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1
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Fan C, Wang Q, Krijger PHL, Cats D, Selle M, Khorosjutina O, Dhanjal S, Schmierer B, Mei H, de Laat W, Ten Dijke P. Identification of a SNAI1 enhancer RNA that drives cancer cell plasticity. Nat Commun 2025; 16:2890. [PMID: 40133308 PMCID: PMC11937597 DOI: 10.1038/s41467-025-58032-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
Enhancer RNAs (eRNAs) are a pivotal class of enhancer-derived non-coding RNAs that drive gene expression. Here we identify the SNAI1 enhancer RNA (SNAI1e; SCREEM2) as a key activator of SNAI1 expression and a potent enforcer of transforming growth factor-β (TGF-β)/SMAD signaling in cancer cells. SNAI1e depletion impairs TGF-β-induced epithelial-mesenchymal transition (EMT), migration, in vivo extravasation, stemness, and chemotherapy resistance in breast cancer cells. SNAI1e functions as an eRNA to cis-regulate SNAI1 enhancer activity by binding to and strengthening the enrichment of the transcriptional co-activator bromodomain containing protein 4 (BRD4) at the local enhancer. SNAI1e selectively promotes the expression of SNAI1, which encodes the EMT transcription factor SNAI1. Furthermore, we reveal that SNAI1 interacts with and anchors the inhibitory SMAD7 in the nucleus, and thereby prevents TGF-β type I receptor (TβRI) polyubiquitination and proteasomal degradation. Our findings establish SNAI1e as a critical driver of SNAI1 expression and TGF-β-induced cell plasticity.
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Affiliation(s)
- Chuannan Fan
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Qian Wang
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Peter H L Krijger
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Davy Cats
- Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
| | - Miriam Selle
- Department of Medical Biochemistry and Biophysics, SciLifeLab and Karolinska Institute, Solna, Sweden
| | - Olga Khorosjutina
- Department of Medical Biochemistry and Biophysics, SciLifeLab and Karolinska Institute, Solna, Sweden
| | - Soniya Dhanjal
- Department of Medical Biochemistry and Biophysics, SciLifeLab and Karolinska Institute, Solna, Sweden
| | - Bernhard Schmierer
- Department of Medical Biochemistry and Biophysics, SciLifeLab and Karolinska Institute, Solna, Sweden
| | - Hailiang Mei
- Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
| | - Wouter de Laat
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
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2
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Li S, Zhang J, Wang X, Wang X, Song Y, Song X, Wang X, Cao W, Zhao C, Qi J, Zheng X, Xing Y. Super-Enhancer Target Gene CBP/p300-Interacting Transactivator With Glu/Asp-Rich C-Terminal Domain, 2 Cooperates With Transcription Factor Forkhead Box J3 to Inhibit Pulmonary Vascular Remodeling. Cell Prolif 2025:e13817. [PMID: 39907030 DOI: 10.1111/cpr.13817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 01/03/2025] [Accepted: 01/15/2025] [Indexed: 02/06/2025] Open
Abstract
The function of super-enhancers (SEs) in pulmonary hypertension (PH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), is currently unknown. We identified SEs-targeted genes in PASMCs with chromatin immunoprecipitation (ChIP)-sequence by H3K27ac antibody and proved that CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2 (CITED2) is an SEs-targeted gene through bioinformatics prediction, ChIP-PCR, dual-luciferase reporter gene assays and other experimental methods. We also found that the expression of CITED2 and the transcription factor Forkhead Box J3 (FOXJ3) was reduced in hypoxic mouse PASMCs. In addition, the expression of CITED2 and FOXJ3 also decreased in both the patients with idiopathic pulmonary arterial hypertension (iPAH) and the human PASMCs exposed to hypoxia. The decreased expression of CITED2 was reversed by co-transfection of FOXJ3 and SEs plasmids. Overexpressing of CITED2 attenuated the PASMCs proliferation induced by hypoxia. Lentiviral overexpression of CITED2 also reversed hypoxia-induced pulmonary hypertension mice model. Mechanically, the expression of CITED2 by affecting by FOXJ3, which binding with three SEs located in the about 2000 bp of TSS. In conclusion, we first identified that CITED2 is a kind of SEs-targeted gene, modulated by FOXJ3. The FOXJ3/SEs/CITED2 axis may become a new therapeutic target of PH.
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Affiliation(s)
- Songyue Li
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Jingya Zhang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Xu Wang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Xinru Wang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Yuyu Song
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Xinyue Song
- Central Laboratory, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Xiuli Wang
- Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Weiwei Cao
- Department of Pharmaceutical Analysis, Harbin Medical University-Daqing, Heilongjiang, People's Republic of China
| | - Chong Zhao
- Department of Literature Retrieval, Harbin Medical University-Daqing, Heilongjiang, People's Republic of China
| | - Jing Qi
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Xiaodong Zheng
- Department of Medical Genetics, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
| | - Yan Xing
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, People's Republic of China
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3
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Bao Y, Teng S, Zhai H, Zhang Y, Xu Y, Li C, Chen Z, Ren F, Wang Y. SE-lncRNAs in Cancer: Classification, Subcellular Localisation, Function and Corresponding TFs. J Cell Mol Med 2024; 28:e70296. [PMID: 39690143 DOI: 10.1111/jcmm.70296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 11/22/2024] [Accepted: 12/04/2024] [Indexed: 12/19/2024] Open
Abstract
Emerging evidence highlights certain long noncoding RNAs (lncRNAs) transcribed from or interacting with super-enhancer (SE) regulatory elements. These lncRNAs, known as SE-lncRNAs, are strongly linked to cancer and regulate cancer progression through multiple interactions with downstream targets. The expression of SE-lncRNAs is controlled by various transcription factors (TFs), and dysregulation of these TFs can contribute to cancer development. In this review, we discuss the characteristics, classification and subcellular distribution of SE-lncRNAs and summarise the role of key TFs in the transcription and regulation of SE-lncRNAs. Moreover, we examine the distinct functions and potential mechanisms of SE-lncRNAs in cancer progression.
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Affiliation(s)
- Yuxin Bao
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Songling Teng
- Department of Hand Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Hanjie Zhai
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Yuanzhuang Zhang
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Yeqiu Xu
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Chenghao Li
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Zhenjun Chen
- Department of Neurosurgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Fu Ren
- Department of Anatomy, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning, P. R. China
| | - Yong Wang
- Fourth Department of Orthopaedic Surgery, Central Hospital Affiliated To Shenyang Medical College, Shenyang, Liaoning, P. R. China
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4
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Wei D, Yuan L, Xu X, Wu C, Huang Y, Zhang L, Zhang J, Jing T, Liu Y, Wang B. Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer. Cancer Lett 2024; 605:217284. [PMID: 39366545 DOI: 10.1016/j.canlet.2024.217284] [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: 06/07/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/06/2024]
Abstract
Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.
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MESH Headings
- Gemcitabine
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Humans
- Drug Resistance, Neoplasm/genetics
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/metabolism
- Epigenesis, Genetic
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- beta Catenin/genetics
- beta Catenin/metabolism
- Cell Line, Tumor
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Enhancer Elements, Genetic
- Wnt Signaling Pathway/genetics
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Dianhui Wei
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Yuan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xiaoli Xu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Chengsi Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Yiwen Huang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jilong Zhang
- Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, China.
| | - Tiantian Jing
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
| | - Yizhen Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Boshi Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
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5
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Chu LY, Wu FC, Fang WK, Hong CQ, Huang LS, Zou HY, Peng YH, Chen H, Xie JJ, Xu YW. Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma. Biomed J 2024; 47:100662. [PMID: 37774793 PMCID: PMC11340493 DOI: 10.1016/j.bj.2023.100662] [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: 04/22/2023] [Revised: 08/25/2023] [Accepted: 09/22/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.
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Affiliation(s)
- Ling-Yu Chu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Fang-Cai Wu
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Wang-Kai Fang
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Chao-Qun Hong
- Department of Oncological Laboratory Research, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Li-Sheng Huang
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hai-Ying Zou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China.
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China.
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China.
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6
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Tapia A, Liu X, Malhi NK, Yuan D, Chen M, Southerland KW, Luo Y, Chen ZB. Role of long noncoding RNAs in diabetes-associated peripheral arterial disease. Cardiovasc Diabetol 2024; 23:274. [PMID: 39049097 PMCID: PMC11271017 DOI: 10.1186/s12933-024-02327-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/18/2024] [Indexed: 07/27/2024] Open
Abstract
Diabetes mellitus (DM) is a metabolic disease that heightens the risks of many vascular complications, including peripheral arterial disease (PAD). Various types of cells, including but not limited to endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages (MΦs), play crucial roles in the pathogenesis of DM-PAD. Long non-coding RNAs (lncRNAs) are epigenetic regulators that play important roles in cellular function, and their dysregulation in DM can contribute to PAD. This review focuses on the developing field of lncRNAs and their emerging roles in linking DM and PAD. We review the studies investigating the role of lncRNAs in crucial cellular processes contributing to DM-PAD, including those in ECs, VSMCs, and MΦ. By examining the intricate molecular landscape governed by lncRNAs in these relevant cell types, we hope to shed light on the roles of lncRNAs in EC dysfunction, inflammatory responses, and vascular remodeling contributing to DM-PAD. Additionally, we provide an overview of the research approach and methodologies, from identifying disease-relevant lncRNAs to characterizing their molecular and cellular functions in the context of DM-PAD. We also discuss the potential of leveraging lncRNAs in the diagnosis and therapeutics for DM-PAD. Collectively, this review provides a summary of lncRNA-regulated cell functions contributing to DM-PAD and highlights the translational potential of leveraging lncRNA biology to tackle this increasingly prevalent and complex disease.
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Affiliation(s)
- Alonso Tapia
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, 91010, USA
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Xuejing Liu
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Naseeb Kaur Malhi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Dongqiang Yuan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Muxi Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Kevin W Southerland
- Division of Vascular and Endovascular Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA
| | - Yingjun Luo
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Zhen Bouman Chen
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, 91010, USA.
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
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Bohrer C, Varon E, Peretz E, Reinitz G, Kinor N, Halle D, Nissan A, Shav-Tal Y. CCAT1 lncRNA is chromatin-retained and post-transcriptionally spliced. Histochem Cell Biol 2024; 162:91-107. [PMID: 38763947 PMCID: PMC11227459 DOI: 10.1007/s00418-024-02294-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 05/21/2024]
Abstract
Super-enhancers are unique gene expression regulators widely involved in cancer development. Spread over large DNA segments, they tend to be found next to oncogenes. The super-enhancer c-MYC locus forms long-range chromatin looping with nearby genes, which brings the enhancer and the genes into proximity, to promote gene activation. The colon cancer-associated transcript 1 (CCAT1) gene, which is part of the MYC locus, transcribes a lncRNA that is overexpressed in colon cancer cells through activation by MYC. Comparing different types of cancer cell lines using RNA fluorescence in situ hybridization (RNA FISH), we detected very prominent CCAT1 expression in HeLa cells, observed as several large CCAT1 nuclear foci. We found that dozens of CCAT1 transcripts accumulate on the gene locus, in addition to active transcription occurring from the gene. The accumulating transcripts are released from the chromatin during cell division. Examination of CCAT1 lncRNA expression patterns on the single-RNA level showed that unspliced CCAT1 transcripts are released from the gene into the nucleoplasm. Most of these unspliced transcripts were observed in proximity to the active gene but were not associated with nuclear speckles in which unspliced RNAs usually accumulate. At larger distances from the gene, the CCAT1 transcripts appeared spliced, implying that most CCAT1 transcripts undergo post-transcriptional splicing in the zone of the active gene. Finally, we show that unspliced CCAT1 transcripts can be detected in the cytoplasm during splicing inhibition, which suggests that there are several CCAT1 variants, spliced and unspliced, that the cell can recognize as suitable for export.
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Affiliation(s)
- Chaya Bohrer
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel
| | - Eli Varon
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel
| | - Eldar Peretz
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel
| | - Gita Reinitz
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel
| | - Noa Kinor
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel
| | - David Halle
- Biochemistry Laboratory, Samson Assuta Ashdod University Hospital, Ashdod, Israel
| | - Aviram Nissan
- Ziv Medical Center, Safed, Israel
- Surgical Innovation Laboratory, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Yaron Shav-Tal
- The Mina and Everard Goodman Faculty of Life Sciences and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel.
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8
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Liu S, Dai W, Jin B, Jiang F, Huang H, Hou W, Lan J, Jin Y, Peng W, Pan J. Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets. Mol Cancer 2024; 23:122. [PMID: 38844984 PMCID: PMC11157854 DOI: 10.1186/s12943-024-02033-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.
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Affiliation(s)
- Shenglan Liu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Wei Dai
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Bei Jin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Feng Jiang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Hao Huang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Wen Hou
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Jinxia Lan
- College of Public Health and Health Management, Gannan Medical University, Ganzhou, 341000, China
| | - Yanli Jin
- College of Pharmacy, Jinan University Institute of Tumor Pharmacology, Jinan University, Guangzhou, 510632, China
| | - Weijie Peng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China.
| | - Jingxuan Pan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
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9
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Shen Z, Naveed M, Bao J. Untacking small RNA profiling and RNA fragment footprinting: Approaches and challenges in library construction. WILEY INTERDISCIPLINARY REVIEWS. RNA 2024; 15:e1852. [PMID: 38715192 DOI: 10.1002/wrna.1852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 06/06/2024]
Abstract
Small RNAs (sRNAs) with sizes ranging from 15 to 50 nucleotides (nt) are critical regulators of gene expression control. Prior studies have shown that sRNAs are involved in a broad range of biological processes, such as organ development, tumorigenesis, and epigenomic regulation; however, emerging evidence unveils a hidden layer of diversity and complexity of endogenously encoded sRNAs profile in eukaryotic organisms, including novel types of sRNAs and the previously unknown post-transcriptional RNA modifications. This underscores the importance for accurate, unbiased detection of sRNAs in various cellular contexts. A multitude of high-throughput methods based on next-generation sequencing (NGS) are developed to decipher the sRNA expression and their modifications. Nonetheless, distinct from mRNA sequencing, the data from sRNA sequencing suffer frequent inconsistencies and high variations emanating from the adapter contaminations and RNA modifications, which overall skew the sRNA libraries. Here, we summarize the sRNA-sequencing approaches, and discuss the considerations and challenges for the strategies and methods of sRNA library construction. The pros and cons of sRNA sequencing have significant implications for implementing RNA fragment footprinting approaches, including CLIP-seq and Ribo-seq. We envision that this review can inspire novel improvements in small RNA sequencing and RNA fragment footprinting in future. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.
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Affiliation(s)
- Zhaokang Shen
- Department of Obstetrics and Gynecology, Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China (USTC), Hefei, Anhui, China
| | - Muhammad Naveed
- Hefei National Laboratory for Physical Sciences at Microscale, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China (USTC), Hefei, Anhui, China
- Department of Obstetrics and Gynecology, Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jianqiang Bao
- Department of Obstetrics and Gynecology, Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China (USTC), Hefei, Anhui, China
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10
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Yu X, Bu C, Yang X, Jiang W, He X, Sun R, Guo H, Shang L, Ou C. Exosomal non-coding RNAs in colorectal cancer metastasis. Clin Chim Acta 2024; 556:117849. [PMID: 38417779 DOI: 10.1016/j.cca.2024.117849] [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: 06/08/2023] [Revised: 02/24/2024] [Accepted: 02/25/2024] [Indexed: 03/01/2024]
Abstract
Colorectal cancer (CRC) is a type of gastrointestinal cancer with high morbidity and mortality rates, and is often accompanied by distant metastases. Metastasis is a major cause of shortened survival time and poor treatment outcomes for patients with CRC. However, the molecular mechanisms underlying the metastasis of CRC remain unclear. Exosomes are a class of small extracellular vesicles that originate from almost all human cells and can transmit biological information (e.g., nucleic acids, lipids, proteins, and metabolites) from secretory cells to target recipient cells. Recent studies have revealed that non-coding RNAs (ncRNAs) can be released by exosomes into the tumour microenvironment or specific tissues, and play a pivotal role in tumorigenesis by regulating a series of key molecules or signalling pathways, particularly those involved in tumour metastasis. Exosomal ncRNAs have potential as novel therapeutic targets for CRC metastasis, and can also be used as liquid biopsy biomarkers because of their specificity and sensitivity. Therefore, further investigations into the biological function and clinical value of exosomal ncRNAs will be of great value for the prevention, early diagnosis, and treatment of CRC metastasis.
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Affiliation(s)
- Xiaoqian Yu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Chiwen Bu
- Department of General Surgery, People's Hospital of Guanyun County, Lianyungang 222200, Jiangsu, China
| | - Xuejie Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Wenying Jiang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Ru Sun
- Department of Blood Transfusion, Affiliated Hospital of North Sichuan Medical College, Xichang 637000, Sichuan, China
| | - Hongbin Guo
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Li Shang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
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11
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Xu C, Xu P, Zhang J, He S, Hua T, Huang A. Research progress and perspectives of noncoding RNAs in adrenocortical carcinoma: A review. Medicine (Baltimore) 2024; 103:e36908. [PMID: 38277554 PMCID: PMC10817030 DOI: 10.1097/md.0000000000036908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/18/2023] [Indexed: 01/28/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy. Although surgery can cure localized disease, but the majority of patients experience recurrence of ACC. The 5-year survival rate of patients with metastatic ACC is <15%, and the prognosis is poor. Therefore, it is urgent to explore the potential diagnostic markers and therapeutic targets for ACC. Recently, it has been proved that non-coding RNA (ncRNAs) is widely involved in pathological and physiological processes, including tumorigenesis and development. Aberrantly expressed ncRNAs have been found to be involved in the pathogenesis of ACC. Here, we summarized the expression patterns and the molecular mechanism of the involvement of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in ACC development. To explore the clinical value of ncRNAs as noninvasive biomarkers of ACC, we also displayed the relationship between the expression level of ncRNAs and the diagnosis and prognosis of patients with ACC.
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Affiliation(s)
- Changfen Xu
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
| | - Peiyao Xu
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
| | - Jiaqi Zhang
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
| | - Sheng He
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
| | - Tingting Hua
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
| | - Aiwu Huang
- Department of Gynecology and Obstetrics, Hangzhou Lin’an TCM Hospital, Lin’an District, Hangzhou, China
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12
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Chu J, Liu W, Hu X, Zhang H, Jiang J. P2RY13 is a prognostic biomarker and associated with immune infiltrates in renal clear cell carcinoma: A comprehensive bioinformatic study. Health Sci Rep 2023; 6:e1646. [PMID: 38045624 PMCID: PMC10691167 DOI: 10.1002/hsr2.1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/03/2023] [Accepted: 10/10/2023] [Indexed: 12/05/2023] Open
Abstract
Background and Aims Clear cell renal cell carcinoma (ccRCC) is a common and aggressive form of cancer with a high incidence globally. This study aimed to investigate the role of P2RY13 in the progression of ccRCC and elucidate its mechanism of action. Methods Gene Expression Omnibus and The Cancer Genome Atlas databases were used to extract gene expression profiles of ccRCC. These profiles were annotated and visualized by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses, as well as Gene Set Enrichment Analysis (GSEA). The STRING database was used to establish a protein-protein interaction network and to analyze the functional similarity. The GEPIA2 database was used to predict survival associated with hub genes. Meanwhile, the TIMER2.0 database was used to assess immune cell infiltration and its link with the hub genes. Immunohistochemistry (IHC) was used to determine the difference between ccRCC and adjacent normal tissue. Results We identified 272 differentially expressed genes (DEGs). GO and KEGG analyses suggested that DEGs were primarily involved in lymphocyte activation, inflammatory response, immunological effector mechanism pathways. By cytohubba, the 20 highest-scoring hub genes were screened to identify critical genes in the protein-protein interaction network linked with ccRCC. Resting dendritic cells, CD8 T cells, and activated mast cells all showed a significant positive correlation with these hub genes. Moreover, a higher immune score was associated with increased prognostic risk scores, which in turn correlated with a poorer prognosis. IHC revealed that P2RY13 was expressed at higher levels in ccRCC compared to para-cancer tissues. Conclusion Identifying the DEGs will aid in the understanding of the causes and molecular mechanisms involved in ccRCC. P2RY13 may play a pivotal role in the progression and prognosis of ccRCC, potentially driving carcinogenesis though immune system mechanisms.
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Affiliation(s)
- Jie Chu
- Department of OncologyThe First People's Hospital of ZiyangZiyangChina
| | - Wei Liu
- Department of General Family MedicineThe First People's Hospital of NeiJiangNeiJiangChina
| | - Xinyue Hu
- Department of Clinical Laboratory, Kunming First People's HospitalKunming Medical UniversityKunmingChina
| | - Huiling Zhang
- Department of OncologyThe First People's Hospital of ZiyangZiyangChina
| | - Jiudong Jiang
- Department of SurgeryThe First People's Hospital of ZiYangZiyangChina
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13
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Zhang K, Lu J, Fang F, Zhang Y, Yu J, Tao Y, liu W, Lu L, Zhang Z, Chu X, Wang J, Li X, Tian Y, Li Z, Li Q, Sang X, Ma L, Wang N, Pan J, Hu S. Super Enhancer Regulatory Gene FYB1 Promotes the Progression of T Cell Acute Lymphoblastic Leukemia by Activating IGLL1. J Immunol Res 2023; 2023:3804605. [PMID: 37767202 PMCID: PMC10522422 DOI: 10.1155/2023/3804605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 03/24/2023] [Accepted: 07/25/2023] [Indexed: 09/29/2023] Open
Abstract
Background Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.
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Affiliation(s)
- Kunlong Zhang
- Children's Hospital of Soochow University, Suzhou 215003, China
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Jun Lu
- Department of Hematology, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Fang Fang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Yongping Zhang
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Juanjuan Yu
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Yanfang Tao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Wenyuan liu
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Lihui Lu
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Zimu Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Xinran Chu
- Department of Hematology, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Jianwei Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Xiaolu Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Yuanyuan Tian
- Department of Hematology, Children's Hospital of Soochow University, Suzhou 215003, China
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Zhiheng Li
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Qian Li
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Xu Sang
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Li Ma
- Children's Hospital of Soochow University, Suzhou 215003, China
| | - Ningling Wang
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China
| | - Shaoyan Hu
- Department of Hematology, Children's Hospital of Soochow University, Suzhou 215003, China
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14
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Wang M, Chen Q, Wang S, Xie H, Liu J, Huang R, Xiang Y, Jiang Y, Tian D, Bian E. Super-enhancers complexes zoom in transcription in cancer. J Exp Clin Cancer Res 2023; 42:183. [PMID: 37501079 PMCID: PMC10375641 DOI: 10.1186/s13046-023-02763-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/13/2023] [Indexed: 07/29/2023] Open
Abstract
Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.
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Affiliation(s)
- MengTing Wang
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - QingYang Chen
- Department of Clinical MedicineThe Second School of Clinical Medical, Anhui Medical University, Hefei, China
| | - ShuJie Wang
- Department of Clinical MedicineThe Second School of Clinical Medical, Anhui Medical University, Hefei, China
| | - Han Xie
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China
| | - RuiXiang Huang
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China
| | - YuFei Xiang
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China
| | - YanYi Jiang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China.
| | - DaSheng Tian
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China.
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China.
| | - ErBao Bian
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, 230601, Anhui Province, China.
- Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China.
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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15
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Chen Z, Tian D, Chen X, Cheng M, Xie H, Zhao J, Liu J, Fang Z, Zhao B, Bian E. Super-enhancer-driven lncRNA LIMD1-AS1 activated by CDK7 promotes glioma progression. Cell Death Dis 2023; 14:383. [PMID: 37385987 PMCID: PMC10310775 DOI: 10.1038/s41419-023-05892-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 05/07/2023] [Accepted: 06/15/2023] [Indexed: 07/01/2023]
Abstract
Long non-coding RNAs (lncRNAs) are tissue-specific expression patterns and dysregulated in cancer. How they are regulated still needs to be determined. We aimed to investigate the functions of glioma-specific lncRNA LIMD1-AS1 activated by super-enhancer (SE) and identify the potential mechanisms. In this paper, we identified a SE-driven lncRNA, LIMD1-AS1, which is expressed at significantly higher levels in glioma than in normal brain tissue. High LIMD1-AS1 levels were significantly associated with a shorter survival time of glioma patients. LIMD1-AS1 overexpression significantly enhanced glioma cells proliferation, colony formation, migration, and invasion, whereas LIMD1-AS1 knockdown inhibited their proliferation, colony formation, migration, and invasion, and the xenograft tumor growth of glioma cells in vivo. Mechanically, inhibition of CDK7 significantly attenuates MED1 recruitment to the super-enhancer of LIMD1-AS1 and then decreases the expression of LIMD1-AS1. Most importantly, LIMD1-AS1 could directly bind to HSPA5, leading to the activation of interferon signaling. Our findings support the idea that CDK7 mediated-epigenetically activation of LIMD1-AS1 plays a crucial role in glioma progression and provides a promising therapeutic approach for patients with glioma.
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Affiliation(s)
- Zhigang Chen
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - Dasheng Tian
- Department of Orthopaedics, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - Xueran Chen
- Department of Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, Anhui, 230601, China
- Anhui Province Key Laboratory of Medical Physics and Technology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, Anhui, 230601, China
| | - Meng Cheng
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - Han Xie
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - JiaJia Zhao
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - Jun Liu
- Department of Orthopaedics, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China
| | - Zhiyou Fang
- Department of Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, Anhui, 230601, China.
- Anhui Province Key Laboratory of Medical Physics and Technology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, Anhui, 230601, China.
| | - Bing Zhao
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China.
- Cerebral Vascular Disease Research Center, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China.
| | - Erbao Bian
- Department of Neurosurgery, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China.
- Department of Orthopaedics, the Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui, 230601, China.
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16
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Ohira T, Yoshimura K, Kugoh H. Human artificial chromosome carrying 3p21.3-p22.2 region suppresses hTERT transcription in oral cancer cells. Chromosome Res 2023; 31:17. [PMID: 37353691 PMCID: PMC10289923 DOI: 10.1007/s10577-023-09726-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/24/2023] [Accepted: 06/06/2023] [Indexed: 06/25/2023]
Abstract
Telomerase is a ribonucleoprotein ribonucleic enzyme that elongates telomere repeat sequences at the ends of chromosomes and contributes to cellular immortalization. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been observed to be reactivated in immortalized cells. Notably, most cancer cells have been found to have active hTERT mRNA transcription, resulting in continuous cell division, which is crucial for malignant transformation. Therefore, discovering mechanisms underlying the regulation of hTERT transcription is an attractive target for cancer-specific treatments.Loss of heterozygosity (LOH) of chromosome 3p21.3 has been frequently observed in human oral squamous cell carcinoma (OSCC). Moreover, we previously reported that HSC3 OSCC microcell hybrid clones with an introduced human chromosome 3 (HSC3#3) showed inhibition of hTERT transcription compared with the parental HSC3 cells. This study examined whether hTERT transcription regulators are present in the 3p21.3 region. We constructed a human artificial chromosome (HAC) vector (3p21.3-HAC) with only the 3p21.3-p22.2 region and performed functional analysis using the 3p21.3-HAC. HSC3 microcell hybrid clones with an introduced 3p21.3-HAC exhibited significant suppression of hTERT transcription, similar to the microcell hybrid clones with an intact chromosome 3. In contrast, HSC3 clones with truncated chromosome 3 with deletion of the 3p21.3 region (3delp21.3) showed no effect on hTERT expression levels. These results provide direct evidence that hTERT suppressor gene(s) were retained in the 3p21.3 region, suggesting that the presence of regulatory factors that control telomerase enzyme activity may be involved in the development of OSCC.
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Affiliation(s)
- Takahito Ohira
- Department of Chromosome Biomedical Engineering, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan
- Chromosome Engineering Research Center, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan
| | - Kaho Yoshimura
- Department of Chromosome Biomedical Engineering, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan
| | - Hiroyuki Kugoh
- Department of Chromosome Biomedical Engineering, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan.
- Division of Genome and Cellular Function, Department of Molecular and Cellular Biology, Tottori University, 86 Nishi-Cho, Yonago, Tottori, 683-8503, Japan.
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17
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Cianci P, Tartaglia N, Ambrosi A, Restini E. Editorial: Artificial intelligence in colorectal cancers. Front Oncol 2023; 13:1206311. [PMID: 37287913 PMCID: PMC10242180 DOI: 10.3389/fonc.2023.1206311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Affiliation(s)
- Pasquale Cianci
- Department of Surgery and Traumatology, Azienda Sanitaria Locale della Provincia di Barletta Andri Trani (ASL BT), Andria, Italy
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Nicola Tartaglia
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Ambrosi
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Enrico Restini
- Department of Surgery and Traumatology, Azienda Sanitaria Locale della Provincia di Barletta Andri Trani (ASL BT), Andria, Italy
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Zhang Y, Zhan L, Li J, Jiang X, Yin L. Insights into N6-methyladenosine (m6A) modification of noncoding RNA in tumor microenvironment. Aging (Albany NY) 2023; 15:3857-3889. [PMID: 37178254 PMCID: PMC10449301 DOI: 10.18632/aging.204679] [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: 08/25/2022] [Accepted: 04/15/2023] [Indexed: 05/15/2023]
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.
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Affiliation(s)
- YanJun Zhang
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Lijuan Zhan
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Jing Li
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Xue Jiang
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Li Yin
- Department of Biopharmaceutics, Yulin Normal University, Guangxi, Yulin 537000, China
- Bioengineering and Technology Center for Native Medicinal Resources Development, Yulin Normal University, Yulin 537000, China
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19
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Zhuang HH, Qu Q, Teng XQ, Dai YH, Qu J. Superenhancers as master gene regulators and novel therapeutic targets in brain tumors. Exp Mol Med 2023; 55:290-303. [PMID: 36720920 PMCID: PMC9981748 DOI: 10.1038/s12276-023-00934-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 11/27/2022] [Accepted: 12/04/2022] [Indexed: 02/02/2023] Open
Abstract
Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.
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Affiliation(s)
- Hai-Hui Zhuang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410007, PR China
- Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410007, PR China
| | - Xin-Qi Teng
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China
| | - Ying-Huan Dai
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, 410011, PR China
| | - Jian Qu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China.
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20
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Li J, Wang J, Wang Y, Zhao X, Su T. E2F1 combined with LINC01004 super-enhancer to promote hepatocellular carcinoma cell proliferation and metastasis. Clin Epigenetics 2023; 15:17. [PMID: 36721155 PMCID: PMC9887888 DOI: 10.1186/s13148-023-01428-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 01/13/2023] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Super-enhancer-associated lncRNAs play important roles in the occurrence and development of malignant tumors, including hepatocellular carcinoma (HCC). OBJECTIVES The current work aimed to identify and characterize super-enhancer-associated lncRNAs in the pathogenesis of HCC. METHODS H3K27ac ChIP-seq data from HepG2 cell line and two HCC tissues were used to identify super-enhancer-associated lncRNAs in HCC. JQ-1 treatment and CRISPR-dCas9 system were performed to confirm super-enhancer activity. Quantitative real-time PCR (qPCR), ChIP-qPCR, and dual-luciferase reporter system assay demonstrated the regulation of E2F1 on super-enhancer. Functional loss experiment was used to identify the function of LINC01004. RESULTS In this study, we identified and characterized LINC01004, a novel super-enhancer-associated lncRNA, as a crucial oncogene in HCC. LINC01004 was upregulated in liver cancer tissues and was associated with poor patient prognosis. Moreover, LINC01004 promoted cell proliferation and metastasis of HCC. The binding of E2F1 to the super-enhancer could promote the transcription of LINC01004, while the inhibition of super-enhancer activity decreased LINC01004 expression. CONCLUSION This finding might provide mechanistic insights into the molecular mechanisms underlying hepatocarcinogenesis and the biological function of super-enhancer. LINC01004 can serve as a potential therapeutic target for HCC patient.
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Affiliation(s)
- Jingxuan Li
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Jiying Wang
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Yanping Wang
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xueyan Zhao
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Tao Su
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China.
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21
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Li XP, Qu J, Teng XQ, Zhuang HH, Dai YH, Yang Z, Qu Q. The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors. Int J Biol Sci 2023; 19:1036-1048. [PMID: 36923930 PMCID: PMC10008685 DOI: 10.7150/ijbs.78535] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/09/2022] [Indexed: 02/05/2023] Open
Abstract
Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.
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Affiliation(s)
- Xiang-Ping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410007, PR China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410007, PR China
| | - Jian Qu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, Changsha 410011, PR China.,Hunan key laboratory of the research and development of novel pharmaceutical preparations, Changsha Medical University, Changsha, 410219, PR China
| | - Xin-Qi Teng
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, Changsha 410011, PR China
| | - Hai-Hui Zhuang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, Changsha 410011, PR China
| | - Ying-Huan Dai
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha 410011, PR China
| | - Zhi Yang
- Department of Colorectal and Anal Surgery, Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha 410007, PR China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410007, PR China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410007, PR China.,Hunan key laboratory of the research and development of novel pharmaceutical preparations, Changsha Medical University, Changsha, 410219, PR China
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22
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Wang D, Han Y, Peng L, Huang T, He X, Wang J, Ou C. Crosstalk between N6-methyladenosine (m6A) modification and noncoding RNA in tumor microenvironment. Int J Biol Sci 2023; 19:2198-2219. [PMID: 37151887 PMCID: PMC10158024 DOI: 10.7150/ijbs.79651] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 04/05/2023] [Indexed: 05/09/2023] Open
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.
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Affiliation(s)
- Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yingying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Lushan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- ✉ Corresponding authors: Chunlin Ou. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Junpu Wang. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Xiaoyun He. Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha 410031, Hunan, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- ✉ Corresponding authors: Chunlin Ou. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Junpu Wang. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Xiaoyun He. Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- ✉ Corresponding authors: Chunlin Ou. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Junpu Wang. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China. ; Xiaoyun He. Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
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23
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Saadi W, Fatmi A, Pallardó FV, García-Giménez JL, Mena-Molla S. Long Non-Coding RNAs as Epigenetic Regulators of Immune Checkpoints in Cancer Immunity. Cancers (Basel) 2022; 15:cancers15010184. [PMID: 36612180 PMCID: PMC9819025 DOI: 10.3390/cancers15010184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/19/2022] [Accepted: 12/25/2022] [Indexed: 12/30/2022] Open
Abstract
In recent years, cancer treatment has undergone significant changes, predominantly in the shift towards immunotherapeutic strategies using immune checkpoint inhibitors. Despite the clinical efficacy of many of these inhibitors, the overall response rate remains modest, and immunotherapies for many cancers have proved ineffective, highlighting the importance of knowing the tumor microenvironment and heterogeneity of each malignancy in patients. Long non-coding RNAs (lncRNAs) have attracted increasing attention for their ability to control various biological processes by targeting different molecular pathways. Some lncRNAs have a regulatory role in immune checkpoints, suggesting they might be utilized as a target for immune checkpoint treatment. The focus of this review is to describe relevant lncRNAs and their targets and functions to understand key regulatory mechanisms that may contribute in regulating immune checkpoints. We also provide the state of the art on super-enhancers lncRNAs (selncRNAs) and circular RNAs (circRNAs), which have recently been reported as modulators of immune checkpoint molecules within the framework of human cancer. Other feasible mechanisms of interaction between lncRNAs and immune checkpoints are also reported, along with the use of miRNAs and circRNAs, in generating new tumor immune microenvironments, which can further help avoid tumor evasion.
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Affiliation(s)
- Wiam Saadi
- Department of Biology, Faculty of Nature, Life and Earth Sciences, University of Djillali Bounaama, Khemis Miliana 44225, Algeria
- Correspondence: (W.S.); (S.M.-M.)
| | - Ahlam Fatmi
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
| | - Federico V. Pallardó
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
| | - José Luis García-Giménez
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
| | - Salvador Mena-Molla
- INCLIVA Health Research Institute, INCLIVA, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- Correspondence: (W.S.); (S.M.-M.)
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24
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Yang X, Wang C, Nie H, Zhou J, He X, Ou C. Minichromosome maintenance gene family: potential therapeutic targets and prognostic biomarkers for lung squamous cell carcinoma. Aging (Albany NY) 2022; 14:9167-9185. [PMID: 36445337 PMCID: PMC9740372 DOI: 10.18632/aging.204399] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022]
Abstract
The minichromosome maintenance (MCM) gene family comprises of ten members with key roles in eukaryotic DNA replication and are associated with the occurrence and progression of many tumors. However, whether the MCM family contributes to lung squamous cell carcinoma (LUSC) is unclear. In this study, we performed bioinformatic analysis to identify the roles of MCM genes in patients with LUSC. We also evaluated their differential gene expression, prognostic correlation, DNA methylation, functional enrichment of genetic alterations, and immunomodulation. According to the Tumor Immune Estimation Resource database, the expression of MCM2-10 mRNA was elevated in LUSC tissues. According to the Gene Expression Profiling Interactive Analysis database, MCM2-8 and MCM10 were considerably upregulated in LUSC tissues, and protein levels of all MCMs were increased in LUSC tissues. In addition, among the MCM family members, the expression of MCM3 and MCM7 showed the strongest correlation with the prognoses of patients with LUSC. To clarify the role and mechanisms of the MCM family, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment studies were performed. We detected a significant correlation between the expression patterns of MCM family members and infiltrating immune cells. In conclusion, our results improve the understanding of the aberrant expression of MCM family members in LUSC. These findings demonstrate the potential of the MCM family as therapeutic targets and biomarkers for the diagnosis and prognosis of LUSC.
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Affiliation(s)
- Xuejie Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Chunrong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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25
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Peng LS, Duan SL, Li RQ, Wang D, Han YY, Huang T, Yu YP, Ou CL, Wang JP. Prognostic value and immune infiltration of the gasdermin family in lung adenocarcinoma. Front Oncol 2022; 12:1043862. [PMID: 36505798 PMCID: PMC9732578 DOI: 10.3389/fonc.2022.1043862] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022] Open
Abstract
Background The GSDM family includes six members, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5), and PJVK (Pejvakin, DFNB59), which can induce pyroptosis, thereby regulating the tumorigenesis of various cancers. However, the clinical characteristics and role of the GSDM family in LUAD are not well understood. Methods In this study, several important bioinformatics databases were used to integrate the analysis of the expression, prognostic value, and immune infiltration of GSDMs in LUAD. These databases include UALCAN, DiseaseMeth, GEPIA, THPA, cBioPortal, TIMER, WebGestalt, STRING database, and Cytoscape. Results The findings from the UALCAN database revealed that the expression of all six GSDMs based on the tumor stage in LUAD was increased (particularly GSDMD). Our IHC results verified it. Additionally, the DiseaseMeth database showed that the methylation levels of GSDMA, GSDMB, GSDMC, and GSDMD were decreased. The expression of six GSDMs was related to shorter overall survival in patients with LUAD, according to the GEPIA database. The cBioPortal database was further used to explore the alteration rate and correlated genes in LUAD. Subsequently, these genes were subjected to functional enrichment and protein-protein interaction network analyses. We identified that the GSDM family regulate several signaling pathways, including immune-associated signaling pathways. According to tumor-infiltrating immune cell analysis from the TIMER database, GSDM family members are associated with the infiltration of important immune cells and their signature markers. Conclusions GSDM family may be prognostic markers and novel strategies for the treatment of LUAD.
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Affiliation(s)
- Lu-Shan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Sai-Li Duan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Run-Qi Li
- Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan, China
| | - Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying-Ying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu-Pei Yu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chun-Lin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Chun-Lin Ou, ; Jun-Pu Wang,
| | - Jun-Pu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China,Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan, China,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China,*Correspondence: Chun-Lin Ou, ; Jun-Pu Wang,
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26
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Cao Z, Shu Y, Wang J, Wang C, Feng T, Yang L, Shao J, Zou L. Super enhancers: Pathogenic roles and potential therapeutic targets for acute myeloid leukemia (AML). Genes Dis 2022; 9:1466-1477. [PMID: 36157504 PMCID: PMC9485276 DOI: 10.1016/j.gendis.2022.01.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 11/04/2022] Open
Abstract
Acute myeloid leukemia (AML) is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments. The potent anti-cancer effects of bromodomain and extra-terminal domain (BET) inhibitors, targeting the key component of super enhancers, in early clinical trials on AML patients, implies the critical role of super enhancers in AML. Here, we review the concept and characteristic of super enhancer, and then summarize the current researches about super enhancers in AML pathogenesis, diagnosis and classification, followed by illustrate the potential super enhancer-related targets and drugs, and propose the future directions of super enhancers in AML. This information provides integrated insight into the roles of super enhancers in this disease.
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Affiliation(s)
- Ziyang Cao
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
- Institute of Pediatric Infection, Immunity, Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, PR China
| | - Yi Shu
- Center for Clinical Molecular Laboratory Medicine of Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
| | - Jinxia Wang
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
- Institute of Pediatric Infection, Immunity, Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, PR China
| | - Chunxia Wang
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
- Institute of Pediatric Infection, Immunity, Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, PR China
| | - Tienan Feng
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Li Yang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
| | - Jingbo Shao
- Department of Hematology/Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
| | - Lin Zou
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, PR China
- Institute of Pediatric Infection, Immunity, Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, PR China
- Center for Clinical Molecular Laboratory Medicine of Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
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27
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Liang X, Meng Y, Li C, Liu L, Wang Y, Pu L, Hu L, Li Q, Zhai Z. Super-Enhancer–Associated nine-gene prognostic score model for prediction of survival in chronic lymphocytic leukemia patients. Front Genet 2022; 13:1001364. [PMID: 36186463 PMCID: PMC9521409 DOI: 10.3389/fgene.2022.1001364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a type of highly heterogeneous mature B-cell malignancy with various disease courses. Although a multitude of prognostic markers in CLL have been reported, insights into the role of super-enhancer (SE)–related risk indicators in the occurrence and development of CLL are still lacking. A super-enhancer (SE) is a cluster of enhancers involved in cell differentiation and tumorigenesis, and is one of the promising therapeutic targets for cancer therapy in recent years. In our study, the CLL-related super-enhancers in the training database were processed by LASSO-penalized Cox regression analysis to screen a nine-gene prognostic model including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. The SE-related risk score was further constructed and it was found that the predictive performance with overall survival and time-to-treatment (TTT) was satisfactory. Moreover, a high correlation was found between the risk score and already known prognostic markers of CLL. In the meantime, we noticed that the expressions of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from those of healthy donors (p < 0.01). Moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly. Finally, an interactive nomogram consisting of the nine-gene risk group and four clinical traits was established. The inhibitors of mTOR and cyclin-dependent kinases (CDKs) were considered effective in patients in the high-risk group according to the pRRophetic algorithm. Collectively, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification and treatment of CLL patients in the future.
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28
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Huang T, Peng L, Han Y, Wang D, He X, Wang J, Ou C. Lipid nanoparticle-based mRNA vaccines in cancers: Current advances and future prospects. Front Immunol 2022; 13:922301. [PMID: 36090974 PMCID: PMC9458914 DOI: 10.3389/fimmu.2022.922301] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 08/08/2022] [Indexed: 12/24/2022] Open
Abstract
Messenger RNA (mRNA) vaccines constitute an emerging therapeutic method with the advantages of high safety and efficiency as well as easy synthesis; thus, they have been widely used in various human diseases, especially in malignant cancers. However, the mRNA vaccine technology has some limitations, such as instability and low transitive efficiency in vivo, which greatly restrict its application. The development of nanotechnology in the biomedical field offers new strategies and prospects for the early diagnosis and treatment of human cancers. Recent studies have demonstrated that Lipid nanoparticle (LNP)-based mRNA vaccines can address the poor preservation and targeted inaccuracy of mRNA vaccines. As an emerging cancer therapy, mRNA vaccines potentially have broad future applications. Unlike other treatments, cancer mRNA vaccines provide specific, safe, and tolerable treatments. Preclinical studies have used personalized vaccines to demonstrate the anti-tumor effect of mRNA vaccines in the treatment of various solid tumors, including colorectal and lung cancer, using these in a new era of therapeutic cancer vaccines. In this review, we have summarized the latest applications and progress of LNP-based mRNA vaccines in cancers, and discussed the prospects and limitations of these fields, thereby providing novel strategies for the targeted therapy of cancers.
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Affiliation(s)
- Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Lushan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoyun He, ; Junpu Wang, ; Chunlin Ou,
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, School of Basic Medicine, Central South University, Changsha, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoyun He, ; Junpu Wang, ; Chunlin Ou,
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoyun He, ; Junpu Wang, ; Chunlin Ou,
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29
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Wang Y, Nie H, Li H, Liao Z, Yang X, He X, Ma J, Zhou J, Ou C. The Hippo Pathway Effector Transcriptional Co-activator With PDZ-Binding Motif Correlates With Clinical Prognosis and Immune Infiltration in Colorectal Cancer. Front Med (Lausanne) 2022; 9:888093. [PMID: 35865173 PMCID: PMC9295930 DOI: 10.3389/fmed.2022.888093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
The transcriptional co-activator with PDZ-binding motif (TAZ) is a downstream effector of the Hippo pathway. It has been identified as an oncogene in certain tumor types; however, the function and role of TAZ in colorectal cancer (CRC) has not been illustrated. Here, we aimed to analyze the expression and role of TAZ in CRC. In this study, we investigated the expression level of TAZ in 127 CRC and matched adjacent normal tissues by immunohistochemistry (IHC) and analyzed its correlation with clinicopathological characteristics in CRC. Moreover, we further analyzed the role of TAZ in the CRC-associated immunology using integrative bioinformatic analyses. The cBioPortal and WebGestalt database were used to analyze the co-expressed genes and related pathways of TAZ in CRC by gene ontology (GO) and KEGG enrichment analyses. Meanwhile, the correlations between TAZ and the infiltrating immune cells and gene markers were analyzed by TIMER database. Our study revealed that TAZ expression is higher in CRC tissues than in matched adjacent non-tumor tissues. In addition, CRC patients with higher TAZ expression demonstrated poor overall survival (OS) and recurrent-free survival rates as compared to CRC patients with lower expression of TAZ. Furthermore, the TAZ expression was identified to closely associate with the immune infiltration of CD4 + T, CD8 + T, and B cells. Taken together, our findings suggest that TAZ may serve as a promising prognostic biomarker and therapeutic target in CRC.
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Affiliation(s)
- Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Huiling Li
- Department of Pathology, Rizhao City People’s Hospital, Rizhao, China
| | - Zhiming Liao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xuejie Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Jian Ma
- Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Chunlin Ou,
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30
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Wen Y, Zhang X, Li X, Tian L, Shen S, Ma J, Ai F. Histone deacetylase (HDAC) 11 inhibits matrix metalloproteinase (MMP) 3 expression to suppress colorectal cancer metastasis. J Cancer 2022; 13:1923-1932. [PMID: 35399729 PMCID: PMC8990422 DOI: 10.7150/jca.66914] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/17/2022] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence has implicated invasion and metastasis are the major common reason of treatment failure and the leading cause of death in colorectal cancer (CRC). Many members of the HDAC family have been reported to be key factors in the genesis and progression of cancer. Until now, few research focused on the actual expression patterns of HDAC11 in most malignancies. In the current study, we found that the expression of HDAC11 is decreased in mouse colitis tissues and colitis-associated cancer (CAC) tissue compared with normal colon tissue. Clinically HDAC11 expression is significantly lower in colorectal cancer tissues of patients and correlated with lymph node metastasis. Additionally, HDAC11 is downregulated in the relative high metastatic potential colorectal cancer cells. We also found HDAC11 inhibits the migration and invasion of colorectal cancer cell by downregulating Mmp3 expression. At the molecular level, the expression of HDAC11 inversely correlated with the level of histone H3K9 and H3K14 acetylation. In addition, analysis of chromatin-protein association by ChIP-qPCR demonstrated that the level of H3K9 acetylation correlated with the upregulation of Mmp3. Through a better understanding of this previously unknown role of HDAC11 in migration and invasion of colorectal cancer, HDAC11 may become a novel candidate for developing rational therapeutic strategies.
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Affiliation(s)
- Yuqing Wen
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
| | - Xuemei Zhang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xiayu Li
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Shourong Shen
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Jian Ma
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
| | - Feiyan Ai
- Department of Gastroenterology, the Third Xiangya Hospital, Central South University, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Changsha, China
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31
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Nie H, Wu Y, Ou C, He X. Comprehensive Analysis of SMC Gene Family Prognostic Value and Immune Infiltration in Patients With Pancreatic Adenocarcinoma. Front Med (Lausanne) 2022; 9:832312. [PMID: 35372377 PMCID: PMC8965256 DOI: 10.3389/fmed.2022.832312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/09/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic adenocarcinoma (PAAD) is a malignant tumor with high morbidity and mortality worldwide. Members from the structural maintenance of chromosomes (SMC) gene family function as oncogenes in various tumor types, but their roles in PAAD have not been elucidated. In this study, we aimed to explore the role of the SMC family in tumor progression and cancer immune infiltration in PAAD using integrative bioinformatic analyses. The results showed that the SMC 1A, 2, 3, 4, and 6 were overexpressed in PAAD tissues; of these, SMC 1A, 4, 5, and 6 could be potential prognostic biomarkers for PAAD. The expression of SMC genes was found to be strongly associated with immune cell infiltration. According to the infiltrative status of various immune cells, the mRNA expression of SMC genes in PAAD was associated with the overall and recurrence-free survival of patients. In conclusion, the SMC gene family is associated with PAAD and may be involved in tumorigenesis and cancer-immune interactions; thus, members from this gene family may serve as promising prognostic and therapeutic biomarkers of PAAD.
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Affiliation(s)
- Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yanhao Wu
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
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32
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Ginghina O, Hudita A, Zamfir M, Spanu A, Mardare M, Bondoc I, Buburuzan L, Georgescu SE, Costache M, Negrei C, Nitipir C, Galateanu B. Liquid Biopsy and Artificial Intelligence as Tools to Detect Signatures of Colorectal Malignancies: A Modern Approach in Patient's Stratification. Front Oncol 2022; 12:856575. [PMID: 35356214 PMCID: PMC8959149 DOI: 10.3389/fonc.2022.856575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 01/19/2023] Open
Abstract
Colorectal cancer (CRC) is the second most frequently diagnosed type of cancer and a major worldwide public health concern. Despite the global efforts in the development of modern therapeutic strategies, CRC prognosis is strongly correlated with the stage of the disease at diagnosis. Early detection of CRC has a huge impact in decreasing mortality while pre-lesion detection significantly reduces the incidence of the pathology. Even though the management of CRC patients is based on robust diagnostic methods such as serum tumor markers analysis, colonoscopy, histopathological analysis of tumor tissue, and imaging methods (computer tomography or magnetic resonance), these strategies still have many limitations and do not fully satisfy clinical needs due to their lack of sensitivity and/or specificity. Therefore, improvements of the current practice would substantially impact the management of CRC patients. In this view, liquid biopsy is a promising approach that could help clinicians screen for disease, stratify patients to the best treatment, and monitor treatment response and resistance mechanisms in the tumor in a regular and minimally invasive manner. Liquid biopsies allow the detection and analysis of different tumor-derived circulating markers such as cell-free nucleic acids (cfNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) in the bloodstream. The major advantage of this approach is its ability to trace and monitor the molecular profile of the patient's tumor and to predict personalized treatment in real-time. On the other hand, the prospective use of artificial intelligence (AI) in medicine holds great promise in oncology, for the diagnosis, treatment, and prognosis prediction of disease. AI has two main branches in the medical field: (i) a virtual branch that includes medical imaging, clinical assisted diagnosis, and treatment, as well as drug research, and (ii) a physical branch that includes surgical robots. This review summarizes findings relevant to liquid biopsy and AI in CRC for better management and stratification of CRC patients.
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Affiliation(s)
- Octav Ginghina
- Department II, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Ariana Hudita
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Marius Zamfir
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Andrada Spanu
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Mara Mardare
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | - Irina Bondoc
- Department of Surgery, “Sf. Ioan” Clinical Emergency Hospital, Bucharest, Romania
| | | | - Sergiu Emil Georgescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Carolina Negrei
- Department of Toxicology, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
| | - Cornelia Nitipir
- Department II, University of Medicine and Pharmacy “Carol Davila” Bucharest, Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, Bucharest, Romania
| | - Bianca Galateanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
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33
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Peng L, Wang D, Han Y, Huang T, He X, Wang J, Ou C. Emerging Role of Cancer-Associated Fibroblasts-Derived Exosomes in Tumorigenesis. Front Immunol 2022; 12:795372. [PMID: 35058933 PMCID: PMC8764452 DOI: 10.3389/fimmu.2021.795372] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are the most important component of the stromal cell population in the tumor microenvironment and play an irreplaceable role in oncogenesis and cancer progression. Exosomes, a class of small extracellular vesicles, can transfer biological information (e.g., proteins, nucleic acids, and metabolites as messengers) from secreting cells to target recipient cells, thereby affecting the progression of human diseases, including cancers. Recent studies revealed that CAF-derived exosomes play a crucial part in tumorigenesis, tumor cell proliferation, metastasis, drug resistance, and the immune response. Moreover, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins strongly correlates with clinical pathological characterizations of cancer patients. Gaining deeper insight into the participation of CAF-derived exosomes in tumorigenesis may lead to novel diagnostic biomarkers and therapeutic targets in human cancers.
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Affiliation(s)
- Lushan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,Department of Pathology, School of Basic Medicine, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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34
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Cianci P, Restini E. Artificial intelligence in colorectal cancer management. Artif Intell Cancer 2021; 2:79-89. [DOI: 10.35713/aic.v2.i6.79] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/22/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023] Open
Abstract
Artificial intelligence (AI) is a new branch of computer science involving many disciplines and technologies. Since its application in the medical field, it has been constantly studied and developed. AI includes machine learning and neural networks to create new technologies or to improve existing ones. Various AI supporting systems are available for a personalized and novel strategy for the management of colorectal cancer (CRC). This mini-review aims to summarize the progress of research and possible clinical applications of AI in the investigation, early diagnosis, treatment, and management of CRC, to offer elements of knowledge as a starting point for new studies and future applications.
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Affiliation(s)
- Pasquale Cianci
- Department of Surgery and Traumatology, ASL BAT, Lorenzo Bonomo Hospital, Andria 76123, Puglia, Italy
| | - Enrico Restini
- Department of Surgery and Traumatology, ASL BAT, Lorenzo Bonomo Hospital, Andria 76123, Puglia, Italy
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35
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Zhou H, He X, He Y, Ou C, Cao P. Exosomal circRNAs: Emerging Players in Tumor Metastasis. Front Cell Dev Biol 2021; 9:786224. [PMID: 34957113 PMCID: PMC8692866 DOI: 10.3389/fcell.2021.786224] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis is an important feature of malignant tumors, and is the primary cause of poor prognosis and treatment failure, in addition to representing a potentially fatal challenge for cancer patients. Exosomes are small extracellular vesicles 30–150 nm in diameter that transmit cargo, such as DNA, RNA, and proteins, as a means of intercellular communication. Exosomes play crucial roles in a range of human diseases, especially malignant tumors. A growing number of studies have verified that circRNAs can be enveloped in exosomes and transferred from secretory cells to recipient cells, thereby regulating tumor progression, especially tumor metastasis. Exosomal circRNAs regulate tumor cell metastasis not only by regulating the signaling pathways, but also by affecting the tumor microenvironment. Moreover, exosomal circRNAs have the potential to serve as valuable diagnostic biomarkers and novel therapeutic targets in cancer patients. In this review, we summarize the mechanism by which exosomal circRNAs modulate metastatic phenomena in various types of tumors, and put forward the prospects of clinical applications of exosomal circRNAs in tumor therapy.
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Affiliation(s)
- Hao Zhou
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Yuxiang He
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Pengfei Cao, ; Chunlin Ou,
| | - Pengfei Cao
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Pengfei Cao, ; Chunlin Ou,
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36
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Cione E, Cannataro R, Gallelli L, De Sarro G, Caroleo MC. Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options. Pharmaceuticals (Basel) 2021; 14:ph14121257. [PMID: 34959658 PMCID: PMC8706321 DOI: 10.3390/ph14121257] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell-cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved in various physio-pathological conditions. Exosome-miRNAs are associated with numerous diseases, including type 2 diabetes, a complex multifactorial metabolic disorder linked to obesity. In addition, exosome-miRNAs are emerging as essential regulators in the progression of diabetes, principally for pancreatic β-cell injury and insulin resistance. Here, we have clustered the recent findings concerning exosome-miRNAs associated with β-cell dysfunction to provide a novel approach for the early diagnosis and therapy of diabetes.
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Affiliation(s)
- Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, CS, Italy;
- GalaScreen Laboratories, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, CS, Italy;
- Correspondence:
| | - Roberto Cannataro
- GalaScreen Laboratories, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, CS, Italy;
| | - Luca Gallelli
- Department of Health Science, University of Catanzaro and Operative Unit of Clinical Pharmacology and Pharmacovigilance, Mater Domini Hospital, 88100 Catanzaro, CZ, Italy; (L.G.); (G.D.S.)
| | - Giovambattista De Sarro
- Department of Health Science, University of Catanzaro and Operative Unit of Clinical Pharmacology and Pharmacovigilance, Mater Domini Hospital, 88100 Catanzaro, CZ, Italy; (L.G.); (G.D.S.)
| | - Maria Cristina Caroleo
- Department of Pharmacy, Health and Nutritional Sciences, Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, CS, Italy;
- GalaScreen Laboratories, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, CS, Italy;
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37
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Della Bella E, Pagani S, Martini F, De Mattei M. Editorial: The Epigenetics in Osteogenic and Chondrogenic Differentiation of Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:784791. [PMID: 34746159 PMCID: PMC8569890 DOI: 10.3389/fcell.2021.784791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 11/26/2022] Open
Affiliation(s)
| | - Stefania Pagani
- Complex Structure of Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Fernanda Martini
- Section of Experimental Medicine, Department Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy.,Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Monica De Mattei
- Section of Experimental Medicine, Department Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
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38
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lncRNA cytoskeleton regulator RNA (CYTOR): Diverse functions in metabolism, inflammation and tumorigenesis, and potential applications in precision oncology. Genes Dis 2021; 10:415-429. [DOI: 10.1016/j.gendis.2021.08.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 08/20/2021] [Indexed: 12/19/2022] Open
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39
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Nie H, Wang Y, Yang X, Liao Z, He X, Zhou J, Ou C. Clinical Significance and Integrative Analysis of the SMC Family in Hepatocellular Carcinoma. Front Med (Lausanne) 2021; 8:727965. [PMID: 34527684 PMCID: PMC8437102 DOI: 10.3389/fmed.2021.727965] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Worldwide, hepatocellular carcinoma (HCC) is one of the most malignant cancers with poor prognosis. The structural maintenance of chromosomes (SMC) gene family has been shown to play important roles in human cancers. Nevertheless, the role of SMC members in HCC is not well-understood. In this study, we comprehensively explored the role of the SMC family in HCC using a series of bioinformatic analysis tools. Studies have demonstrated that the mRNA expression levels of SMC1A, SMC1B, SMC2, SMC4, and SMC6 are significantly overexpressed in HCC, and the protein levels of SMC1A, SMC2, SMC3, SMC4, SMC5, and SMC6 are similarly elevated. Moreover, HCC patients with high SMC2 and SMC4 expression levels exhibit poor survival. Using KEGG and GO analyses, we analyzed the enrichment of gene expression in the biological functions and pathways of the SMC family in HCC. Immune infiltration analysis revealed that the expression of the SMC family is closely associated with B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and DCs. In conclusion, our findings will enhance a more thorough understanding of the SMC family in HCC progression and provide new directions for the diagnosis and treatment of HCC in the future.
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Affiliation(s)
- Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xuejie Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhiming Liao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Departments of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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40
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Nie H, Liao Z, Wang Y, Zhou J, He X, Ou C. Exosomal long non-coding RNAs: Emerging players in cancer metastasis and potential diagnostic biomarkers for personalized oncology. Genes Dis 2021; 8:769-780. [PMID: 34522707 PMCID: PMC8427254 DOI: 10.1016/j.gendis.2020.12.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/06/2020] [Accepted: 12/12/2020] [Indexed: 02/07/2023] Open
Abstract
Metastasis is a major challenge in the treatment of cancer. Exosomes are a class of small extracellular vesicles (EVs) that play critical roles in several human diseases, especially cancer, by transferring information (e.g., DNA, RNA, and protein) via cell-to-cell communication. Numerous recent studies have shown that exosomal long non-coding RNAs (lncRNAs) play crucial regulatory roles in cancer metastasis in the tumor microenvironment by altering the expression of several key signaling pathways and molecules. Due to their specificity and sensitivity, exosomal lncRNAs have potential as novel tumor markers and therapeutic targets in the treatment of cancer metastasis. In this review, we aim to summarize the roles of exosomal lncRNAs in cancer metastasis, the mechanisms underlying their roles, and their potential clinical applications.
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Affiliation(s)
- Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
| | - Zhujun Liao
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
| | - Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
| | - Xiaoyun He
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, PR China
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41
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Sun R, He XY, Mei C, Ou CL. Role of exosomal long non-coding RNAs in colorectal cancer. World J Gastrointest Oncol 2021; 13:867-878. [PMID: 34457192 PMCID: PMC8371516 DOI: 10.4251/wjgo.v13.i8.867] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/11/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
Exosomes are a class of small extracellular vesicles, 30-150 nm in diameter, that transfer biological information (e.g., DNA, RNA, and protein) via cell-to-cell communication. Exosomes play critical roles in the occurrence and development of human cancers, including colorectal cancer (CRC). Recent studies have shown that long non-coding RNAs (lncRNAs) can be encapsulated in exosomes, which transfer lncRNAs from secretory cells into recipient cells. This process affects the progression of CRC, since exosomal lncRNAs display special and extensive functions in CRC tumorigenesis, including malignant proliferation, metastasis, chemoresistance, and inflammatory response. Moreover, due to their specificity and sensitivity, exosomal lncRNAs are released into body fluids (e.g., urine, sputum, and plasma), which have the potential to be biomarkers of CRC tumorigenesis within screening efforts and medical and epidemiologic research. In this review, we aim to clarify the function and mechanism of exosomal lncRNAs in CRC tumorigenesis and provide a strategy for early diagnosis and medical treatment of this malignancy.
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Affiliation(s)
- Ru Sun
- Department of Blood Transfusion, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiao-Yun He
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Cheng Mei
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Chun-Lin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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42
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Li L, Wang N, Zhu M, Xiong Y, Wang F, Guo G, Wang X, Gu Y. Aberrant super-enhancer-driven oncogene ENC1 promotes the radio-resistance of breast carcinoma. Cell Death Dis 2021; 12:777. [PMID: 34362881 PMCID: PMC8346480 DOI: 10.1038/s41419-021-04060-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 11/29/2022]
Abstract
Poor response of tumors to radiotherapy is a major clinical obstacle. Because of the dynamic characteristics of the epigenome, identification of possible epigenetic modifiers may be beneficial to confer radio-sensitivity. This research was set to examine the modulation of ectodermal-neural cortex 1 (ENC1) in radio-resistance in breast carcinoma (BC). In silico identification and immunohistochemical staining revealed that overexpression of ENC1 promoted BC metastasis to the bone and brain. Moreover, its overexpression promoted the translocation of YAP1/TAZ into the nucleus and enhanced expression of GLI1, CTGF, and FGF1 through the Hippo pathway. ENC1 expression was controlled by a ~10-kb long SE. ENC1-SEdistal deletion reduced ENC1 expression and inhibited the malignant behavior of BC cells and their resistance to radiotherapy. The binding sites on the ENC1-SE region enriched the shared sequence between TCF4 and ENC1 promoter. Knocking-down TCF4 inhibited luciferase activity and H3K27ac-enriched binding of the ENC1-SE region. Additionally, SE-driven ENC1 overexpression mediated by TCF4 may have clinical implications in radio-resistance in BC patients. Our findings indicated that ENC1 overexpression is mediated by SE and the downstream TCF4 to potentiate the Hippo/YAP1/TAZ pathway. Targeting this axis might be a therapeutic strategy for overcoming BC radio-resistance.
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Affiliation(s)
- Lin Li
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Nan Wang
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Mingzhi Zhu
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Youyi Xiong
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Fang Wang
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Guangcheng Guo
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Xinxing Wang
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Yuanyan Gu
- Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.
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43
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He X, Kuang G, Wu Y, Ou C. Emerging roles of exosomal miRNAs in diabetes mellitus. Clin Transl Med 2021; 11:e468. [PMID: 34185424 PMCID: PMC8236118 DOI: 10.1002/ctm2.468] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 12/14/2022] Open
Abstract
Exosomes are small extracellular vesicles 40-160 nm in diameter that are secreted by almost all cell types. Exosomes can carry diverse cargo including RNA, DNA, lipids, proteins, and metabolites. Exosomes transfer substances and information between cells by circulating in body fluids and are thus involved in diverse physiological and pathological processes in the human body. Recent studies have closely associated exosomal microRNAs (miRNAs) with various human diseases, including diabetes mellitus (DM), which is a complex multifactorial metabolic disorder disease. Exosomal miRNAs are emerging as pivotal regulators in the progression of DM, mainly in terms of pancreatic β-cell injury and insulin resistance. Exosomal miRNAs are closely associated with DM-associated complications, such as diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic cardiomyopathy (DCM), etc. Further investigations of the mechanisms of action of exosomal miRNAs and their role in DM will be valuable for the thorough understanding of the physiopathological process of DM. Here, we have summarized recent findings regarding exosomal miRNAs associated with DM to provide a new strategy for identifying potential diagnostic biomarkers and drug targets for the early diagnosis and treatment, respectively, of DM.
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Affiliation(s)
- Xiaoyun He
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunan410008China
- Departments of Ultrasound Imaging, Xiangya HospitalCentral South UniversityChangshaHunan410008China
| | - Gaoyan Kuang
- Department of OrthopedicsThe First Affiliated Hospital of Hunan University of Chinese MedicineChangshaHunan410007China
- Postdoctoral Research WorkstationHinye Pharmaceutical Co. LtdChangshaHunan410331China
| | - Yongrong Wu
- Hunan university of Chinese MedicineChangshaHunan410208China
| | - Chunlin Ou
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunan410008China
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44
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Li GH, Qu Q, Qi TT, Teng XQ, Zhu HH, Wang JJ, Lu Q, Qu J. Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance. J Exp Clin Cancer Res 2021; 40:174. [PMID: 34011395 PMCID: PMC8132395 DOI: 10.1186/s13046-021-01974-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/05/2021] [Indexed: 02/06/2023] Open
Abstract
Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient transcriptional state into a stably resistant one. Super-enhancers (SEs) are central to the maintenance of identity of cancer cells and promote SE-driven-oncogenic transcriptions to which cancer cells become highly addicted. This dependence on SE-driven transcription to maintain chemoresistance offers an Achilles' heel for chemoresistance. Indeed, the inhibition of SE components dampens oncogenic transcription and inhibits tumor growth to ultimately achieve combined sensitization and reverse the effects of drug resistance. No reviews have been published on SE-related mechanisms in the cancer chemoresistance. In this review, we investigated the structure, function, and regulation of chemoresistance-related SEs and their contributions to the chemotherapy via regulation of the formation of cancer stem cells, cellular plasticity, the microenvironment, genes associated with chemoresistance, noncoding RNAs, and tumor immunity. The discovery of these mechanisms may aid in the development of new drugs to improve the sensitivity and specificity of cancer cells to chemotherapy drugs.
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Affiliation(s)
- Guo-Hua Li
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China
| | - Ting-Ting Qi
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Xin-Qi Teng
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Hai-Hong Zhu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Jiao-Jiao Wang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
| | - Qiong Lu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
| | - Jian Qu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
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45
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Alloro R, Sinagra E. Artificial intelligence and colorectal cancer: How far can you go? Artif Intell Cancer 2021; 2:7-11. [DOI: 10.35713/aic.v2.i2.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/01/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Artificial intelligence is an emerging technology whose application is rapidly increasing in several medical fields. The numerous applications of artificial intelligence in gastroenterology have shown promising results, especially in the setting of gastrointestinal oncology. Therefore, we would like to highlight and summarize the research progress and clinical application value of artificial intelligence in the diagnosis, treatment, and prognosis of colorectal cancer to provide evidence for its use as a promising diagnostic and therapeutic tool in this setting.
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Affiliation(s)
- Rita Alloro
- Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), Unit of General and Oncological Surgery, Paolo Giaccone University Hospital, University of Palermo, Palermo 90127, Italy
| | - Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto G. Giglio, Palermo 90015, Italy
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46
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Li Q, Xie H, Jin Z, Huang J, Wang S, Zhang Z. Overexpression of Long Noncoding RNA LBX2-AS1 Promotes the Proliferation of Colorectal Cancer. Technol Cancer Res Treat 2021; 20:1533033821997829. [PMID: 33733923 PMCID: PMC7983235 DOI: 10.1177/1533033821997829] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: LBX2 antisense RNA 1 (LBX2-AS1), a long noncoding RNA, has been identified to
be closely associated with the progression of various cancers. However, the
role of LBX2-AS1 in colorectal cancer (CRC) is still poorly understood. In
this study, we aimed to investigate the expression and function of LBX2-AS1
in CRC. Material and Methods: Expression data from the Gene Expression Omnibus (GEO) and Gene Expression
Profiling Interactive Analysis (GEPIA) databases and results obtained from
clinical samples/patients were used to determine the correlation between
LBX2-AS1 expression and pathological stages, overall survival (OS).
Furthermore, knockdown of LBX2-AS1 in CRC cells using the short interfering
RNA (siRNA) technique, and observed its biological functions using western
blotting, quantitative reverse transcription-polymerase chain reaction
(qRT-PCR), cell counting kit-8 (CCK-8) and flow cytometry assay in the CRC
cell line. Results: Our study demonstrated that the expression levels of LBX2-AS1 were higher in
CRC cell lines than in normal colon mucosal cell lines. Bioinformatics
analysis revealed that CRC patients with high LBX2-AS1 expression levels had
poor OS. Furthermore, knockdown of LBX2-AS1 in CRC cells could attenuate the
proliferative ability of CRC cells in vitro, which is
associated with decreased expression of cyclin-dependent kinase (CDK) 3,
CDK6, and CCND1 and enhanced expression of cyclin-dependent kinase inhibitor
1A. Conclusions: LBX2-AS1 plays a crucial role in the tumorigenesis of CRC, providing a
potential therapeutic target for CRC patients.
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Affiliation(s)
- Qing Li
- Department of Radiation Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, People's Republic of China.,Key Laboratory of Medical Imaging and Artifical Intelligence of Hunan Province
| | - Hui Xie
- Department of Radiation Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, People's Republic of China.,Key Laboratory of Medical Imaging and Artifical Intelligence of Hunan Province
| | - Zefu Jin
- Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Jing Huang
- Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Shuting Wang
- Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Zijian Zhang
- Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
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47
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Li PC, Tu MJ, Ho PY, Batra N, Tran MM, Qiu JX, Wun T, Lara PN, Hu X, Yu AX, Yu AM. In vivo fermentation production of humanized noncoding RNAs carrying payload miRNAs for targeted anticancer therapy. Am J Cancer Res 2021; 11:4858-4871. [PMID: 33754032 PMCID: PMC7978307 DOI: 10.7150/thno.56596] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/17/2021] [Indexed: 12/19/2022] Open
Abstract
Rationale: Noncoding RNAs (ncRNAs) such as microRNAs (miRs or miRNAs) play important roles in the control of cellular processes through posttranscriptional gene regulation. However, ncRNA research is limited to utilizing RNA agents synthesized in vitro. Recombinant RNAs produced and folded in living cells shall better recapitulate biologic RNAs. Methods: Herein, we developed a novel platform for in vivo fermentation production of humanized recombinant ncRNA molecules, namely hBERAs, carrying payload miRNAs or siRNAs. Target hBERAs were purified by anion exchange FPLC method. Functions of hBERA/miRNAs were investigated in human carcinoma cells and antitumor activities were determined in orthotopic osteosarcoma xenograft spontaneous lung metastasis mouse models. Results: Proper human tRNAs were identified to couple with optimal hsa-pre-miR-34a as new fully-humanized ncRNA carriers to accommodate warhead miRNAs or siRNAs. A group of 30 target hBERAs were all heterogeneously overexpressed (each accounting for >40% of total bacterial RNA), which facilitated large-scale production (8-31 mg of individual hBERAs from 1L bacterial culture). Model hBERA/miR-34a-5p and miR-124-3p were selectively processed to warhead miRNAs in human carcinoma cells to modulate target gene expression, enhance apoptosis and inhibit invasiveness. In addition, bioengineered miR-34a-5p and miR-124-3p agents both reduced orthotopic osteosarcoma xenograft tumor growth and spontaneous pulmonary metastases significantly. Conclusion: This novel ncRNA bioengineering technology and resulting recombinant ncRNAs are unique additions to conventional technologies and tools for basic research and drug development.
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48
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Liao Z, Nie H, Wang Y, Luo J, Zhou J, Ou C. The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis. Front Oncol 2021; 11:641343. [PMID: 33718238 PMCID: PMC7947863 DOI: 10.3389/fonc.2021.641343] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/29/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers, with extremely high rates of morbidity and mortality. The main cause of death in CRC is distant metastasis; it affects patient prognosis and survival and is one of the key challenges in the treatment of CRC. Long non-coding RNAs (lncRNAs) are a group of non-coding RNA molecules with more than 200 nucleotides. Abnormal lncRNA expression is closely related to the occurrence and progression of several diseases, including cancer. Recent studies have shown that numerous lncRNAs play pivotal roles in the CRC metastasis, and reversing the expression of these lncRNAs through artificial means can reduce the malignant phenotype of metastatic CRC to some extent. This review summarizes the major mechanisms of lncRNAs in CRC metastasis and proposes lncRNAs as potential therapeutic targets for CRC and molecular markers for early diagnosis.
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Affiliation(s)
- Zhiming Liao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Jingjing Luo
- Teaching and Research Room of Biochemistry and Molecular Biology, Medical School of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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49
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Boija A, Klein IA, Young RA. Biomolecular Condensates and Cancer. Cancer Cell 2021; 39:174-192. [PMID: 33417833 PMCID: PMC8721577 DOI: 10.1016/j.ccell.2020.12.003] [Citation(s) in RCA: 181] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022]
Abstract
Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated-or will likely be implicated-in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer.
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Affiliation(s)
- Ann Boija
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
| | - Isaac A Klein
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
| | - Richard A Young
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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50
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He X, Yu B, Kuang G, Wu Y, Zhang M, Cao P, Ou C. Long noncoding RNA DLEU2 affects the proliferative and invasive ability of colorectal cancer cells. J Cancer 2021; 12:428-437. [PMID: 33391439 PMCID: PMC7738996 DOI: 10.7150/jca.48423] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/24/2020] [Indexed: 12/17/2022] Open
Abstract
Emerging evidence indicates that long noncoding RNAs (lncRNAs) are closely associated with colorectal cancer (CRC) tumorigenesis. One example is lncRNA Deleted in Lymphocytic Leukemia 2 (DLEU2). However, how DLEU2 contributes to CRC is still poorly understood. This study sought to investigate the effects of DLEU2 on CRC pathogenesis, and the underlying mechanism involved. Using a quantitative real-time polymerase chain reaction (qRT-PCR) assay, we demonstrated that the expression levels of DLEU2 in 45 pairs of CRC tissues were higher than those in the corresponding normal colon mucosal tissues. In addition, CRC patients with high DLEU2 expression levels exhibited poor overall survival (OS) and recurrence-free survival (RFS), as determined by analyses and measurements from the GEO and GEPIA databases. When DLEU2 was silenced using short interfering RNA (siRNA) in CRC cell line, the results demonstrated that DLEU2 silencing suppressed CRC cell tumorigenesis in vitro, which was associated with decreased expression of cyclin dependent kinase 6(CDK6), ZEB1, and ZEB2 as well as enhancing the expression of Cyclin-dependent kinase inhibitor 1A (CDKN1A). Taken together, the results of this study suggested that DLEU2 may play critical roles in the progression of CRC and may serve as a prognostic biomarker for CRC.
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Affiliation(s)
- Xiaoyun He
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Bingbing Yu
- Department of Pathology, Dezhou People's Hospital, Dezhou 253056, Shandong, China
| | - Gaoyan Kuang
- Department of Orthopedics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan, China
| | - Yongrong Wu
- Department of Orthopedics, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan, China
| | - Meili Zhang
- Department of Pathology, Dezhou People's Hospital, Dezhou 253056, Shandong, China
| | - Pengfei Cao
- Department of Hematology, Xiangya hospital, Central South University, Changsha 410008, Hunan, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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