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long noncoding rna(lncrna)H19:An essential developmental regulator with expanding roles in cancer,stem cell differentiation,and metabolic diseases

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Genes & Diseases 2023年第4期10卷 1351-1366页

作者： Junyi Liao Bowen Chen Zhenglin Zhu Chengcheng Du Shengqiang Gao Guozhi Zhao Piao Zhao Yonghui Wang Annie Wang Zander Schwartz Lily Song Jeffrey Hong William Wagstaff Rex CHaydon Hue HLuu Jiaming Fan Russell RReid Tong-Chuan He Lewis Shi Ning Hu Wei Huang Departments of Orthopedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Research Center Chongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA The Medical Scientist Training Program The University of Chicago Pritzker School of MedicineChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mrna for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding rnas(ncrnas).It has been shown that ncrnas,especially long non-coding rnas(lncrnas),may play crucial regulatory roles in gene *** one of the first isolated and reported lncrnas,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and ***,H19 mediates diverse regulatory functions by serving as competing endogenous rnas(Cernas),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mrnas or ***,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic *** discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of ***,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

关键词： Cancer Epigenetic regulation H19 Lncrna long-noncoding rna Metabolic diseases Stem cell differentiation

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Crosstalk between long noncoding rna and microrna in Cancer

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CELLULAR ONCOLOGY 2023年第4期46卷 885-908页

作者： Bhattacharjee, Rahul Prabhakar, Neeraj Kumar, Lamha Bhattacharjee, Arkadyuti Kar, Sulagna Malik, Sumira Kumar, Dhruv Ruokolainen, Janne Negi, Arvind Jha, Niraj Kumar Kesari, Kavindra Kumar Kalinga Inst Ind Technol KIIT DU KIIT Sch Biotechnol Bhubaneswar Orissa India Univ Hamburg Ctr Struct Syst Biol Dept Phys DESYBldg 15Notkestr 852267 Hamburg Germany Indian Inst Sci Educ & Res Sch Biol Thiruvananthapuram India Amity Univ Jharkhand Amity Inst Biotechnol Ranchi 834001 Jharkhand India UPES Univ Sch Hlth Sci & Technol SoHST Dehra Dun Uttaranchal India Aalto Univ Sch Sci Dept Appl Phys Espoo 00076 Finland Aalto Univ Sch Chem Engn Dept Bioprod & Biosyst Espoo 00076 Finland Sharda Univ Sch Engn & Technol SET Dept Biotechnol Greater Noida 201310 Uttar Pradesh India Lovely Profess Univ Sch Bioengn & Biosci Phagwara 144411 India Uttaranchal Univ Sch Appl & Life Sci SALS Dept Biotechnol Dehra Dun 248007 India Univ Helsinki Fac Biol & Environm Sci Bioctr 3 Helsinki Finland Abo Akad Univ Pharm Tykistokatu 6A Turku Finland

mirnas and lncrnas play a central role in cancer-associated gene regulations. The dysregulated expression of lncrnas has been reported as a hallmark of cancer progression, acting as an independent prediction marker for an individual cancer patient. The interplay of mirna and lncrna decides the variation of tumorigenesis that could be mediated by acting as sponges for endogenous rnas, regulating mirna decay, mediating intra-chromosomal interactions, and modulating epigenetic components. This paper focuses on the influence of crosstalk between lncrna and mirna on cancer hallmarks such as epithelial-mesenchymal transition, hijacking cell death, metastasis, and invasion. Other cellular roles of crosstalks, such as neovascularization, vascular mimicry, and angiogenesis were also discussed. Additionally, we reviewed crosstalk mechanism with specific host immune responses and targeting interplay (between lncrna and mirna) in cancer diagnosis and management.

关键词： Microrna long-noncoding rna Cancer Epithelial-mesenchymal transition Metastasis Angiogenesis Neovascularization Vascular mimicry

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The long noncoding rna LUCAT1 promotes tumorigenesis by controlling ubiquitination and stability of DNA methyltransferase 1 in esophageal squamous cell carcinoma

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CANCER LETTERS 2018年 417卷 47-57页

作者： Yoon, Jung-Ho You, Bo-Hyun Park, Chan Hyuk Kim, Yeong Jin Nam, Jin-Wu Lee, Sang Kil Yonsei Univ Brain Korea PLUS Project Med Sci 21 Seoul South Korea Hanyang Univ Dept Life Sci Coll Nat Sci Seoul 133791 South Korea Yonsei Univ Coll Med Severance Hosp Div GastroenterolInst GastroenterolDept Interna Seoul South Korea Hanyang Univ Res Inst Convergence Basic Sci Seoul 133791 South Korea

Available targeted therapies for esophageal squamous cell carcinoma (ESCC) are limited;thus, further genetic and epigenetic studies are needed. Recently, many long noncoding rnas (Incrnas) have been reported to be involved in various cancers. Here, we investigated whether the lncrna LUCAT1 was related to the carcinogenesis of ESCC based on previous studies in lung cancer. LUCAT1 was significantly upregulated in ESCC cell lines and cancer tissue compared with normal cells and adjacent normal tissues. LUCAT1 knockdown reduced cell proliferation, induced apoptosis, and upregulated tumor-suppressor genes by reducing DNA methylation in KYSE-30 cells. Moreover, LUCAT1 sirna reduced DNA methyltransferase 1 (DNMT1) protein levels without affecting transcription. Patients with high LUCAT1 expression had significantly lower survival rates than patients with low LUCAT1 expression. Our results thus suggest that LUCAT1 regulates the stability of DNMT1 and inhibits the expression of tumor suppressors through DNA methylation, leading to the formation and metastasis of ESCC. We identified LUCAT1 as a potential target for drug development and as a biomarker for ESCC. (C) 2017 Elsevier B.V. All rights reserved.

关键词： LUCAT1 DNA methyltransferase 1 Esophagus squamous cell carcinoma long-noncoding rna DNA methylation Epigenetics

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Genetic variation at the long noncoding rna H19 gene is associated with the risk of hypertrophic cardiomyopathy

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EPIGENOMICS 2018年第7期10卷 865-873页

作者： Gomez, Juan Lorca, Rebeca Reguero, Julian R. Martin, Maria Moris, Cesar Alonso, Belen Iglesias, Sara Diaz-Molina, Beatriz Avanzas, Pablo Coto, Eliecer Hosp Univ Cent Asturias Unidad Referencia Cardiopatias Familiar HUCA Genet Mol & Cardiol Oviedo Spain Univ Oviedo Dept Biol Func Oviedo Spain Inst Invest Sanitaria Principado Asturias ISPA Oviedo Spain Univ Oviedo Dept Med Oviedo Spain Red Invest Renal REDINREN Madrid Spain

Aim: The long noncoding rna H19 and its hostmicro rnamiR-675 have been found deregulated in cardiac hypertrophy and heart failure tissues. Our aim was to investigate whether the H19 gene variants were associated with the risk of hypertrophic cardiomyopathy (HCM). Patients & methods: We genotyped two H19 tag single nucleotide polymorphisms in 405 HCM patients and 550 controls, and sequenced this gene in 100 patients. Results: The rs2107425 C was significantly increased in sarcomere no-mutation patients (n = 225;p = 0.01): CC versus CT + TT, p = 0.017;odd ratios: 1.51. Sequencing of the H19 coding transcript identified two patients heterozygous carriers for a rare variant, rs945977096 G/A, that was absent among the controls. Conclusion: Our study suggested a significant association between H19 variants and the risk of developing HCM.

关键词： gene polymorphism H19 gene hypertrophic cardiomyopathy long-noncoding rna

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Upregulation of the interferon-inducible antiviral gene RSAD2 in neuroendocrine prostate cancer via PVT1 exon 9 dependent and independent pathways

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JOUrnaL OF BIOLOGICAL CHEMISTRY 2025年第4期301卷 108370页

作者： Bonacci, Rachel E. McGill, Meghan Le, Nu Thuy Anh Barkarar, Murtaza Finnegan, Colin Wilson, Maya Ajagbe, Oluwabusola Udekwu, Chinedum C. Gorski, Kathryn Manohar, Jyothi Sboner, Andrea Ogunwobi, Olorunseun O. Michigan State Univ Dept Biochem & Mol Biol E Lansing MI 48824 USA Weill Cornell Med Englander Inst Precis Med New York NY USA

PVT1 exon 9 overexpression is a newly uncovered aberration in prostate cancer (PCa). We have previously demonstrated the exon 9 region of PVT1 is overexpressed in some patient PCa tissues and caused development of neuroendocrine prostate cancer (NEPC) in vitro and in vivo. In this study, we focused on elucidating downstream mechanisms induced by PVT1 exon 9 overexpression with the goal of further understanding its role in NEPC development. rna-seq analysis of a PVT1 exon 9 overexpressing PCa model revealed significant enrichment of genes responsible for inducing inflammatory processes including RSAD2. We observed RSAD2 overexpression in all NEPC models examined whereas PVT1 exon 9 was overexpressed only in a subset of the NEPC models. We identified two distinct pathways in which RSAD2 is overexpressed: one dependent and one independent on PVT1 exon 9 over-expression. Knockdown of RSAD2 suppressed cell proliferation and migration suggestive of its role as a therapeutic target in NEPC. We identified RSAD2 induces increased cell proliferation, colony formation, and may be involved in the transition between CRPC and NEPC. Distinct differences between PVT1 exon 9-dependent and PVT1 exon 9-independent NEPC models include differences in type II interferon signaling and AR modulation. PVT1 exon 9 binds to RSAD2 protein and disruption of binding significantly impedes downstream interferon gamma secretion by PVT1 exon 9-dependent NEPC cells. These novel findings indicate the importance of these two independent pathways in NEPC, the need to identify relevant NEPC patient populations and study strategies for targeting PVT1 exon 9 and/or RSAD2.

关键词： cell biology prostate cancer interferon cellular immune response long-noncoding rna androgen receptor PVT1 neuroendocrine

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A novel lncrna ABCE1-5 regulates pulmonary fibrosis by targeting KRT14

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AMERICAN JOUrnaL OF PHYSIOLOGY-CELL PHYSIOLOGY 2025年第5期328卷 C1487-C1500页

作者： Gao, Shuwei Wei, Yanqiu Li, Chen Xie, Bingbing Zhang, Xinran Cui, Ye Dai, Huaping China Japan Friendship Hosp Natl Ctr Resp Med Ctr Resp Med Beijing Peoples R China China Japan Friendship Hosp Natl Clin Res Ctr Resp Dis Ctr Resp Med Beijing Peoples R China Chinese Acad Med Sci China Japan Friendship Hosp Inst Resp Med Ctr Resp Med Beijing Peoples R China China Japan Friendship Hosp Ctr Resp Med Dept Pulm & Crit Care Med Beijing Peoples R China China Japan Friendship Hosp Ctr Resp Med Dept Clin Res & Data Management Beijing Peoples R China Capital Med Univ Sch Basic Med Sci Dept Immunol Beijing Peoples R China

Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. long noncoding rnas (lncrnas) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncrnas are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncrna microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss- and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and bronchial epithelial cell line (BEAS-2B) cell apoptosis while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated transforming growth factor-beta (TGF-beta)-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 revealing the antifibrotic effect of ABCE1-5 in bleomycin (BLM)-treated mice. Mechanistically, rna pull-down (RPD)-mass spectrometry and rna immunoprecipitation assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mrna stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt;overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT si

关键词： ABCE1-5 Krt-14 long-noncoding rna mTOR pulmonary fibrosis

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long non-coding rna H19 promotes proliferation inhepatocellular carcinoma cells via H19/miR-107/CDK6 axis

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Oncology Research 2023年第6期31卷 989-1005页

作者： ARCHITTAPON NOKKEAW PANNATHON THAMJAMRASSRI NAPHAT CHANTARAVISOOT PISIT TANGKIJVANICH CHAIYABOOT ARIYACHET Department of Biochemistry Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand Center of Excellence in Hepatitis and Liver Cancer Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand Department of Biochemistry Medical Biochemistry ProgramFaculty of MedicineChulalongkorn UniversityBangkok10330Thailand Center of Excellence in Systems Biology Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide;nevertheless, currenttherapeutic options are limited or ineffective for many patients. Therefore, elucidation of molecular mechanisms inHCC biology could yield important insights for the intervention of novel therapies. Recently, various studies havereported dysregulation of long non-coding rnas (lncrnas) in the initiation and progression of HCC, including H19;however, the biological function of H19 in HCC remains unclear. Here, we show that knockdown of H19 disruptedHCC cell growth, impaired the G1-to-S phase transition, and promoted apoptosis, while overexpression of H19yielded the opposite results. Screening for expression of cell cycle-related genes revealed a significant downregulationof CDK6 at both rna and protein levels upon H19 suppression. Bioinformatic analysis of the H19 sequence and the3′ untranslated region (3′ UTR) of CDK6 transcripts showed several binding sites for microrna-107 (miR-107), andthe dual luciferase reporter assay confirmed their direct interaction with miR-107. Consistently, blockage of miR-107activity alleviated the growth suppression phenotypes induced by H19 downregulation, suggesting that H19 serves asa molecular sponge for miR-107 to promote CDK6 expression and cell cycle progression. Together, this studydemonstrates a mechanistic function of H19 in driving the proliferation of HCC cells and suggests H19 suppressionas a novel approach for HCC treatment.

关键词： HCC H19 long-noncoding rna Microrna Cyclin-dependent kinase CDK6

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N1-methyladenosine profiling of long non-coding rna in colorectal cancer

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IUBMB LIFE 2021年第10期73卷 1235-1243页

作者： Shi, Liuhong Chen, Wenwen Zhang, Zizhen Chen, Jingyu Xue, Meng Zhejiang Univ Dept Ultrasound Affiliated Hosp 2 Sch Med Hangzhou Peoples R China Zhejiang Univ Dept Gastroenterol Affiliated Hosp 2 Sch Med 88 Jiefang Rd Hangzhou 310009 Zhejiang Peoples R China Zhejiang Univ Inst Gastroenterol Hangzhou Peoples R China Zhejiang Univ Canc Ctr Hangzhou Peoples R China

N1-methyladenosine (m1A), is a unique methyl group that confers post-transcriptional modification of gene expression, and plays important roles in various human diseases. However, the abundance of this modification and its effects on long non-coding rnas (lncrnas) in human colorectal cancer (CRC) remain unclear. In this study, methylated rna immunoprecipitation sequencing was performed in three pairs of human CRC and nontumorous tissues to identify m1A peaks and its correlation with differential alterations of lncrna expression in CRC. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment pathway analyses were applied to predict the potential roles of m1A on gene expression. We found that CRC and adjacent tissues had a noticeable difference in m1A distribution. Notably, HGGAGRA and WGGANGA were recognized as the most significantly enriched motifs, respectively. Co-analysis of methylation and rna sequencing demonstrated downregulated lncrnas along with m1A modification in CRC. GO and KEGG pathway analyses revealed that the unique distribution of m1A sites in lncrnas had a significant correlation with CRC signaling pathways. In conclusion, our results delineated the distribution pattern of m1A methylation on lncrnas, and provided potential roles of this modification in different pathways and tumor progression of CRC.

关键词： colorectal cancer gene ontology Kyoto encyclopedia of genes and genomes long-noncoding rna motif N1-methyladenosine peak

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Mining diverse small rna species in the deep transcriptome

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TRENDS IN BIOCHEMICAL SCIENCES 2015年第1期40卷 4-7页

作者： Vickers, Kasey C. Roteta, Leslie A. Hucheson-Dilks, Holli Han, Leng Guo, Yan Vanderbilt Univ Sch Med Dept Med Nashville TN 37212 USA Vanderbilt Univ Sch Med VANTAGE Nashville TN 37212 USA Univ Texas Houston MD Anderson Canc Ctr Houston TX 77030 USA Vanderbilt Univ Sch Med Dept Canc Biol Nashville TN 37212 USA

Transcriptomes of many species are proving to be exquisitely diverse, and many investigators are now using high-throughput sequencing to quantify non-protein-coding rnas, namely small rnas (srna). Unfortunately, most studies are focused solely on microrna changes, and many investigators are not analyzing the full compendium of srna species present in their large datasets. We provide here a rationale to include all types of srnas in srna sequencing analyses, which will aid in the discovery of their biological functions and physiological relevance.

关键词： small rna rna sequencing long-noncoding rna transcriptome microrna high-throughput sequencing data analysis

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noncoding rnas: Stress, Glucocorticoids, and Posttraumatic Stress Disorder

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BIOLOGICAL PSYCHIATRY 2018年第10期83卷 849-865页

作者： Daskalakis, Nikolaos P. Provost, Allison C. Hunter, Richard G. Guffanti, Guia Harvard Med Sch McLean Hosp Dept Psychiat Belmont MA USA Cohen Vet Biosci Inc Cambridge MA USA Univ Massachusetts Dept Psychol Boston MA 02125 USA

Posttraumatic stress disorder (PTSD) is a pathologic response to trauma that impacts similar to 8% of the population and is highly comorbid with other disorders, such as traumatic brain injury. PTSD affects multiple biological systems throughout the body, including the hypothalamic-pituitary-adrenal axis, cortical function, and the immune system, and while the study of the biological underpinnings of PTSD and related disorders are numerous, the roles of non-coding rnas (ncrnas) are just emerging. Moreover, deep sequencing has revealed that ncrnas represent most of the transcribed mammalian genome. Here, we present developing evidence that ncrnas are involved in critical aspects of PTSD pathophysiology. In that regard, we summarize the roles of three classes of ncrnas in PTSD and related disorders: micrornas, long-noncoding rnas, and retrotransposons. This review evaluates findings from both animal and human studies with a special focus on the role of ncrnas in hypothalamic-pituitary-adrenal axis abnormalities and glucocorticoid dysfunction in PTSD and traumatic brain injury. We conclude that ncrnas may prove to be useful biomarkers to facilitate personalized medicines for trauma-related brain disorders.

关键词： Glucocorticoids long-noncoding rna Microrna noncoding rna PTSD Retrotransposons Stress TBI

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