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1
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Oka S, Akagi Y, Mituyoshi T, Ono K. Successful treatment of myeloid blast phase chronic myelogenous leukemia with the JAK2 V617 F mutation by combination therapy with asciminib and ropeginterferon alfa-2b in an elderly patient. Int J Hematol 2025:10.1007/s12185-025-03994-2. [PMID: 40299271 DOI: 10.1007/s12185-025-03994-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 04/30/2025]
Abstract
The co-occurrence of JAK2 V617F mutations and the BCR::ABL1 translocation in the same patient is rare, and the current standard treatment for aggressive myeloid blast phase chronic myeloid leukemia (CML-myeloid BP) with JAK2 V617F mutations remains inadequate, particularly in transplant-ineligible patients. Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase that specifically targets the ABL1 myristoyl pocket, has emerged as a novel alternative to standard tyrosine kinase inhibitor (TKI) therapy. Ropeginterferon alfa-2b (ropegIFNα2b) is a novel site-selective, monopegylated recombinant human IFN with long-term safety and efficacy in patients with polycythemia vera (PV). Here, we report a case of successful combination therapy with asciminib and ropegIFNα2b in a patient with CML-myeloid BP who had a long history of PV with JAK2 V617F refractory to induction chemotherapy with several TKIs. The combination of asciminib and ropegIFNα2b is a promising new treatment option for these patients.
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Affiliation(s)
- Satoko Oka
- Division of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Wakayama, Japan.
| | - Yuina Akagi
- Division of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Wakayama, Japan
| | - Takaya Mituyoshi
- Division of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Wakayama, Japan
| | - Kazuo Ono
- Division of Pathology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan
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2
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Azadegan C, Santoro J, Whetstine JR. Connecting the dots: Epigenetic regulation of extrachromosomal and inherited DNA amplifications. J Biol Chem 2025; 301:108454. [PMID: 40154613 DOI: 10.1016/j.jbc.2025.108454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 04/01/2025] Open
Abstract
DNA amplification has intrigued scientists for decades. Since its discovery, significant progress has been made in understanding the mechanisms promoting DNA amplification and their associated function(s). While DNA copy gains were once thought to be regulated purely by stochastic processes, recent findings have revealed the important role of epigenetic modifications in driving these amplifications and their integration into the genome. Furthermore, advances in genomic technology have enabled detailed characterization of these genomic events in terms of size, structure, formation, and regulation. This review highlights how our understanding of DNA amplifications has evolved over time, tracing its trajectory from initial discovery to the contemporary landscape. We describe how recent discoveries have started to uncover how these genomic events occur by controlled biological processes rather than stochastic mechanisms, presenting opportunities for therapeutic modulation.
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Affiliation(s)
- Chloe Azadegan
- Drexel University, College of Medicine, Philadelphia, Pennsylvania, USA; Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - John Santoro
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Johnathan R Whetstine
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
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3
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Arshadi A, Tolomeo D, Venuto S, Storlazzi CT. Advancements in Focal Amplification Detection in Tumor/Liquid Biopsies and Emerging Clinical Applications. Genes (Basel) 2023; 14:1304. [PMID: 37372484 PMCID: PMC10298061 DOI: 10.3390/genes14061304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Focal amplifications (FAs) are crucial in cancer research due to their significant diagnostic, prognostic, and therapeutic implications. FAs manifest in various forms, such as episomes, double minute chromosomes, and homogeneously staining regions, arising through different mechanisms and mainly contributing to cancer cell heterogeneity, the leading cause of drug resistance in therapy. Numerous wet-lab, mainly FISH, PCR-based assays, next-generation sequencing, and bioinformatics approaches have been set up to detect FAs, unravel the internal structure of amplicons, assess their chromatin compaction status, and investigate the transcriptional landscape associated with their occurrence in cancer cells. Most of them are tailored for tumor samples, even at the single-cell level. Conversely, very limited approaches have been set up to detect FAs in liquid biopsies. This evidence suggests the need to improve these non-invasive investigations for early tumor detection, monitoring disease progression, and evaluating treatment response. Despite the potential therapeutic implications of FAs, such as, for example, the use of HER2-specific compounds for patients with ERBB2 amplification, challenges remain, including developing selective and effective FA-targeting agents and understanding the molecular mechanisms underlying FA maintenance and replication. This review details a state-of-the-art of FA investigation, with a particular focus on liquid biopsies and single-cell approaches in tumor samples, emphasizing their potential to revolutionize the future diagnosis, prognosis, and treatment of cancer patients.
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Affiliation(s)
| | | | | | - Clelia Tiziana Storlazzi
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (A.A.); (D.T.); (S.V.)
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Lee YC, Chiou JT, Chang LS. AMPK inhibition induces MCL1 mRNA destabilization via the p38 MAPK/miR-22/HuR axis in chronic myeloid leukemia cells. Biochem Pharmacol 2023; 209:115442. [PMID: 36720359 DOI: 10.1016/j.bcp.2023.115442] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/15/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023]
Abstract
The oncogenic and tumor-suppressive roles of AMPK in chronic myeloid leukemia (CML) are controvertible. This study aimed to investigate the cytotoxic effects of the AMPK inhibitor Compound C in the CML cell lines K562, KU812, and MEG-01. Compared to K562 cells, KU812 and MEG-01 cells were more sensitive to Compound C-mediated cytotoxicity. Moreover, Compound C induced SIRT3 upregulation in K562 cells but not in KU812 or MEG-01 cells. SIRT3 silencing increased the sensitivity of K562 cells to Compound C. Additionally; Compound C-induced autophagy attenuated its induced apoptosis in KU812 and MEG-01 cells. Compound C-induced ROS-mediated AMPKα inactivation resulted in the downregulation of apoptotic regulator MCL1 in KU812 and MEG-01 cells. Mechanistically, AMPK inhibition activated p38 MAPK-mediated miR-22 expression, which in turn inhibited HuR expression, thereby reducing MCL1 mRNA stability. Overexpression of constitutively active AMPKα1 and abolishment of the activation of p38 MAPK inhibited Compound C-induced cell death and MCL1 downregulation. Furthermore, Compound C synergistically enhanced the cytotoxicity of BCR-ABL inhibitors and the BCL2 inhibitor ABT-199. Collectively, this study indicates that Compound C induces MCL1 downregulation through the AMPK/p38 MAPK/miR-22/HuR pathway, thereby inducing apoptosis of KU812 and MEG-01 cells. Furthermore, our findings suggest that AMPK inhibition is a promising strategy for improving CML therapy.
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Affiliation(s)
- Yuan-Chin Lee
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Jing-Ting Chiou
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Long-Sen Chang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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5
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Zhang G, Hou J, Mei C, Wang X, Wang Y, Wang K. Effect of circular RNAs and N6-methyladenosine (m6A) modification on cancer biology. Biomed Pharmacother 2023; 159:114260. [PMID: 36657303 DOI: 10.1016/j.biopha.2023.114260] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/09/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
N6-methyladenosine (m6A), as the most abundant and well-known RNA modification, has been found to play an important role in cancer. Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA molecules generated by the reverse splicing process. Recent studies have revealed the vital roles of circRNAs in many diseases, including tumorigenesis. Accumulating evidence also shows an association between m6A modification and circRNAs. This study aimed to review the interactions between m6A modification and circRNAs and illustrate their roles in tumorigenesis. m6A modification can modulate the biogenesis, translation, cytoplasmic export, degradation, and other functions of circRNAs in different tumors. circRNAs can also modulate m6A modification by affecting writers, erasers, and readers. We focused on the potential regulatory mechanisms and the biological consequences of m6A modification of circRNAs, as well as the interactions in tumors of different systems. Finally, we listed the possible development directions of m6A modification and circRNAs, which might facilitate the clinical application of tumor therapy. AVAILABILITY OF DATA AND MATERIALS: Not applicable. Keywords.
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Affiliation(s)
- Gong Zhang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Junhui Hou
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Chenxue Mei
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yuan Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Sarkar N, Singh A, Kumar P, Kaushik M. Protein kinases: Role of their dysregulation in carcinogenesis, identification and inhibition. Drug Res (Stuttg) 2023; 73:189-199. [PMID: 36822216 DOI: 10.1055/a-1989-1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of genes in the genome, which encode for all the protein kinases. Certain mutations in the kinome have been linked to dysregulation of protein kinases, which in turn can lead to several diseases and disorders including cancer. In this review, we have briefly discussed the role of protein kinases in various biochemical processes by categorizing cancer associated phenotypes and giving their protein kinase examples. Various techniques have also been discussed, which are being used to analyze the structure of protein kinases, and associate their roles in the oncogenesis. We have also discussed protein kinase inhibitors and United States Federal Drug Administration (USFDA) approved drugs, which target protein kinases and can serve as a counter to protein kinase dysregulation and mitigate the effects of oncogenesis. Overall, this review briefs about the importance of protein kinases, their roles in oncogenesis on dysregulation and how their inhibition via various drugs can be used to mitigate their effects.
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Affiliation(s)
- Niloy Sarkar
- Nano-Bioconjugate Chemistry Lab, Cluster Innovation Centre, University of Delhi, Delhi, India.,Department of Environmental Studies, University of Delhi, Delhi, India
| | - Amit Singh
- Nano-Bioconjugate Chemistry Lab, Cluster Innovation Centre, University of Delhi, Delhi, India.,Department of Chemistry, University of Delhi, Delhi, India
| | - Pankaj Kumar
- Nano-Bioconjugate Chemistry Lab, Cluster Innovation Centre, University of Delhi, Delhi, India.,Department of Chemistry, University of Delhi, Delhi, India
| | - Mahima Kaushik
- Nano-Bioconjugate Chemistry Lab, Cluster Innovation Centre, University of Delhi, Delhi, India
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7
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Hu L, Zheng B, Yang Y, Chen C, Hu M. Construction of circRNA-miRNA-mRNA Network Reveal Functional circRNAs and Key Genes in Acute Myeloid Leukemia. Int J Gen Med 2023; 16:1491-1504. [PMID: 37123885 PMCID: PMC10145421 DOI: 10.2147/ijgm.s402671] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 04/04/2023] [Indexed: 05/02/2023] Open
Abstract
Introduction CircRNA is closely correlated with a wide variety of processes of acute myeloid leukemia (AML), whereas the novel circRNAs, their molecular mechanism and the specific function they played in AML should be explored in depth. Methods The microarray chip data of AML patients and normal samples in the Gene Expression Omnibus (GEO) database were selected to differentially expressed (DE) circRNA, miRNA, and mRNA genes. The miRNA gene was the intersection of the circRNA target gene predicted using CSCD and the miRNA gene screened from AML patients, while the mRNA gene was the intersection of the target gene mRNA of miRNA predicted using miRanda and miRTarBase software and the mRNA gene screened from AML patients. The hub mRNAs related to survival were further screened through Cox proportional hazard regression. CircRNA/miRNA/mRNA interaction network was constructed by using Cytoscape software.10 circRNAs and 6 miRNAs in bone marrow mononuclear cells (BMMNCs) of AML patients (n=43) and healthy controls (n=35) were determined by RT-qPCR. Correlations between them were analyzed by Pearson correlation coefficient. Results 10 circRNAs, 6 miRNAs, and 33 mRNAs were identified. Subsequently, the network of circRNAs, miRNAs, and hub genes was built using Cystoscope. Four key circRNAs, seven hub genes and their regulatory pathways were identified. The result of RT-qPCRs showed that hsa_circ_0009581 and hsa_circ_0005273 were significantly upregulated in AML patients while hsa_circ_0000497 and hsa_circ_0001947 were significantly downregulated. Hsa-miR-150-5p was significantly downregulated; hsa-miR-454-3p was upregulated in AML patients. Hsa_circ_0009581 and hsa-miR-150-5p; hsa_ circ_0001947 and hsa-miR-454-3p were inversely correlated using Pearson's correlation coefficient. Conclusion This study suggests that differentially expressed circRNAs take on a critical significance to AML development and may be the effective therapeutic targets. We suppose that hsa_circ_0009581 promotes leukemia development through hsa-miR-150-5p and hsa_circ_0001947 through hsa-miR-454-3p. hsa_circ_0001947 and hsa_circ_0009581 may provide new directions in the pathogenesis of AML.
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Affiliation(s)
- Lianbo Hu
- Physical Examination Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China
| | - Bingrong Zheng
- Department of Hematology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Yang Yang
- Department of Hematology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chunmei Chen
- Department of Hematology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Meiwei Hu
- Department of Hematology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- Correspondence: Meiwei Hu, Department of Hematology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318 Chaowang Road, Hangzhou, Zhejiang, 310014, People’s Republic of China, Email
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8
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Deng W, Murugan S, Lindberg J, Chellappa V, Shen X, Pawitan Y, Vu TN. Fusion Gene Detection Using Whole-Exome Sequencing Data in Cancer Patients. Front Genet 2022; 13:820493. [PMID: 35251131 PMCID: PMC8888970 DOI: 10.3389/fgene.2022.820493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/31/2022] [Indexed: 12/13/2022] Open
Abstract
Several fusion genes are directly involved in the initiation and progression of cancers. Numerous bioinformatics tools have been developed to detect fusion events, but they are mainly based on RNA-seq data. The whole-exome sequencing (WES) represents a powerful technology that is widely used for disease-related DNA variant detection. In this study, we build a novel analysis pipeline called Fuseq-WES to detect fusion genes at DNA level based on the WES data. The same method applies also for targeted panel sequencing data. We assess the method to real datasets of acute myeloid leukemia (AML) and prostate cancer patients. The result shows that two of the main AML fusion genes discovered in RNA-seq data, PML-RARA and CBFB-MYH11, are detected in the WES data in 36 and 63% of the available samples, respectively. For the targeted deep-sequencing of prostate cancer patients, detection of the TMPRSS2-ERG fusion, which is the most frequent chimeric alteration in prostate cancer, is 91% concordant with a manually curated procedure based on four other methods. In summary, the overall results indicate that it is challenging to detect fusion genes in WES data with a standard coverage of ∼ 15–30x, where fusion candidates discovered in the RNA-seq data are often not detected in the WES data and vice versa. A subsampling study of the prostate data suggests that a coverage of at least 75x is necessary to achieve high accuracy.
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Affiliation(s)
- Wenjiang Deng
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Sarath Murugan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Johan Lindberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Venkatesh Chellappa
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Xia Shen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Biostatistics Group, Greater Bay Area Institute of Precision Medicine, Fudan University, Guangzhou, China
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Yudi Pawitan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Yudi Pawitan, ; Trung Nghia Vu,
| | - Trung Nghia Vu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Yudi Pawitan, ; Trung Nghia Vu,
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9
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Wang L, Li L, Chen R, Huang X, Ye X. Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients. Cancer Manag Res 2021; 13:4987-5000. [PMID: 34188552 PMCID: PMC8236273 DOI: 10.2147/cmar.s314343] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients.
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Affiliation(s)
- Lulu Wang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Program in Clinical Medicine, School of Medicine of Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Li Li
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Rongrong Chen
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Program in Clinical Medicine, School of Medicine of Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Xianbo Huang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Xiujin Ye
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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10
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Yan Z, Fan G, Li H, Jiao Y, Fu W, Weng J, Huo R, Wang J, Xu H, Wang S, Cao Y, Zhao J. The CTSC-RAB38 Fusion Transcript Is Associated With the Risk of Hemorrhage in Brain Arteriovenous Malformations. J Neuropathol Exp Neurol 2021; 80:71-78. [PMID: 33120410 DOI: 10.1093/jnen/nlaa126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Brain arteriovenous malformations (bAVMs) are congenital anomalies of blood vessels that cause intracranial hemorrhage in children and young adults. Chromosomal rearrangements and fusion genes play an important role in tumor pathogenesis, though the role of fusion genes in bAVM pathophysiological processes is unclear. The aim of this study was to identify fusion transcripts in bAVMs and analyze their effects. To identify fusion transcripts associated with bAVM, RNA sequencing was performed on 73 samples, including 66 bAVM and 7 normal cerebrovascular samples, followed by STAR-Fusion analysis. Reverse transcription polymerase chain reaction and Sanger sequencing were applied to verify fusion transcripts. Functional pathway analysis was performed to identify potential effects of different fusion types. A total of 21 fusion transcripts were detected. Cathepsin C (CTSC)-Ras-Related Protein Rab-38 (RAB38) was the most common fusion and was detected in 10 of 66 (15%) bAVM samples. In CTSC-RAB38 fusion-positive samples, CTSC and RAB38 expression was significantly increased and activated immune/inflammatory signaling. Clinically, CTSC-RAB38 fusion bAVM cases had a higher hemorrhage rate than non-CTSC-RAB38 bAVM cases (p < 0.05). Our study identified recurrent CTSC-RAB38 fusion transcripts in bAVMs, which may be associated with bAVM hemorrhage by promoting immune/inflammatory signaling.
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Affiliation(s)
- Zihan Yan
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Guangming Fan
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease.,Chaoyang Central Hospital, Liaoning Province, China
| | - Hao Li
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Yuming Jiao
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Weilun Fu
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Jiancong Weng
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Ran Huo
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Jie Wang
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Hongyuan Xu
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Shuo Wang
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Yong Cao
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease
| | - Jizong Zhao
- From the Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.,China National Clinical Research Center for Neurological Diseases.,Center of Stroke, Beijing Institute for Brain Disorders.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease.,Savaid Medical School, University of the Chinese Academy of Sciences, Beijing, China
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11
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Chi HT, Thuong NTL, Ly BTK. Sphagneticola Trilobata (L.) Pruski (Asteraceae) Methanol Extract Induces Apoptosis in Leukemia Cells through Suppression of BCR/ABL. PLANTS 2021; 10:plants10050980. [PMID: 34068907 PMCID: PMC8156756 DOI: 10.3390/plants10050980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/08/2021] [Accepted: 05/11/2021] [Indexed: 11/16/2022]
Abstract
We will study the effects of the methanol extract of Sphagneticola trilobata (L.) Pruski (Asteraceae) (MeST) on the growth of leukemia cells that may contain the BCR/ABL gene. This study also clarifies the mechanism of this effect on these cells. For this purpose, the cells harboring wild-type BCR/ABL, imatinib-resistant BCR/ABL (K562 and TCCYT315I), or Ba/F3 cells transfected with wild-type or mutant BCR/ABL genes were used. The results showed that MeST effectively inhibited the viability of leukemia cells in both a dose- and time-dependent manner. The effect of MeST seems to be more sensitive in the cells that carry imatinib-resistant BCR/ABL (especially the T315I BCR/ABL mutation) than those with wild-type BCR/ABL. Furthermore, we have demonstrated that the death caused by MeST is apoptosis and the treatment with MeST could suppress the expression of BCR/ABL, subsequently altering the downstream cascade of BCR/ABL such as AKT and MAPK signaling. In conclusion, MeST has been able to suppress the growth of leukemia cells harboring BCR/ABL. The mechanism of the anti-leukemic effect of MeST on cells harboring imatinib-resistant BCR/ABL mutations could be due to the disruption of the BCR/ABL oncoprotein signaling cascade.
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12
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Sampaio MM, Santos MLC, Marques HS, Gonçalves VLDS, Araújo GRL, Lopes LW, Apolonio JS, Silva CS, Santos LKDS, Cuzzuol BR, Guimarães QES, Santos MN, de Brito BB, da Silva FAF, Oliveira MV, Souza CL, de Melo FF. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94. [PMID: 33680875 PMCID: PMC7918527 DOI: 10.5306/wjco.v12.i2.69] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) 1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
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Affiliation(s)
- Mariana Miranda Sampaio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Mariana Novaes Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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14
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Luebeck J, Coruh C, Dehkordi SR, Lange JT, Turner KM, Deshpande V, Pai DA, Zhang C, Rajkumar U, Law JA, Mischel PS, Bafna V. AmpliconReconstructor integrates NGS and optical mapping to resolve the complex structures of focal amplifications. Nat Commun 2020; 11:4374. [PMID: 32873787 PMCID: PMC7463033 DOI: 10.1038/s41467-020-18099-z] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022] Open
Abstract
Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.
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Affiliation(s)
- Jens Luebeck
- Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, 92093, USA
- Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Ceyda Coruh
- Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Siavash R Dehkordi
- Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Joshua T Lange
- Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA, 92093, USA
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Kristen M Turner
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Viraj Deshpande
- Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Dave A Pai
- Bionano Genomics, Inc., San Diego, CA, 92121, USA
| | - Chao Zhang
- Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Utkrisht Rajkumar
- Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Julie A Law
- Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Paul S Mischel
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, 92093, USA
- Moores Cancer Center, University of California at San Diego, La Jolla, CA, 92093, USA
- Department of Pathology, University of California at San Diego, La Jolla, CA, 92093, USA
| | - Vineet Bafna
- Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA.
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Lu M, Xiong H, Xia ZK, Liu B, Wu F, Zhang HX, Hu CH, Liu P. circRACGAP1 promotes non-small cell lung cancer proliferation by regulating miR-144-5p/CDKL1 signaling pathway. Cancer Gene Ther 2020; 28:197-211. [PMID: 32778770 DOI: 10.1038/s41417-020-00209-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/20/2020] [Accepted: 07/29/2020] [Indexed: 01/16/2023]
Abstract
Circular RNAs (circRNAs) are involved in the regulation of many pathophysiological processes as non-coding RNAs. This study focuses on the role of circRACGAP1 in the development of non-small cell lung cancer (NSCLC). Expression patterns of circRACGAP1 and miR-144-5p in NSCLC tissues and cell lines were quantified by qRT-PCR analysis. Then, the function of circRACGAP1 on cell proliferation and tumorigenesis were confirmed in vitro and in vivo using CCK-8 assay, colony formation, EdU incorporation, and xenograft technique. The regulation of circRACGAP1 on Gefitinib resistance of NSCLC cells was evaluated by flow cytometry. The regulatory network of circRACGAP1/miR-144-5p/CDKL1 was verified by luciferase reporter assay and RNA pull-down. Western blotting analysis was performed to assess the biomarkers of cell cycle and apoptosis-associated proteins. CircRACGAP1 was highly expressed and miR-144-5p was inhibited both in NSCLC tissues and cell lines, suggesting their negative correlation in NSCLC. Knockdown of circRACGAP1 suppressed cell proliferation via arresting the cell cycle. miR-144-5p was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-144-5p directly targeted the 3'-UTR of CDKL1 to regulate cell cycle of NSCLC cells. circRACGAP1 knockdown dramatically inhibited the tumor growth and enhanced the sensitivity of NSCLC to Gefitinib in vitro and in vivo. In summary, our study revealed a novel machinery of circRACGAP1/miR-144-5p/CDKL1 for the NSCLC tumorigenesis and development, providing potential diagnostic and therapeutic targets for NSCLC.
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Affiliation(s)
- Min Lu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Hui Xiong
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Zhen-Kun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Bin Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Hai-Xia Zhang
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Chun-Hong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China
| | - Ping Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, PR China.
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Abstract
Supplemental Digital Content is available in the text Background: Fusion genes may play an important role in tumorigenesis, prognosis, and drug resistance; however, studies on fusion genes in endometrial cancer (EC) are rare. This study aimed to identify new fusion genes and to explore their clinical significance in EC. Methods: A total of 28 patients diagnosed with EC were enrolled in this study. RNA sequencing was used to obtain entire genomes and transcriptomes. STAR-comparison and STAR-fusion prediction were applied to predict the fusion genes. Chi-square tests and Student t tests were used to verify the clinical significance with SPSS 13.0 software. Results: New fusion genes were found, and the number of fusion genes varied from 3 to 110 among all patients with EC. The type of fusion genes varied and included messenger RNA (mRNA)-mRNA, long non-coding RNA (lncRNA)-lncRNA, and lncRNA-mRNA. There were six fusion genes with high fusion rates, namely, RP11–123O10.4–GRIP1, RP11–444D3.1–SOX5, RP11–680G10.1–GSE1, NRIP1–AF127936.7, RP11–96H19.1–RP11–446N19.1, and DPH7–PTP4A3. Further studies showed that these fusion genes are related to stage, grade, and recurrence, in which NRIP1–AF127936.7 and DPH7–PTP4A3 were found only in stage III patients with EC. DPH7–PTP4A3 was found in grades 2 and 3, and recurrent patients with EC. Conclusion: Fusion genes play an essential role in EC. Six genes that are overexpressed with high fusion rates are identified. NRIP1–AF127936.7 and DPH7–PTP4A3 might be related to stage, and DPH7–PTP4A3 be related to grade and recurrence.
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17
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Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update. Int J Mol Sci 2019; 20:ijms20246141. [PMID: 31817512 PMCID: PMC6940932 DOI: 10.3390/ijms20246141] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/29/2019] [Accepted: 12/04/2019] [Indexed: 12/24/2022] Open
Abstract
Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.
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Schütte J, Reusch J, Khandanpour C, Eisfeld C. Structural Variants as a Basis for Targeted Therapies in Hematological Malignancies. Front Oncol 2019; 9:839. [PMID: 31555592 PMCID: PMC6722867 DOI: 10.3389/fonc.2019.00839] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/14/2019] [Indexed: 11/13/2022] Open
Abstract
Structural variants (SV) are changes in the genomic landscape that can alter gene expression levels and thus lead to disease development. The most common and best studied SVs in hematological malignancies are chromosomal translocations. Here, parts of two genes that are normally on different chromosomes come into close proximity due to a failure in DNA repair. As a consequence, fusion proteins which show a different function and/or cellular localization compared to the two original proteins are expressed, sometimes even at different levels. The identification of chromosomal translocations is often used to identify the specific disease a patient is suffering from. In addition, SVs such as deletions, duplications, inversions and single nucleotide polymorphisms (SNPs) can occur in hematopoietic cells and lead to their malignant transformations. Changes in the 3D genome structure have also recently been shown to impact disease development. In this review, we describe a variety of SVs occurring in different subtypes of hematological malignancies. Currently, most therapeutic approaches target fusion proteins which are the cellular product of chromosomal translocations. However, amplifications and SNPs also play a role in disease progression and can be targeted. We present some examples for different types of structural variants and how they are currently treated.
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Affiliation(s)
- Judith Schütte
- Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Julia Reusch
- Medizinische Fakultät, Universität Münster, Münster, Germany
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19
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Su M, Xiao Y, Ma J, Tang Y, Tian B, Zhang Y, Li X, Wu Z, Yang D, Zhou Y, Wang H, Liao Q, Wang W. Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers. Mol Cancer 2019; 18:90. [PMID: 30999909 PMCID: PMC6471953 DOI: 10.1186/s12943-019-1002-6] [Citation(s) in RCA: 311] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 03/13/2019] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer.
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Affiliation(s)
- Min Su
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China.,Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Yuhang Xiao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410001, People's Republic of China
| | - Junliang Ma
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Yanyan Tang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Bo Tian
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Yuqin Zhang
- Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410001, People's Republic of China
| | - Xu Li
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Zhining Wu
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Desong Yang
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Yong Zhou
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Hui Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Qianjin Liao
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. .,Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China.
| | - Wenxiang Wang
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, People's Republic of China. .,Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
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20
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Affiliation(s)
- Ji-Un Kang
- Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Korea
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