upregulation of Growth Arrest-Specific Gene 3 (gas3) and Disruption of β1 Integrin Function
- Author
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Yaacov Ben-David, Michael C. Archer, Paul B. Fisher, Rupesh Dash, Qi Li, Burton B. Yang, Sze W. Shan, Eldad Zacksenhaus, Jeff C. Liu, Laura M. Vecchiarelli-Federico, Yanmei Li, Guodong Liu, and You-Jun Li
- Abstract
PDF file - 5906K, Supplemental Table I - Inhibition of mammary carcinogenesis in Wistar-Furth rats by mda-7/IL-24 Supplemental Table II - Microarray analysis of differential gene expression in FE1.2 + IL-24S compared to FE1.2 + IL-24AS cells. Supplemental Figure 1: Serum starvation induces GAS3 expression in both FE1.2 and FE1.3 cells. Supplemental Figure 2: GAS3 downregulation decreases the growth of cells in soft agar. Supplemental Figure 3: STAT3 inhibition reduced attachment of attaches cells to culture plates. Supplemental Figure 4: GAS3 expression reduced attachment of confluent cells to culture plates. Supplemental Figure 5: Binding of GAS3 to β1 integrin using immunoprecipitation assay. Supplemental Figure 6: GAS3 expression inhibits attachment to and proliferation on fibronectin coated culture plates. Supplemental Figure 7: GAS3 expression increases attachment to laminin coated culture plates. Supplemental Figure 8: GAS3 expression by immunohistochemistry.
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- 2023
26. Data from mda-7/IL-24 Expression Inhibits Breast Cancer through Upregulation of Growth Arrest-Specific Gene 3 (gas3) and Disruption of β1 Integrin Function
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Yaacov Ben-David, Michael C. Archer, Paul B. Fisher, Rupesh Dash, Qi Li, Burton B. Yang, Sze W. Shan, Eldad Zacksenhaus, Jeff C. Liu, Laura M. Vecchiarelli-Federico, Yanmei Li, Guodong Liu, and You-Jun Li
- Abstract
Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10−9), and the incidence of metastases is significantly reduced in patients with HER2+ breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin–fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy. Mol Cancer Res; 11(6); 593–603. ©2013 AACR.
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- 2023
27. Data from Characterization of the Oncogenic Activity of the Novel TRIM59 Gene in Mouse Cancer Models
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Jim W. Xuan, Fen Wang, Norman M. Greenberg, Burton B. Yang, Jonathan I. Izawa, Leda Raptis, Siu-Pok Yee, Madeleine Moussa, Ahmed Elmaadawi, Fei Jiang, and Fatma Valiyeva
- Abstract
A novel TRIM family member, TRIM59 gene was characterized to be upregulated in SV40 Tag oncogene–directed transgenic and knockout mouse prostate cancer models as a signaling pathway effector. We identified two phosphorylated forms of TRIM59 (p53 and p55) and characterized them using purified TRIM59 proteins from mouse prostate cancer models at different stages with wild-type mice and NIH3T3 cells as controls. p53/p55-TRIM59 proteins possibly represent Ser/Thr and Tyr phosphorylation modifications, respectively. Quantitative measurements by ELISA showed that the p-Ser/Thr TRIM59 correlated with tumorigenesis, whereas the p-Tyr-TRIM59 protein correlated with advanced cancer of the prostate (CaP). The function of TRIM59 was elucidated using short hairpin RNA (shRNA)-mediated knockdown of the gene in human CaP cells, which caused S-phase cell-cycle arrest and cell growth retardation. A hit-and-run effect of TRIM59 shRNA knockdown was observed 24 hours posttransfection. Differential cDNA microarrray analysis was conducted, which showed that the initial and rapid knockdown occurred early in the Ras signaling pathway. To confirm the proto-oncogenic function of TRIM59 in the Ras signaling pathway, we generated a transgenic mouse model using a prostate tissue–specific gene (PSP94) to direct the upregulation of the TRIM59 gene. Restricted TRIM59 gene upregulation in the prostate revealed the full potential for inducing tumorigenesis, similar to the expression of SV40 Tag, and coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag–mediated oncogenesis. The finding of a possible novel oncogene in animal models will implicate a novel strategy for diagnosis, prognosis, and therapy for cancer. Mol Cancer Ther; 10(7); 1229–40. ©2011 AACR.
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- 2023
28. Supplementary Figures 1 - 3 from The Role of Versican in Modulating Breast Cancer Cell Self-renewal
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Albert J. Yee, Burton B. Yang, Yaou Zhang, Arun Seth, Bing L. Yang, Wang Sheng, Xiangling Yang, Ling Fang, and William Weidong Du
- Abstract
PDF file - 269K, Figure S1. The mammosphere cells expressed high levels of versican V1, Sca-1, Sox2, and ALDH1. Figure S2. Versican G3 enhanced breast cancer colony formation. Figure S3. Expression of versican G3 domain promoted breast cancer cells expression of cell self-renewal markers.
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- 2023
29. Supplementary Methods, Figures 1-4, Tables 1-2 from Characterization of the Oncogenic Activity of the Novel TRIM59 Gene in Mouse Cancer Models
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Jim W. Xuan, Fen Wang, Norman M. Greenberg, Burton B. Yang, Jonathan I. Izawa, Leda Raptis, Siu-Pok Yee, Madeleine Moussa, Ahmed Elmaadawi, Fei Jiang, and Fatma Valiyeva
- Abstract
Supplementary Methods, Figures 1-4, Tables 1-2 from Characterization of the Oncogenic Activity of the Novel TRIM59 Gene in Mouse Cancer Models
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- 2023
30. Figure S4 from miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway
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Chun Peng, Sergey N. Krylov, Burton B. Yang, Basel Refky, Barbara C. Vanderhyden, Asma Amleh, Jelena Brkić, Gang Ye, Heba Shawer, Stefanie Bernaudo, Jacob A. O'Brien, and Mohamed Salem
- Abstract
Grouping of tumour samples in TCGA ovarian cancer database for the analysis of FOXA2 and VCAN expression
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- 2023
31. Supplementary Tables from miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway
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Chun Peng, Sergey N. Krylov, Burton B. Yang, Basel Refky, Barbara C. Vanderhyden, Asma Amleh, Jelena Brkić, Gang Ye, Heba Shawer, Stefanie Bernaudo, Jacob A. O'Brien, and Mohamed Salem
- Abstract
Table S1 to S3. Description of clinical samples; sequences of primers, siRNAs, and microRNA mimics and inhibitors; and analysis of top regulated genes by mir-590.
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- 2023
32. Data from miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway
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Chun Peng, Sergey N. Krylov, Burton B. Yang, Basel Refky, Barbara C. Vanderhyden, Asma Amleh, Jelena Brkić, Gang Ye, Heba Shawer, Stefanie Bernaudo, Jacob A. O'Brien, and Mohamed Salem
- Abstract
miRNAs play important roles in gene regulation, and their dysregulation is associated with many diseases, including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared with low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in patients with EOC than in subjects with benign gynecologic disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3′ UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, whereas knockout of FOXA2 increased VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2–VCAN pathway.Significance: Low FOXA2/high VCAN levels mediate the tumor-promoting effects of miR-590-3p and negatively correlate with ovarian cancer survival. Cancer Res; 78(15); 4175–90. ©2018 AACR.
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- 2023
33. Supplementary Figures 1-8 from The Ability of Versican to Simultaneously Cause Apoptotic Resistance and Sensitivity
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Burton B. Yang, Zhaoqun Deng, Wang Sheng, Ling Zhong, Yi-Zhen Xie, Sen-Zhu Li, Daniel Y. Lee, and David P. LaPierre
- Abstract
Supplementary Figures 1-8 from The Ability of Versican to Simultaneously Cause Apoptotic Resistance and Sensitivity
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- 2023
34. Data from The Ability of Versican to Simultaneously Cause Apoptotic Resistance and Sensitivity
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Burton B. Yang, Zhaoqun Deng, Wang Sheng, Ling Zhong, Yi-Zhen Xie, Sen-Zhu Li, Daniel Y. Lee, and David P. LaPierre
- Abstract
Expression of the extracellular matrix proteoglycan versican is associated with more than 10 types of cancers, often being secreted by stromal cells in response to tumor signals. Previous work in our lab has shown that overexpression of the V1 versican isoform in cultured fibroblasts (V1 cells) increases both proliferation and apoptotic resistance. We show here that V1 cells induced tumor formation in nude mice and that, in keeping with previously shown apoptotic resistance, V1 cells have down-regulated Fas mRNA and protein levels. Unexpectedly, however, V1 cells were found to be sensitized to a wide range of cytotoxic agents. This combination of selective apoptotic resistance and sensitivity is often seen in cancer cells. V1 cells were also shown to have high resting levels of p53 and murine double minute-2 proteins, correlating with apoptotic sensitivity. Treatment with UV radiation induced p21 expression in vector-transfected cells but not in V1 cells. As p21 induces cell cycle arrest and inhibits apoptosis, its loss in V1 cells, coupled with high resting levels of proapoptotic p53, may be at least partially involved in their premature death following cytotoxic treatment. This study further supports the importance of versican in cancer cell biology and the complexity of apoptosis regulation. [Cancer Res 2007;67(10):4742–50]
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- 2023
35. CircRNAs regulate the crosstalk between inflammation and tumorigenesis: The bilateral association and molecular mechanisms
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Javeria Qadir, Shuo-yang Wen, Hui Yuan, and Burton B. Yang
- Subjects
Pharmacology ,Drug Discovery ,Genetics ,Molecular Medicine ,Molecular Biology - Abstract
Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs i.e., circular RNAs (circRNAs) has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation induced cancer or tumor related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/ triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the diagnostic/prognostic and therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.
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- 2022
36. Circular RNAs in cancer: Limitations in functional studies and diagnostic potential
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Feiya Li, Alina T. He, Qiwei Yang, and Burton B. Yang
- Subjects
0301 basic medicine ,Cancer Research ,Mechanism (biology) ,Cancer ,RNA, Circular ,Computational biology ,Biology ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,03 medical and health sciences ,Therapeutic approach ,030104 developmental biology ,0302 clinical medicine ,Circular RNA ,Neoplasms ,030220 oncology & carcinogenesis ,microRNA ,Translational regulation ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Biomarker (medicine) ,Ovarian cancer - Abstract
Circular RNAs (circRNAs) are a large class of noncoding RNAs, generated from a process called back-splicing, that possess critical regulatory functions in many cellular events. A large body of literature has reported various circRNA functions and their underlying mechanisms, including sponging miRNA, exerting transcriptional and translational regulation, interacting with proteins, and translating into peptides and proteins. CircRNA dysregulation has been implicated in many cancers, including lung, breast, liver, gastric, colorectal, and ovarian cancer. They are detectable in bodily fluids and relatively stable, making them potential cancer biomarker candidates. Furthermore, targeting circRNA expression levels is a potential therapeutic approach for treating cancers. In this review, we describe the functional mechanisms of circRNAs and discuss limitations of current mechanism studies. Following this, we outline the potential of circRNAs to be effective biomarkers in various cancers and present circRNA-based therapeutic approaches. Finally, we discuss challenges in using circRNAs as diagnostic and therapeutic tools and propose future research directions.
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- 2021
37. An antisense circular RNA circSCRIB enhances cancer progression by suppressing parental gene splicing and translation
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Nan Wu, Albert Yee, Ling Fang, Jian Ma, Burton B. Yang, Kaixuan Zeng, William W. Du, and Juanjuan Lyu
- Subjects
SCRIB ,RNA Splicing ,Down-Regulation ,Breast Neoplasms ,Biology ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Cell Movement ,Circular RNA ,Cell Line, Tumor ,Drug Discovery ,Genetics ,Humans ,RNA, Antisense ,Molecular Biology ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Messenger RNA ,Sequence Analysis, RNA ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Intron ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,RNA, Circular ,Cell biology ,Gene Expression Regulation, Neoplastic ,Antisense Orientation ,030220 oncology & carcinogenesis ,RNA splicing ,Molecular Medicine ,Original Article ,Female ,Precursor mRNA - Abstract
Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.
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- 2021
38. A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling
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Le Zhou, Nan Wu, Chi Zhou, Alina T He, Juanjuan Lyu, Xiangmin Li, Weining Yang, Kevin Y Du, Feiya Li, Jindong Xu, Sheng Wang, Katarina Maksimovic, Jian Ma, William W. Du, Chao Zhang, Burton B. Yang, and Kaixuan Zeng
- Subjects
0301 basic medicine ,Gene isoform ,Physiology ,Cell Adhesion Molecules, Neuronal ,Neuroligin ,Protein Serine-Threonine Kinases ,030204 cardiovascular system & hematology ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Ventricular Dysfunction ,medicine ,Animals ,Humans ,Protein Isoforms ,Myocytes, Cardiac ,Myofibroblasts ,Cells, Cultured ,Ventricular Remodeling ,Tumor Suppressor Proteins ,RNA, Circular ,medicine.disease ,Fibrosis ,Cell biology ,030104 developmental biology ,Heart failure ,Collagen ,Carrier Proteins ,Cardiology and Cardiovascular Medicine ,Protein Binding - Abstract
Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA–derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload–induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.
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- 2021
39. Silencing mouse circular RNA circSlc8a1 by circular antisense cA-circSlc8a1 induces cardiac hepatopathy
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Nan Wu, Feiya Li, Weining Yang, William W. Du, Faryal Mehwish Awan, Chao Zhang, Juanjuan Lyu, Sema Misir, Kaixuan Zeng, Esra Eshaghi, and Burton B. Yang
- Subjects
Pharmacology ,Drug Discovery ,Genetics ,Molecular Medicine ,Molecular Biology - Abstract
Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective in vivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases.
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- 2022
40. Circular RNAs modulate Hippo-YAP signaling: functional mechanisms in cancer
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Javeria Qadir, Feiya Li, and Burton B. Yang
- Subjects
Mammals ,Neoplasms ,Medicine (miscellaneous) ,Animals ,Apoptosis ,RNA, Circular ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cell Proliferation ,Signal Transduction - Abstract
The Hippo signaling pathway is an evolutionarily conserved network that regulates organ size and tissue homeostasis in mammals. This pathway controls various cell functions, such as growth, proliferation, survival, apoptosis, and stemness by switching 'on' or 'off' its inhibitory and/or transcriptional module, thereby regulating target gene(s) expression. Altered Hippo signaling has been implicated in various forms of cancers. Increasing evidence suggests cross-talk between the Hippo signaling pathway and non-coding RNAs, in particular circular RNAs (circRNAs). In this context, the current review presents the mechanistic interplay between the Hippo pathway and related circRNAs in various forms of cancers, along with the capabilities of these circRNAs to function either as tumor suppressors or oncogenes through miRNA sponging or protein binding mechanisms. Furthermore, we discuss the constraints and limitations in circRNA mechanistic studies while highlighting some outstanding questions regarding the roles of circRNAs associated with the Hippo-YAP pathway in cancer. Finally, we delineate the potential of these circRNAs to be employed as diagnostic and prognostic biomarkers, as well as molecular hotspots for cancer therapy.
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- 2022
41. Rapid Development of Targeting circRNAs in Cardiovascular Diseases
- Author
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Si Tong Huo, Zhiyong Wu, Lina Chen, Chang Wen, Burton B. Yang, Chao Zhang, Sen Lian, Honghao Chen, Nan Wu, William W. Du, and Daogang Guan
- Subjects
0301 basic medicine ,lcsh:RM1-950 ,Ischemic injury ,Computational biology ,Biology ,Article ,03 medical and health sciences ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Drug Discovery ,Molecular Medicine ,Disease treatment - Abstract
Circular RNAs (circRNAs) are circularized, single-stranded RNAs that are covalently linked. With their abundance in tissues and developmental stage-specific expression, circRNAs participate in a variety of physiological and pathological processes. In this review, we discuss the development of circRNAs used as biomarkers and therapeutic targets for cardiovascular diseases (CVDs), focusing on recent discoveries and applications of exosomal circRNAs that highlight opportunities and challenges. Some studies have identified a spectrum of circRNAs that are differentially expressed in CVDs, while other studies further manipulated specific circRNA expression and showed an ameliorated pathogenic state such as ischemic injury, hypertrophy, and cardiac fibrosis. Studies and applications of circRNAs are being rapidly developed. We expect to see clinical use of circRNAs as biomarkers and targets for disease treatment in the near future., Graphical Abstract, Large numbers of differentially expressed circRNAs have been identified in pathogenic heart tissues and cells. Gain-of-function and loss-of-function approaches are being developed to manipulate specific circRNA expression in order to modulate heart conditions. circRNAs may be used as potential biomarkers for early diagnosis and may be targets for therapeutic strategies.
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- 2020
42. Dietary Cyanidin-3-Glucoside Attenuates High-Fat-Diet–Induced Body-Weight Gain and Impairment of Glucose Tolerance in Mice via Effects on the Hepatic Hormone FGF21
- Author
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Yasaman Badakhshi, Weijuan Shao, Burton B. Yang, Lili Tian, Wenhua Ling, Tianru Jin, Hongmei Ning, Zhuolun Song, and Patricia L. Brubaker
- Subjects
Leptin ,Male ,medicine.medical_specialty ,FGF21 ,Nutrition and Disease ,medicine.medical_treatment ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Diet, High-Fat ,Weight Gain ,Incretins ,Anthocyanins ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Glucosides ,Glucagon-Like Peptide 1 ,Internal medicine ,Glucose Intolerance ,Weight Loss ,Gene expression ,medicine ,Animals ,030304 developmental biology ,2. Zero hunger ,0303 health sciences ,Nutrition and Dietetics ,business.industry ,Insulin ,food and beverages ,Proglucagon ,Dietary Fats ,Glucagon-like peptide-1 ,3. Good health ,Fibroblast Growth Factors ,Endocrinology ,Gene Expression Regulation ,Liver ,business ,Homeostasis ,Hormone - Abstract
BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P 3-fold, P
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- 2020
43. The emerging role and significance of circular RNAs in viral infections and antiviral immune responses: possible implication as theranostic agents
- Author
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Faryal Mehwish Awan, Ayesha Obaid, Hussnain Ahmed Janjua, Arif Malik, Anam Naz, Aqsa Ikram, Sumaira Sharif, Aneeqa Hanif, Amjad Ali, and Burton B. Yang
- Subjects
Human cytomegalovirus ,Swine ,Viral protein ,viruses ,Hepatitis C virus ,HIV Infections ,Context (language use) ,Review ,Biology ,medicine.disease_cause ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Influenza, Human ,medicine ,Influenza A virus ,Animals ,Humans ,RNA Viruses ,Precision Medicine ,Molecular Biology ,030304 developmental biology ,Swine Diseases ,Hepatitis B virus ,0303 health sciences ,Herpesviridae Infections ,RNA, Circular ,Cell Biology ,medicine.disease ,Hepatitis C ,Virology ,Virus Diseases ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Bovine Virus Diarrhea-Mucosal Disease ,Cattle ,Simian Vacuolating Virus 40 ,Coronavirus Infections ,Biomarkers - Abstract
Circular RNAs (circRNAs) are ubiquitously expressed, covalently closed rings, produced by pre-mRNA splicing in a reversed order during post-transcriptional processing. Circularity endows 3'-5'-linked circRNAs with stability and resistance to exonucleolytic degradation which raises the question whether circRNAs may be relevant as potential therapeutic targets or agents. High stability in biological systems is the most remarkable property and a major criterion for why circRNAs could be exploited for a range of RNA-centred medical applications. Even though various biological roles and regulatory functions of circRNAs have been reported, their in-depth study is challenging because of their circular structure and sequence-overlap with linear mRNA counterparts. Moreover, little is known about their role in viral infections and in antiviral immune responses. We believe that an in-depth and detailed understanding of circRNA mediated viral protein regulations will increase our knowledge of the biology of these novel molecules. In this review, we aimed to provide a comprehensive basis and overview on the biogenesis, significance and regulatory roles of circRNAs in the context of antiviral immune responses and viral infections including hepatitis C virus infection, hepatitis B virus infection, hepatitis delta virus infection, influenza A virus infection, Epstein-Barr virus infection, kaposi's sarcoma herpesvirus infection, human cytomegalovirus infection, herpes simplex virus infection, human immunodeficiency virus infection, porcine epidemic diarrhoea virus infection, ORF virus infection, avian leukosis virus infection, simian vacuolating virus 40 infection, transmissible gastroenteritis coronavirus infection, and bovine viral diarrhoea virus infection. We have also discussed the critical regulatory role of circRNAs in provoking antiviral immunity, providing evidence for implications as therapeutic agents and as diagnostic markers.
- Published
- 2020
44. The effect of Ganoderma lucidum spore oil in early skin wound healing: interactions of skin microbiota and inflammation
- Author
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He Chunyan, Yun Hao, Jiao Chunwei, Qingping Wu, Liang Huijia, Burton B. Yang, Yizhen Xie, and Aimin Jiang
- Subjects
Lipopolysaccharides ,Male ,Aging ,LPS ,Reishi ,Lipopolysaccharide ,H&E stain ,Inflammation ,Dermatitis ,Proinflammatory cytokine ,Microbiology ,Masson's trichrome stain ,chemistry.chemical_compound ,Mice ,microbiota ,Medicine ,burn ,Animals ,Germ-Free Life ,Medicine, Chinese Traditional ,Skin ,Mice, Inbred ICR ,Wound Healing ,integumentary system ,business.industry ,Cell Biology ,Spores, Fungal ,Staining ,Anti-Bacterial Agents ,Toll-Like Receptor 4 ,chemistry ,inflammation ,TLR4 ,Cytokines ,medicine.symptom ,business ,Wound healing ,Burns ,Oils ,Research Paper - Abstract
The mushroom Ganoderma lucidum (G. lucidum Leyss. ex Fr.) Karst has been a traditional Chinese medicine for millennia. In this study, we isolated the Ganoderma lucidum spore oil (GLSO) and evaluated the effect of GLSO on skin burn wound healing and the underlying mechanisms. Mice were used to perform skin wound healing assay. Wound analysis was performed by photography, hematoxylin/eosin staining, Masson's Trichrome staining and immunohistochemical analysis. Microbiota on the wounds were analyzed using the 16s rRNA sequence and quantitative statistics. The lipopolysaccharide (LPS) content was examined in skin wounds and serum using an enzyme-linked immunosorbent assay (ELISA). The expression of Toll-like receptor 4 (TLR4) and the relative levels of inflammatory cytokines were determined by qPCR and immunofluorescence assay. A pseudo-germfree mouse model treated with antibiotics was used to investigate whether GLSO accelerated skin burn wound healing through the skin microbiota. We found that GLSO significantly accelerated the process of skin wound healing and regulated the levels of gram-negative and gram-positive bacteria. Furthermore, GLSO reduced LPS and TLR4, and levels of some other related inflammatory cytokines. The assay with the pseudo-germfree mice model showed that GLSO had a significant acceleration on skin wound healing in comparison with antibiotic treatment. Thus, GLSO downregulated the inflammation by regulating skin microbiota to accelerate skin wound healing. These findings provide a scientific rationale for the potential therapeutic use of GLSO in skin burn injury.
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- 2020
45. The Circular RNA circSKA3 Binds Integrin β1 to Induce Invadopodium Formation Enhancing Breast Cancer Invasion
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Burton B. Yang, Faryal Mehwish Awan, Weining Yang, Mingyao Liu, Zhenguo Yang, Yu Chen, Elizabeth Liu, William W. Du, Nan Wu, Ling Fang, Qihan He, Xiangmin Li, and Feiya Li
- Subjects
Carcinogenesis ,Breast Neoplasms ,Cell Cycle Proteins ,Pilot Projects ,Transfection ,medicine.disease_cause ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Circular RNA ,Drug Discovery ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Binding Sites ,Chemistry ,Integrin beta1 ,Cancer ,RNA, Circular ,medicine.disease ,Cell biology ,Adaptor Proteins, Vesicular Transport ,HEK293 Cells ,Tumor progression ,030220 oncology & carcinogenesis ,Podosomes ,Invadopodia ,Cancer cell ,Disease Progression ,MCF-7 Cells ,Molecular Medicine ,Original Article ,Female ,Microtubule-Associated Proteins ,HeLa Cells ,Protein Binding - Abstract
Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin β1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin β1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin β1, inducing invadopodium formation.
- Published
- 2020
46. Identification and characterization of chemical components in the bioactive fractions of Cynomorium coccineum that possess anticancer activity
- Author
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Burton B. Yang, Yizhen Xie, Juanjuan Peng, Mouna Sdiri, and Li Xiangmin
- Subjects
Programmed cell death ,HepG2 ,autophagy ,Cell ,Blotting, Western ,Antineoplastic Agents ,Apoptosis ,Vacuole ,Applied Microbiology and Biotechnology ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,Anthraquinones ,Cynomorium coccineum ,medicine ,Humans ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Chromatography, High Pressure Liquid ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Cynomorium ,biology ,cell apoptosis ,Plant Extracts ,Autophagy ,Cell Biology ,Hep G2 Cells ,biology.organism_classification ,Flow Cytometry ,LC3II ,UPLC-Q-Orbitrap/MS ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Microscopy, Fluorescence ,Cytoplasm ,Developmental Biology ,Research Paper - Abstract
Cynomorium coccineum has long been used as the health and medicinal plant known to induce cancer cell death. However, the bioactive compounds of C. coccineum and the underlying mechanism of their regulator in cell autophagy and cell apoptosis remain unexplored. In our previous study, we found that the ethanol extract had antitumor activity through inducing cancer cell death. In this study, by detecting the anti-tumor effect of sequence extracts from Cynomorium coccineum, the active constituents were collected in solvent ethyl acetate. A strategy based on ultra-performance liquid chromatography coupled with hybrid quadrupole-orbitrap mass spectrometry (UPLC-Q-Orbitrap/MS) was first utilized to analyze the chemical constituents of active fraction (ethyl acetate fraction, CS3). A total of 29 compounds including 8 triterpenoids, 6 flavonoids, 4 fatty acids, 8 phenolic acids, 1 anthraquinones, 1 nucleoside and 1 sterol were detected and identified or tentatively identified for the first time in Cynomorium coccineum. We found that CS3 induces cancer cell death accompanied with a great number of vacuoles in the cytoplasm. CS3-induced autophagosome formation was found and confirmed by electron microscopy and the high expression levels of microtubule-associated protein-1 light chain 3-II (LC3II), a marker protein of autophagy. We additionally demonstrated that CS3 activated and increased the pro-apoptotic mitochondrial proteins, BNIP3 and BNIP3L, in mRNA and protein levels. The constituents of CS3 down-regulated anti-apoptotic BCL2, and then releases autophagic protein Beclin-1. These finding for the first time systematically not only explore and identify the active constituents of CS3 in Cynomorium coccineum, but also examined the mechanism associated with CS3-induced cell death via cell autophagy. This active component may serve as a potential source to obtain new autophagy inducer and anti-cancer compounds for hepatocellular carcinoma.
- Published
- 2020
47. CircNF1-419 improves the gut microbiome structure and function in AD-like mice
- Author
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Zeng Miao, Tang Xiaocui, Liu Yadi, Chen Diling, Yuan Xujiang, Qi Longkai, Xie Yizhen, Wang Dongdong, Shuai Ou, Wu Qingping, Zhu Xiangxiang, Li Ran, Guo Yinrui, and Burton B. Yang
- Subjects
Genetics ,microbiome-gut-brain axis ,Aging ,Autophagy ,Lachnospiraceae ,gut microbiome ,Candidatus Arthromitus ,Cell Biology ,Biology ,Gut flora ,biology.organism_classification ,digestive system ,dietary interventions ,Gut microbiome ,Structure and function ,Transcriptome ,Eubacterium ,Research Paper ,circular RNAs ,therapeutic markers - Abstract
Our pre-experiments found that the brain circRNA sequence profiles and gut microbiota in AD-like mice were changed, as circNF1-419 could enhance autophagy to ameliorate senile dementia in AD-like mice, so we conclude that there might some connections between circRNA and gut microbiome. Therefore, we use the over-expressed circNF1-419 adeno-associated virus (AAV) animal system with the aim of identifying possible connections. Our results showed that over-expression of circNF1-419 in brain not only influenced the cholinergic system of brain, but also changed the gut microbiota composition as the Candidatus Arthromitus, Lachnospiraceae FCS020 group, Lachnospiraceae UCG-006, and [Eubacterium] xylanophilum group, and the intestinal homeostasis and physiology, and even the gut microbiota trajectory in new born mice. These findings demonstrate a link between circRNA and gut microbiome, enlarge the 'microbiome- transcriptome' linkage library and provide more information on gut-brain axis.
- Published
- 2020
48. Circular RNA NF1-419 enhances autophagy to ameliorate senile dementia by binding Dynamin-1 and Adaptor protein 2 B1 in AD-like mice
- Author
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Yang Xin, Burton B. Yang, Yong Tianqiao, Qi Longkai, Shuai Ou, Guo Yinrui, Wu Qingping, Liu Yadi, Tang Xiaocui, Xie Yizhen, Chen Diling, Wang Dongdong, and Hu Guoyan
- Subjects
autophagy ,Aging ,Biology ,Rats, Sprague-Dawley ,Transcriptome ,Mice ,Exon ,astrocyte ,Alzheimer Disease ,Circular RNA ,Genes, Neurofibromatosis 1 ,medicine ,Animals ,Adaptor Protein Complex beta Subunits ,Cellular Senescence ,Dynamin I ,biological function ,Dynamin ,Autophagy ,Signal transducing adaptor protein ,circular RNA ,RNA, Circular ,Cell Biology ,Rats ,Cell biology ,medicine.anatomical_structure ,Astrocytes ,Signal transduction ,Research Paper ,Astrocyte - Abstract
Recent studies have demonstrated circular RNAs (circRNAs) to be widely expressed and to have important physiological functions. However, the expression, regulation, and function of circRNAs in neuroglial cells are unknown. Herein, we characterized the expression, regulation, and function of circRNAs in astrocytes. Astrocyte circRNAs were identified by computational analysis of newborn SD rat primary astrocytes cultured with 20 g/L D-galactose. In this manner, 7376 circRNAs were identified, among which most circRNAs (5754) were derived from annot_exons, whereas 27 were antisense, 853 were exon/intron, 329 were intergenic, 41 were intronic, and 372 were one exon. Among these, circNF1-419 was demonstrated to regulate autophagy, in over-expressing circNF1-419 transfected astrocytes, through the PI3K-I/Akt-AMPK-mTOR and PI3K-I/Akt-mTOR signaling pathways. An adenovirus associated virus packaging system (virus titer 1 ×1012), over-expressing circNF1-419 and injected into mouse cerebral cortex, showed autophagy enhancing activity by binding the proteins Dynamin-1 and Adaptor protein 2 B1 (AP2B1). This binding regulated aging markers (p21, p35/25, and p16) and inflammatory factors (TNF-α and NF-κB), and reduced the expression of Alzheimer’s disease marker proteins (Tau, p-Tau, Aβ1-42, and APOE), which delayed senile dementia. Transcriptome analysis of the brain showed that circNF1-419 improved other signaling pathways, especially those related to the synapses of SAMP8 mice. These findings provide novel insights into circNF1-419 and its potential usefulness for the diagnosis and treatment of dementia by regulating Dynamin-1 and AP2B1 mediated autophagy.
- Published
- 2019
49. Posttranscriptional regulation of AKT by circular RNA angiomotin- like 1 mediates chemoresistance against paclitaxel in breast cancer cells
- Author
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Jian Ma, Nan Wu, Qi Yang, Burton B. Yang, William W. Du, Ling Fang, and Steven Hibberd
- Subjects
Aging ,Paclitaxel ,Cell Survival ,Breast Neoplasms ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,circAMOTL1 ,Viability assay ,RNA Processing, Post-Transcriptional ,skin and connective tissue diseases ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Triple-negative breast cancer ,030304 developmental biology ,0303 health sciences ,AKT ,chemoresistance ,circular RNA ,RNA, Circular ,Cell Biology ,Transfection ,medicine.disease ,Angiomotin ,3. Good health ,Gene Expression Regulation, Neoplastic ,Drug Resistance, Neoplasm ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Female ,PAX ,Proto-Oncogene Proteins c-akt ,Research Paper - Abstract
Chemoresistance of triple negative breast cancer against paclitaxel (PAX) is one of the major issues for the patients under chemotherapy. However, the mechanism by which the breast cancer cells are resistant to PAX remains unclear. Here, we identified a circular RNA of angiomotin-like 1 (circAMOTL1) as an important player which may be responsible for the adverse resistance against PAX in breast cancer cells. The circAMOTL1 were overexpressed in MDA-MB-231 breast cancer cells via transfection of circAMOTL1 construct. Overexpression of circAMOTL1 caused significant increase of cell viability, reduction of apoptosis, and enhancement of invasion when MDA-MB-231 cells were exposed to PAX compared to those cells with vector control. Moreover, these resistant effects could be blocked by the application of circAMOTL1 siRNA. In these circAMOTL1 overexpressing cells, we found notable increase of both phosphorylated and total AKT protein, which suggested that AKT might be the downstream factor mediating the resistant effects. Consequently, the gene and protein expression of AKT related pro-apoptotic (BAX and BAK) and anti-apoptotic (BCL-2) factors were significantly changed by circAMOTL1 as well. These results suggest circAMOTL1 may play an important role in the PAX resistance of breast cancer cells via regulation of AKT pathway, facilitation of anti-apoptotic protein and inhibition of pro-apoptotic protein. While providing a new mechanism of PAX resistance in breast cancer cells, our findings may lay groundwork for a novel therapeutic target of the breast cancer treatment in the future.
- Published
- 2019
50. Specific expression and functions of circular RNAs
- Author
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Sema Misir, Nan Wu, and Burton B. Yang
- Subjects
MicroRNAs ,Disease Progression ,Humans ,Proteins ,Cell Biology ,RNA, Circular ,Review Article ,Molecular Biology ,Biomarkers - Abstract
In recent years, circular RNAs (circRNAs), a new class of RNA molecules characterized by their covalently closed circular structure, have become a new research paradigm in RNA biology. Many circRNAs are conserved among eukaryotes, localize in specific subcellular compartments, and play different biological roles. Accumulating evidence shows that circRNAs regulate a diversity of cellular processes by acting as miRNA sponges, anchors for circRNA binding proteins (cRBPs), transcriptional regulators, molecular scaffolds, and sources for translation of small proteins/peptides. The emergence of the biological functions of circRNAs has brought a new perspective to our understanding of cellular physiology and disease pathogenesis. Recent studies have shown that the expression of circRNAs is tissue- and cell type-specific and specifically regulated through development or disease progression, where they exert specific biological functions. However, the mechanisms underlying these remain largely unknown. A deeper understanding of how the specific expression of circRNAs is regulated to exert specific biological functions will enable the use of circRNA as a biomarker in clinical practice and the development of new therapeutic approaches. This review aims to summarize recent developments in circRNA biogenesis, functions, and molecular mechanisms. We also provide some specific circRNAs as examples to show their tissue-specific distribution and evaluate the possibility of applying circRNA technologies in molecular research and therapeutics.
- Published
- 2021
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