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1
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Khoshandam M, Sideris N, Ahmadieh-Yazdi A, Sheykhhasan M, Manoochehri H, Tanzadehpanah H, Mahaki H, Ghadam M, Lak S, Kalhor N, Rabiei M, Al-Musawi S, Dama P. The functional role of LncRNA HOXA-AS2 in multiple human cancers. Pathol Res Pract 2025; 266:155795. [PMID: 39756105 DOI: 10.1016/j.prp.2024.155795] [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: 07/18/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025]
Abstract
Humans have more than 270,000 lncRNAs. Among these, lncRNA HOXA-AS2 is considered a transformative gene involved in various cellular processes, including cell proliferation, apoptosis, migration, and invasion. Thus, it can be regarded as a potential tumor marker for both diagnosis and prognosis. Aberrant expression of lncRNAs is associated with many cancers, including hepatocellular carcinoma (HCC), gallbladder carcinoma (GBC), acute promyelocytic leukemia (APL), lung cancer (LC), prostate cancer (PC), osteosarcoma (OS), colorectal cancer (CRC), cervical cancer (CC), and acute myeloid leukemia (AML). Targeting lncRNAs could be a promising strategy to complement or replace current cancer treatments. As a non-coding oncogene, lncRNA HOXA-AS2 is implicated in multiple cancers and could serve as a potential biomarker for various malignancies. The tumor size and disease stage of several cancers are correlated with HOXA-AS2 expression. Silencing HOXA-AS2 effectively suppresses tumor cell proliferation and promotes apoptosis, thereby inhibiting the progression of multiple cancer types. The regulatory mechanisms of HOXA-AS2 include inducing epithelial-mesenchymal transition (EMT), overexpressing B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), gene silencing, activating AKT-MMP signaling pathways, EZH2 and LSD1, and functioning within a competing endogenous RNA (ceRNA) regulatory network by competitively binding miRNAs. This review surveys recent research on the structure, biological functions, abnormal expression, regulatory mechanisms, and diagnostic and therapeutic potential of HOXA-AS2 in various cancers.
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Affiliation(s)
- Mohadeseh Khoshandam
- Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Nikolaos Sideris
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
| | - Amirhossein Ahmadieh-Yazdi
- Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Ghadam
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Shermin Lak
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran
| | | | | | - Paola Dama
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
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Elimam H, Alhamshry NAA, Hatawsh A, Elfar N, Moussa R, Radwan AF, Abd-Elmawla MA, Elkashlan AM, Zaki MB, Abdel-Reheim MA, Mohammed OA, Doghish AS. Natural products and long noncoding RNA signatures in gallbladder cancer: a review focuses on pathogenesis, diagnosis, and drug resistance. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9549-9571. [PMID: 39028332 DOI: 10.1007/s00210-024-03279-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/02/2024] [Indexed: 07/20/2024]
Abstract
Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs) and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. Curcumin, baicalein, oleanolic acid, shikonin, oxymatrine, arctigenin, liensinine, fangchinoline, and dioscin are a few examples of natural compounds that have demonstrated promising anticancer activities against GBC through the regulation of important signaling pathways. The lncRNAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC, are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR activate oncogenes such as DNMT1, Wnt/β-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor proteins NF-κB, EZH2, and miR-421. Clinically, specific lncRNAs can serve as diagnostic or prognostic biomarkers based on overexpression correlating with advanced TNM stage, metastasis, chemoresistance, and poor survival. Therapeutically, targeting aberrant lncRNAs with siRNA or antisense oligos disrupts their oncogenic signaling and inhibits GBC progression. Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.
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Affiliation(s)
- Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt.
| | - Nora A A Alhamshry
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Abdulrahman Hatawsh
- Biotechnology School, 26th of July Corridor, Sheikh Zayed City, Nile University, Giza, 12588, Egypt
| | - Nourhan Elfar
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, 11578, Egypt
- Egyptian Drug Authority (EDA), Ministry of Health and Population, Cairo, 11567, Egypt
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Cairo, 11795, Egypt
| | - Abdullah F Radwan
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, 11829, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Akram M Elkashlan
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, 11961, Shaqra, Saudi Arabia.
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62521, Egypt.
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
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3
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Wilson C, Swaroop P, Kumar S, Chopra A, Sharawat SK. Molecular leveraging of HOX-embedded non-coding RNAs in the progression of acute myeloid leukemia. Hum Cell 2024; 38:24. [PMID: 39614990 DOI: 10.1007/s13577-024-01149-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
Acute myeloid leukemia (AML) is characterized by impaired differentiation of myeloid cells leading to hematopoietic failure. Despite advances, the molecular mechanisms driving AML remain incompletely understood, limiting the identification and targeting of critical vulnerabilities in leukemic cells. Homeobox (HOX) genes, encoding transcription factors essential for myeloid and lymphoid differentiation, are distributed across four clusters: HOXA (chromosome 7), HOXB (chromosome 17), HOXC (chromosome 12), and HOXD (chromosome 2). In addition to protein-coding sequences, HOX clusters encode non-coding RNAs (ncRNAs), which are functional as transcripts and do not translate into proteins. This is the first study wherein we comprehensively reviewed the literature for HOX-embedded ncRNAs, encompassing long non-coding RNAs (lncRNAs), microRNAs, circular RNAs (circRNAs), and piwiRNAs with a role in AML. To date, there is no evidence of circular RNAs and piwi RNAs encoded from the HOX gene clusters. Our review focuses on how leukemic cells harness the regulatory mechanisms of HOX-cluster-derived ncRNAs, (predominantly HOXA and HOXB) to modulate expression of HOX transcription factors facilitating leukemogenesis. HOX ncRNAs either regulate genes on the same chromosome (e.g., lncRNA HOTTIP) or influence expression of genes on different chromosomes (e.g., HOTAIR, HOX10-AS, miR-196b, and miR-10a). We discuss how specific HOX ncRNA networks are leveraged by leukemic cells, presenting an opportunity to explore targeted therapies and address the molecular heterogeneity of AML. Additionally, the aberrant expression of HOX ncRNAs such as HOXB derived ncRNAs in NPM1 mutated AML suggests their potential utility as improved biomarkers and for prognostication of patients with specific molecular aberrations.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/therapy
- Nucleophosmin/genetics
- Disease Progression
- Genes, Homeobox/genetics
- RNA, Untranslated/genetics
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/physiology
- MicroRNAs/genetics
- Homeodomain Proteins/genetics
- Multigene Family/genetics
- RNA, Circular/genetics
- RNA, Circular/physiology
- Cell Differentiation/genetics
- Transcription Factors/genetics
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Affiliation(s)
- Christine Wilson
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India
| | - Priyanka Swaroop
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sachin Kumar
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India
| | - Anita Chopra
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Surender K Sharawat
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, Room No. 401, 4th Floor, New Delhi, India.
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Hosseini M, Mokhtari MJ. Up-regulation of HOXA-AS2 and MEG3 long non-coding RNAs acts as a potential peripheral biomarker for bipolar disorder. J Cell Mol Med 2024; 28:e70150. [PMID: 39482996 PMCID: PMC11528130 DOI: 10.1111/jcmm.70150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/21/2024] [Accepted: 10/01/2024] [Indexed: 11/03/2024] Open
Abstract
Bipolar disorder (BD) is a psychiatric condition that is frequently misdiagnosed and linked to inadequate treatment. Long non-coding RNAs (lncRNAs) have lately gained recognition as crucial genetic elements and are now regarded as regulatory mechanisms in the neurological system. Our objective was to measure the quantities of HOXA-AS2 and MEG3 ncRNA transcripts. HOXA-AS2 and MEG3 ncRNA levels were checked in the peripheral blood of 50 type I BD and 50 control samples by real-time PCR. Furthermore, we conducted ROC curve analysis and correlation analysis to examine the association between gene expression and specific clinical characteristics in instances with BD. Additionally, a computational study was performed to investigate the binding sites of miRNAs on the HOXA-AS2 and MEG3 lncRNAs. BD subjects showed a significant increase in the expression of HOXA-AS2 and MEG3 compared to controls. The lncRNAs HOXA-AS2 and MEG3 have an area under the ROC curve (AUC) values of 0.70 and 0.71, respectively. There was a significant correlation between the expression levels of ncRNAs HOXA-AS2 and MEG3 in the peripheral blood of patients with BD and occupation scores. The data presented indicate a potential correlation between the expression of HOXA-AS2 and MEG3 lncRNAs with an elevated risk of BD. Furthermore, these lncRNAs may be linked to several molecular pathways. Our findings indicate that the amounts of lncRNAs HOXA-AS2 and MEG3 in transcripts might be a promising potential biomarker for patients with BD.
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Affiliation(s)
- Maryam Hosseini
- Department of Biology, Zarghan BranchIslamic Azad UniversityZarghanIran
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Tiwari P, Tripathi LP. Long Non-Coding RNAs, Nuclear Receptors and Their Cross-Talks in Cancer-Implications and Perspectives. Cancers (Basel) 2024; 16:2920. [PMID: 39199690 PMCID: PMC11352509 DOI: 10.3390/cancers16162920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/30/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) play key roles in various epigenetic and post-transcriptional events in the cell, thereby significantly influencing cellular processes including gene expression, development and diseases such as cancer. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that typically regulate transcription of genes involved in a broad spectrum of cellular processes, immune responses and in many diseases including cancer. Owing to their many overlapping roles as modulators of gene expression, the paths traversed by lncRNA and NR-mediated signaling often cross each other; these lncRNA-NR cross-talks are being increasingly recognized as important players in many cellular processes and diseases such as cancer. Here, we review the individual roles of lncRNAs and NRs, especially growth factor modulated receptors such as androgen receptors (ARs), in various types of cancers and how the cross-talks between lncRNAs and NRs are involved in cancer progression and metastasis. We discuss the challenges involved in characterizing lncRNA-NR associations and how to overcome them. Furthering our understanding of the mechanisms of lncRNA-NR associations is crucial to realizing their potential as prognostic features, diagnostic biomarkers and therapeutic targets in cancer biology.
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Affiliation(s)
- Prabha Tiwari
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Lokesh P. Tripathi
- Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Kanagawa, Japan
- AI Center for Health and Biomedical Research (ArCHER), National Institutes of Biomedical Innovation, Health and Nutrition, Kento Innovation Park NK Building, 3-17 Senrioka Shinmachi, Settsu 566-0002, Osaka, Japan
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Xiao T, Yan A, Tan L, Zhu H, Gao W. LncRNA HOXA‑AS2 is a prognostic and clinicopathological predictor in patients with cancer: A meta‑analysis. Oncol Lett 2024; 27:226. [PMID: 38586205 PMCID: PMC10996033 DOI: 10.3892/ol.2024.14359] [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: 11/21/2023] [Accepted: 02/23/2024] [Indexed: 04/09/2024] Open
Abstract
Elevated expression of long non-coding RNA homeobox A cluster antisense RNA 2 (lncRNA HOXA-AS2) is known to have prognostic value in various solid tumors. The present meta-analysis aimed to comprehensively quantify its prognostic significance across a wider spectrum of malignancies and to provide an updated synthesis of evidence that could refine prognostic models. To achieve this aim, multiple databases were carefully searched for lncRNA HOXA-AS2-related articles published in the past 10 years. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to demonstrate the prognostic value of lncRNA HOXA-AS2 using Stata 15.0 software. The function of lncRNA HOXA-AS2 was inferred from its associations with key clinical outcomes such as lymph node metastasis, distant metastasis, tumor stage and tumor size, which may reflect its role in tumor biology. In the present systematic review and meta-analysis of 454 patients across 7 studies, it was found that high lncRNA HOXA-AS2 expression was significantly associated with a shorter overall survival (OS) time in patients with cancer (HR=2.14; 95% CI, 1.40-3.27; P<0.001). High lncRNA HOXA-AS2 expression was also associated with lymph node metastasis [odds ratio (OR)=2.06; 95% CI, 1.07-3.99; P=0.032], distant metastasis (OR=2.11; 95% CI, 1.15-3.88; P=0.016), advanced tumor stage (OR=2.71; 95% CI, 1.50-4.89; P=0.001) and larger tumor size (OR=2.02; 95% CI, 0.86-4.78; P=0.006). However, no significant association was observed with age (OR=1.00; 95% CI, 0.63-1.59; P=0.991) or sex (OR=1.55; 95% CI, 0.72-3.34; P=0.258). In conclusion, elevated expression of lncRNA HOXA-AS2 was significantly related to poor clinical outcomes in various cancer types, such as osteosarcoma, non-small cell lung cancer and papillary thyroid carcinoma, a finding that was further confirmed by the present study. Specifically, the potential of lncRNAHOXA-AS2 as a biomarker in assessing tumor stage, metastasis risk and OS in patients was demonstrated. However, the results of the present study also indicated that the expression of lncRNA HOXA-AS2 was not significantly associated with age or sex, suggesting its role in cancer progression might be independent of these factors. This insight may direct future research to place more focus on the relationship between lncRNA HOXA-AS2 and specific cancer types and clinical characteristics.
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Affiliation(s)
- Tijun Xiao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Shaoyang University, Shaoyang, Hunan 422000, P.R. China
| | - An Yan
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lifang Tan
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Shaoyang University, Shaoyang, Hunan 422000, P.R. China
| | - Hongwei Zhu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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7
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Motlagh FM, Kadkhoda S, Motamedrad M, Javidzade P, Khalilian S, Modarressi MH, Ghafouri-Fard S. Roles of non-coding RNAs in cell death pathways involved in the treatment of resistance and recurrence of cancer. Pathol Res Pract 2023; 247:154542. [PMID: 37244050 DOI: 10.1016/j.prp.2023.154542] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/13/2023] [Accepted: 05/16/2023] [Indexed: 05/29/2023]
Abstract
Considering the burden of cancer, a number of methods have been applied to control or stop it. However, because of drug resistance or cancer recurrence, these treatments usually face failure. Combination of modulation of expression of non-coding RNAs (ncRNAs) with other treatments can increase treatment-sensitivity of tumors but these approaches still face some challenges. Gathering information in this field is a prerequisite to find more efficient cures for cancer. Cancer cells use ncRNAs to enhance uncontrolled proliferation originated from inactivation of cell death routs. In this review article, the main routes of cell death and involved ncRNAs in these routes are discussed. Moreover, extant information in the role of different ncRNAs on cell death pathways involved in the treatment resistance and cancer recurrence is summarized.
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Affiliation(s)
- Fatemeh Movahedi Motlagh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Sepideh Kadkhoda
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Motamedrad
- Division of Human Nutrition, University of Alberta, Edmonton, AB T6G 2P5, Canada; Department of Biology, Faculty of Science, University of Birjand, Birjand, Iran
| | - Parisa Javidzade
- Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Sheyda Khalilian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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8
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Cornet-Gomez A, Retana Moreira L, Kronenberger T, Osuna A. Extracellular vesicles of trypomastigotes of Trypanosoma cruzi induce changes in ubiquitin-related processes, cell-signaling pathways and apoptosis. Sci Rep 2023; 13:7618. [PMID: 37165081 PMCID: PMC10171165 DOI: 10.1038/s41598-023-34820-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/08/2023] [Indexed: 05/12/2023] Open
Abstract
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. The disease has an acute and a chronic phase in which approximately 30% of the chronic patients suffer from heart disease and/or gastrointestinal symptoms. The pathogenesis of the disease is multifactorial and involves the virulence of the strains, immunological factors and extracellular vesicles (EV) shed by the parasite which participate in cell-cell communication and evasion of the immune response. In this work, we present a transcriptomic analysis of cells stimulated with EV of the trypomastigote stage of T. cruzi. Results after EV-cell incubation revealed 322 differentially expressed genes (168 were upregulated and 154 were downregulated). In this regard, the overexpression of genes related to ubiquitin-related processes (Ube2C, SUMO1 and SUMO2) is highlighted. Moreover, the expression of Rho-GTPases (RhoA, Rac1 and Cdc42) after the interaction was analyzed, revealing a downregulation of the analyzed genes after 4 h of interaction. Finally, a protective role of EV over apoptosis is suggested, as relative values of cells in early and late apoptosis were significantly lower in EV-treated cells, which also showed increased CSNK1G1 expression. These results contribute to a better understanding of the EV-cell interaction and support the role of EV as virulence factors.
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Affiliation(s)
- Alberto Cornet-Gomez
- Grupo de Bioquímica y Parasitología Molecular (CTS 183), Departamento de Parasitología, Instituto de Biotecnología, Universidad de Granada, Campus de Fuentenueva, 18071, Granada, Spain
| | - Lissette Retana Moreira
- Grupo de Bioquímica y Parasitología Molecular (CTS 183), Departamento de Parasitología, Instituto de Biotecnología, Universidad de Granada, Campus de Fuentenueva, 18071, Granada, Spain
- Departamento de Parasitología, Facultad de Microbiología, Universidad de Costa Rica, San José, 11501, Costa Rica
- Centro de Investigación en Enfermedades Tropicales (CIET), Universidad de Costa Rica, San José, 11501, Costa Rica
| | - Thales Kronenberger
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland
| | - Antonio Osuna
- Grupo de Bioquímica y Parasitología Molecular (CTS 183), Departamento de Parasitología, Instituto de Biotecnología, Universidad de Granada, Campus de Fuentenueva, 18071, Granada, Spain.
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9
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Zong H, Zou JQ, Huang JP, Huang ST. Potential role of long noncoding RNA RP5-881L22.5 as a novel biomarker and therapeutic target of colorectal cancer. World J Gastrointest Oncol 2022; 14:2108-2121. [PMID: 36438707 PMCID: PMC9694279 DOI: 10.4251/wjgo.v14.i11.2108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 09/13/2022] [Accepted: 10/19/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND The incidence of colorectal cancer in humans is high, and it is in the top five for cancer-related morbidity and mortality. It is one of the main threats to human health. The function of long noncoding RNAs in tumor occurrence and development has gradually gained attention in recent years. In increasing numbers of studies, researchers have demonstrated that it plays an important role in the pathogenesis of colorectal cancer.
AIM To find out if long noncoding RNA RP5-881L22.5 played a role in the pathogenesis of colorectal cancer in relation to the tumor microenvironment.
METHODS We analyzed the transcriptome data and clinical data in The Cancer Genome Atlas-colon adenocarcinoma. The CIRBERSORT algorithm was applied to evaluate these tumor-infiltrating immune cells in The Cancer Genome Atlas-colon adenocarcinoma cancer tissue samples. Using the “estimate” package in R, we assessed the tumor immune microenvironment. The expression level of RP5-881L22.5 in tumor tissue and adjacent normal tissue samples from 4 pairs of colorectal cancer patients was determined by quantitative reverse transcription PCR. Colorectal cancer cells were tested for invasiveness using a transwell invasion assay after RP5-881L22.5 expression was knocked down.
RESULTS The expression of lncRNA RP5-881L22.5 was related to the clinical characteristics of the tumors, and it was negatively related to the infiltration level of immune cells in the tumor microenvironment and the expression of T cell inhibitory receptors. A major function of its coexpressed mRNA was to regulate tumor immunity, such as the immune response. When quantitative reverse transcription PCR was performed on tumor tissues from 4 pairs of colorectal cancer patients, the results showed that RP5-881L22.5 was highly expressed. Subsequently, knocking down the expression of RP5-881L22.5, the invasiveness of colorectal cancer cell lines was reduced, and the apoptosis rate was increased.
CONCLUSION RP5-881L22.5 plays a crucial role in the microenvironment of tumors as well as in the pathogenesis of colorectal cancer. The relationship between RP5-881L22.5 and the tumor immune microenvironment deserves further study.
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Affiliation(s)
- Hua Zong
- Department of Gastrointestinal Surgery, The Third People’s Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Jian-Qiang Zou
- Department of Gastrointestinal Surgery, The Third People’s Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Jian-Peng Huang
- Department of Gastrointestinal Surgery, The Third People’s Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Shi-Ting Huang
- Department of Gastrointestinal Surgery, The Third People’s Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
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Wang Q, Zhang W, Deng C, Lin S, Zhou Y. HOXA-AS2 may predict the prognosis of solid tumors among Chinese patients: A meta-analysis and bioinformatic analysis. Front Oncol 2022; 12:1030825. [PMID: 36387249 PMCID: PMC9659612 DOI: 10.3389/fonc.2022.1030825] [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: 08/29/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022] Open
Abstract
Background HOXA cluster antisense RNA 2 (lncRNA HOXA-AS2) is a long noncoding RNA (lncRNA) that aberrantly expressed in various cancers and is closely associated with cancer progression. To overcome the limitation of small sample sizes that are inherent to single studies, a meta-analysis was conducted to explore the relationship between the expression level of HOXA-AS2 and cancer prognosis. Methods Correlational studies were retrieved by searching the databases of PubMed, Embase and Web of Science (up to August 10, 2022). The survival and prognosis data included overall survival (OS), and clinical parameters were gathered and analyzed. Results Eighteen publications with 1181 patients who were diagnosed with solid tumors were ultimately included. The results showed that, compared with patients with low HOXA-AS2 expression, patients with high HOXA-AS2 expression tended to have poorer overall survival (OS) (HR= 2.52, 95% CI 1.87-3.38, P < 0.01) and shorter disease-free survival (DFS) (HR=7.19, 95% CI 3.20-16.17, P < 0.01). In addition, elevated HOXA-AS2 expression indicated a larger tumor size (OR =2.43, 95% CI 1.53–3.88,P < 0.01), more advanced TNM stage (OR=3.85, 95% CI 2.79-5.31, P < 0.01), earlier lymph node metastasis (LNM) (OR = 4.41, 95% CI 3.05-6.39, P < 0.01) and distant metastasis (DM) (OR= 2.96, 95% CI 1.87-4.7, P < 0.01). Furthermore, HOXA-AS2 expression was notassociated with age (OR=1.15, 95% CI 0.90-1.47), gender (OR=1.16, 95% CI 0.89-1.53), or tumor differentiation (OR=1.21, 95% CI 0.56-2.63). Moreover, aberrant HOXA-AS2 expression was related to drug sensitivity in various types of cancers. Conclusion The overexpression of HOXA-AS2 predicted poor cancer prognosis in the Chinese population, including poor OS, DFS, TNM, LNM, and DM. HOXA-AS2 could serve as a promising prognostic biomarker and therapeutic target. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022352604.
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Affiliation(s)
- Qiang Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of General Surgery, Jianyang People’s Hospital, Jianyang, China
| | - Wei Zhang
- Department of General Surgery, Jianyang People’s Hospital, Jianyang, China
| | - Chao Deng
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shicheng Lin
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yejiang Zhou
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Yejiang Zhou,
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11
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Huang S, Lu B, Zhu M, Liu M, Sun Z, Pan X, Wei M. Long non-coding RNA LOC644135 is a potential prognostic indicator in cytogenetically normal acute myeloid leukemia. Expert Rev Hematol 2022; 15:657-665. [PMID: 35713000 DOI: 10.1080/17474086.2022.2091542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Acute myeloid leukemia (AML) is a hematological malignancy with highly clinical heterogeneity resulting in poor outcomes. We aim to identify novel prognostic lncRNA in AML expecting to provide new clues for therapy in AML. METHODS Three cohorts were enrolled in this study. Differentially expressed lncRNAs between TCGA-AML cohort and GTEx cohort was identified by DESeq2. The relationship between expression level of LOC644135 and prognosis in AML was analyzed by multiple methods. RESULTS Pan-cancer analysis indicated that LOC644135 was most highly expressed in AML across 33 types of cancer. Patients with high expression of LOC644135 had poor overall prognosis in both TCGA-AML cohort and the TARGET-AML cohort. Especially, high expression of LOC644135 indicated inferior overall survival and event-free survival in CN-AML patients in the TCGA-AML cohort. Besides, CN-AML patients had higher expression of LOC644135 than normal samples. Multivariable analysis suggested that LOC644135 was an independent prognostic factor in AML. GSEA analysis showed that LOC644135 was associated with some immune-related pathways. Besides, high expression of LOC644135 was associated with less infiltration of CD8+ T cell. CONCLUSION Our findings indicated that LOC644135 was an independent prognostic factor in AML and provided a new idea in the development of therapy in AML.
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Affiliation(s)
- Shan Huang
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bo Lu
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Mengyuan Zhu
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Minling Liu
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Ziyi Sun
- Department of Oncology, Taikang Tongji (Wuhan) Hospital, Wuhan, Hubei, China
| | - Xiaofen Pan
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Min Wei
- Department of Oncology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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12
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Zhao N, Guo M, Zhang C, Wang C, Wang K. Pan-Cancer Methylated Dysregulation of Long Non-coding RNAs Reveals Epigenetic Biomarkers. Front Cell Dev Biol 2022; 10:882698. [PMID: 35721492 PMCID: PMC9200062 DOI: 10.3389/fcell.2022.882698] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/28/2022] [Indexed: 11/18/2022] Open
Abstract
Different cancer types not only have common characteristics but also have their own characteristics respectively. The mechanism of these specific and common characteristics is still unclear. Pan-cancer analysis can help understand the similarities and differences among cancer types by systematically describing different patterns in cancers and identifying cancer-specific and cancer-common molecular biomarkers. While long non-coding RNAs (lncRNAs) are key cancer modulators, there is still a lack of pan-cancer analysis for lncRNA methylation dysregulation. In this study, we integrated lncRNA methylation, lncRNA expression and mRNA expression data to illuminate specific and common lncRNA methylation patterns in 23 cancer types. Then, we screened aberrantly methylated lncRNAs that negatively regulated lncRNA expression and mapped them to the ceRNA relationship for further validation. 29 lncRNAs were identified as diagnostic biomarkers for their corresponding cancer types, with lncRNA AC027601 was identified as a new KIRC-associated biomarker, and lncRNA ACTA2-AS1 was regarded as a carcinogenic factor of KIRP. Two lncRNAs HOXA-AS2 and AC007228 were identified as pan-cancer biomarkers. In general, the cancer-specific and cancer-common lncRNA biomarkers identified in this study may aid in cancer diagnosis and treatment.
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Affiliation(s)
- Ning Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Maozu Guo
- School of Electrical and Information Engineering, Beijing University of Civil Engineering and Architecture, Beijing, China
| | - Chunlong Zhang
- College of Information and Computer Engineering, Northeast Forest University, Harbin, China
| | - Chunyu Wang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Kuanquan Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.,School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
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13
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Neyazi S, Ng M, Heckl D, Klusmann JH. Long noncoding RNAs as regulators of pediatric acute myeloid leukemia. Mol Cell Pediatr 2022; 9:10. [PMID: 35596093 PMCID: PMC9123150 DOI: 10.1186/s40348-022-00142-2] [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: 12/03/2021] [Accepted: 03/30/2022] [Indexed: 11/10/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are increasingly emerging as regulators across human development and disease, and many have been described in the context of hematopoiesis and leukemogenesis. These studies have yielded new molecular insights into the contribution of lncRNAs to AML development and revealed connections between lncRNA expression and clinical parameters in AML patients. In this mini review, we illustrate the versatile functions of lncRNAs in AML, with a focus on pediatric AML, and present examples that may serve as future therapeutic targets or predictive factors.
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Affiliation(s)
- Sina Neyazi
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Michelle Ng
- Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Dirk Heckl
- Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
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14
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Le Boiteux E, Guichet PO, Masliantsev K, Montibus B, Vaurs-Barriere C, Gonthier-Gueret C, Chautard E, Verrelle P, Karayan-Tapon L, Fogli A, Court F, Arnaud P. The Long Non-Coding RNA HOXA-AS2 Promotes Proliferation of Glioma Stem Cells and Modulates Their Inflammation Pathway Mainly through Post-Transcriptional Regulation. Int J Mol Sci 2022; 23:ijms23094743. [PMID: 35563134 PMCID: PMC9102906 DOI: 10.3390/ijms23094743] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/15/2022] [Accepted: 04/22/2022] [Indexed: 12/21/2022] Open
Abstract
Glioblastomas represent approximatively half of all gliomas and are the most deadly and aggressive form. Their therapeutic resistance and tumor relapse rely on a subpopulation of cells that are called Glioma Stem Cells (GSCs). Here, we investigated the role of the long non-coding RNA HOXA-AS2 in GSC biology using descriptive and functional analyses of glioma samples classified according to their isocitrate dehydrogenase (IDH) gene mutation status, and of GSC lines. We found that HOXA-AS2 is overexpressed only in aggressive (IDHwt) glioma and GSC lines. ShRNA-based depletion of HOXA-AS2 in GSCs decreased cell proliferation and altered the expression of several hundreds of genes. Integrative analysis revealed that these expression changes were not associated with changes in DNA methylation or chromatin signatures at the promoter of the majority of genes deregulated following HOXA-AS2 silencing in GSCs, suggesting a post-transcriptional regulation. In addition, transcription factor binding motif enrichment and correlation analyses indicated that HOXA-AS2 affects, directly or indirectly, the expression of key transcription factors implicated in GCS biology, including E2F8, E2F1, STAT1, and ATF3, thus contributing to GCS aggressiveness by promoting their proliferation and modulating the inflammation pathway.
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Affiliation(s)
- Elisa Le Boiteux
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
| | - Pierre-Olivier Guichet
- ProDiCeT UR 24144, Université de Poitiers, F-86000 Poitiers, France; (P.-O.G.); (K.M.); (L.K.-T.)
- Laboratoire de Cancérologie Biologique, CHU de Poitiers, F-86000 Poitiers, France
| | - Konstantin Masliantsev
- ProDiCeT UR 24144, Université de Poitiers, F-86000 Poitiers, France; (P.-O.G.); (K.M.); (L.K.-T.)
- Laboratoire de Cancérologie Biologique, CHU de Poitiers, F-86000 Poitiers, France
| | - Bertille Montibus
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
| | - Catherine Vaurs-Barriere
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
| | - Céline Gonthier-Gueret
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
| | - Emmanuel Chautard
- Pathology Department, Jean Perrin Center, F-63000 Clermont-Ferrand, France;
- INSERM, U1240 IMoST, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France
| | - Pierre Verrelle
- CIMB, INSERM U1196 CNRS UMR9187, Curie Institute, F-91400 Orsay, France;
- Radiotherapy Department, Curie Institute, F-75248 Paris, France
- CNRS UMR 9187, INSERM U1196, Institut Curie, PSL Research University and Paris-Saclay University, F-91405 Orsay, France
| | - Lucie Karayan-Tapon
- ProDiCeT UR 24144, Université de Poitiers, F-86000 Poitiers, France; (P.-O.G.); (K.M.); (L.K.-T.)
- Laboratoire de Cancérologie Biologique, CHU de Poitiers, F-86000 Poitiers, France
| | - Anne Fogli
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
- Radiation Oncology Department, Institut Curie, F-75005 Paris, France
| | - Franck Court
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
- Correspondence: (F.C.); (P.A.)
| | - Philippe Arnaud
- Université Clermont Auvergne, CNRS, Inserm, GReD, F-63000 Clermont-Ferrand, France; (E.L.B.); (B.M.); (C.V.-B.); (C.G.-G.); (A.F.)
- Correspondence: (F.C.); (P.A.)
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15
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Bhattacharya M, Gutti RK. Non-coding RNAs: are they the protagonist or antagonist in the regulation of leukemia? Am J Transl Res 2022; 14:1406-1432. [PMID: 35422954 PMCID: PMC8991171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 02/07/2022] [Indexed: 06/14/2023]
Abstract
The idea of functional non-coding RNAs is taking precedence over the previous notion which believed that they only comprise the auxiliary and junk material of the genome. Newer technologies and studies have proven their importance in regulating and affecting several cellular processes. One such area of research wherein their importance has started to take light is in cancer research, particularly leukemia. Myeloid leukemia is a blood malignancy birthed from mutations in hematopoiesis that disable myeloid progenitor cells from proper differentiation. This review will compile the most recent findings regarding the effects of these regulatory non-coding RNAs on the two types of myeloid leukemia. In particular, the effects of circular RNAs, micro RNAs and long non-coding RNAs, on the pathogenesis and proliferation of Acute and Chronic myeloid leukemia will be revealed in a molecular, cellular and prognostic light. The mechanisms of proliferation, gene-to-gene interactions and possible therapeutic effects will also be discussed. Finally, an understanding of the overall "goodness" and "badness" of these non-coding RNAs will be summarised. This review hopes to provide a platform for easy access to data regarding the current non-coding RNAs in myeloid leukemia, for faster and easier research. Finally, the review will summarize a few key players that have protagonistic and antagonistic functions, and those that regulate multiple pathways in leukemia simultaneously.
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Affiliation(s)
- Mrinnanda Bhattacharya
- Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad(PO) Gachibowli, Hyderabad 500046 (TS), India
| | - Ravi Kumar Gutti
- Department of Biochemistry, School of Life Sciences, University of Hyderabad(PO) Gachibowli, Hyderabad 500046 (TS), India
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16
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Park EG, Pyo SJ, Cui Y, Yoon SH, Nam JW. Tumor immune microenvironment lncRNAs. Brief Bioinform 2021; 23:6458113. [PMID: 34891154 PMCID: PMC8769899 DOI: 10.1093/bib/bbab504] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/15/2021] [Accepted: 11/02/2021] [Indexed: 01/17/2023] Open
Abstract
Long non-coding ribonucleic acids (RNAs) (lncRNAs) are key players in tumorigenesis and immune responses. The nature of their cell type-specific gene expression and other functional evidence support the idea that lncRNAs have distinct cellular functions in the tumor immune microenvironment (TIME). To date, the majority of lncRNA studies have heavily relied on bulk RNA-sequencing data in which various cell types contribute to an averaged signal, limiting the discovery of cell type-specific lncRNA functions. Single-cell RNA-sequencing (scRNA-seq) is a potential solution for tackling this limitation despite the lack of annotations for low abundance yet cell type-specific lncRNAs. Hence, updated annotations and further understanding of the cellular expression of lncRNAs will be necessary for characterizing cell type-specific functions of lncRNA genes in the TIME. In this review, we discuss lncRNAs that are specifically expressed in tumor and immune cells, summarize the regulatory functions of the lncRNAs at the cell type level and highlight how a scRNA-seq approach can help to study the cell type-specific functions of TIME lncRNAs.
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Affiliation(s)
- Eun-Gyeong Park
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Sung-Jin Pyo
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Youxi Cui
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Sang-Ho Yoon
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
| | - Jin-Wu Nam
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea.,Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul 04763, Republic of Korea.,Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
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17
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TÜNCEL Ö, KARA M, YAYLAK B, ERDOĞAN İ, AKGÜL B. Noncoding RNAs in apoptosis: identification and function. Turk J Biol 2021; 46:1-40. [PMID: 37533667 PMCID: PMC10393110 DOI: 10.3906/biy-2109-35] [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: 09/11/2021] [Revised: 02/08/2022] [Accepted: 11/14/2021] [Indexed: 08/04/2023] Open
Abstract
Apoptosis is a vital cellular process that is critical for the maintenance of homeostasis in health and disease. The derailment of apoptotic mechanisms has severe consequences such as abnormal development, cancer, and neurodegenerative diseases. Thus, there exist complex regulatory mechanisms in eukaryotes to preserve the balance between cell growth and cell death. Initially, protein-coding genes were prioritized in the search for such regulatory macromolecules involved in the regulation of apoptosis. However, recent genome annotations and transcriptomics studies have uncovered a plethora of regulatory noncoding RNAs that have the ability to modulate not only apoptosis but also many other biochemical processes in eukaryotes. In this review article, we will cover a brief summary of apoptosis and detection methods followed by an extensive discussion on microRNAs, circular RNAs, and long noncoding RNAs in apoptosis.
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Affiliation(s)
- Özge TÜNCEL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Merve KARA
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bilge YAYLAK
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - İpek ERDOĞAN
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bünyamin AKGÜL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
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18
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Singh VK, Thakral D, Gupta R. Regulatory noncoding RNAs: potential biomarkers and therapeutic targets in acute myeloid leukemia. AMERICAN JOURNAL OF BLOOD RESEARCH 2021; 11:504-519. [PMID: 34824883 PMCID: PMC8610797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/09/2021] [Indexed: 06/13/2023]
Abstract
The noncoding RNAs (ncRNA) comprise a substantial segment of the human transcriptome and have emerged as key elements of cellular homeostasis and disease pathogenesis. Dysregulation of these ncRNAs by alterations in the primary RNA motifs and/or aberrant expression levels is relevant in various diseases, especially cancer. The recent research advances indicate that ncRNAs regulate vital oncogenic processes, including hematopoietic cell differentiation, proliferation, apoptosis, migration, and angiogenesis. The ever-expanding role of ncRNAs in cancer progression and metastasis has sparked interest as potential diagnostic and prognostic biomarkers in acute myeloid leukemia. Moreover, advances in antisense oligonucleotide technologies and pharmacologic discoveries of small molecule inhibitors in targeting RNA structures and RNA-protein complexes have opened newer avenues that may help develop the next generation anti-cancer therapeutics. In this review, we have discussed the role of ncRNA in acute myeloid leukemia and their utility as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Vivek Kumar Singh
- Laboratory Oncology, Dr B.R.A, IRCH, All India Institute of Medical Sciences New Delhi 110029, India
| | - Deepshi Thakral
- Laboratory Oncology, Dr B.R.A, IRCH, All India Institute of Medical Sciences New Delhi 110029, India
| | - Ritu Gupta
- Laboratory Oncology, Dr B.R.A, IRCH, All India Institute of Medical Sciences New Delhi 110029, India
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19
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Yang X, Zhang Y, Chen Y, He X, Qian Y, Xu S, Gao C, Mo C, Chen S, Xiao Q. LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression. J Neuroinflammation 2021; 18:197. [PMID: 34511122 PMCID: PMC8436538 DOI: 10.1186/s12974-021-02267-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Background Microglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. Methods In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. Results We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. Conclusions Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02267-z.
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Affiliation(s)
- Xiaodong Yang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Yi Zhang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Yimeng Chen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Xiaoqin He
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Yiwei Qian
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Shaoqing Xu
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Chao Gao
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Chengjun Mo
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China
| | - Shengdi Chen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China.
| | - Qin Xiao
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, 200025, Shanghai, PR China.
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20
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Khalili-Tanha G, Moghbeli M. Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells. Cell Mol Biol Lett 2021; 26:39. [PMID: 34425750 PMCID: PMC8381522 DOI: 10.1186/s11658-021-00282-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 08/17/2021] [Indexed: 12/16/2022] Open
Abstract
Resistance against conventional chemotherapeutic agents is one of the main reasons for tumor relapse and poor clinical outcomes in cancer patients. Various mechanisms are associated with drug resistance, including drug efflux, cell cycle, DNA repair and apoptosis. Doxorubicin (DOX) is a widely used first-line anti-cancer drug that functions as a DNA topoisomerase II inhibitor. However, DOX resistance has emerged as a large hurdle in efficient tumor therapy. Furthermore, despite its wide clinical application, DOX is a double-edged sword: it can damage normal tissues and affect the quality of patients’ lives during and after treatment. It is essential to clarify the molecular basis of DOX resistance to support the development of novel therapeutic modalities with fewer and/or lower-impact side effects in cancer patients. Long non-coding RNAs (lncRNAs) have critical roles in the drug resistance of various tumors. In this review, we summarize the state of knowledge on all the lncRNAs associated with DOX resistance. The majority are involved in promoting DOX resistance. This review paves the way to introducing an lncRNA panel marker for the prediction of the DOX response and clinical outcomes for cancer patients.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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21
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Role of the HOXA cluster in HSC emergence and blood cancer. Biochem Soc Trans 2021; 49:1817-1827. [PMID: 34374409 DOI: 10.1042/bst20210234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
Hematopoiesis, the process of blood formation, is controlled by a complex developmental program that involves intrinsic and extrinsic regulators. Blood formation is critical to normal embryonic development and during embryogenesis distinct waves of hematopoiesis have been defined that represent the emergence of hematopoietic stem or progenitor cells. The Class I family of homeobox (HOX) genes are also critical for normal embryonic development, whereby mutations are associated with malformations and deformity. Recently, members of the HOXA cluster (comprising 11 genes and non-coding RNA elements) have been associated with the emergence and maintenance of long-term repopulating HSCs. Previous studies identified a gradient of HOXA expression from high in HSCs to low in circulating peripheral cells, indicating their importance in maintaining blood cell numbers and differentiation state. Indeed, dysregulation of HOXA genes either directly or by genetic lesions of upstream regulators correlates with a malignant phenotype. This review discusses the role of the HOXA cluster in both HSC emergence and blood cancer formation highlighting the need for further research to identify specific roles of these master regulators in normal and malignant hematopoiesis.
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22
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Varier KM, Dhandapani H, Liu W, Song J, Wang C, Hu A, Ben-David Y, Shen X, Li Y, Gajendran B. An immunotherapeutic approach to decipher the role of long non-coding RNAs in cancer progression, resistance and epigenetic regulation of immune cells. J Exp Clin Cancer Res 2021; 40:242. [PMID: 34303380 PMCID: PMC8305593 DOI: 10.1186/s13046-021-01997-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 05/27/2021] [Indexed: 01/01/2023] Open
Abstract
Immunotherapeutic treatments are gaining attention due to their effective anti-tumor response. Particularly, the revolution of immune checkpoint inhibitors (ICIs) produces promising outcomes for various cancer types. However, the usage of immunotherapy is limited due to its low response rate, suggesting that tumor cells escape the immune surveillance. Rapid advances in transcriptomic profiling have led to recognize immune-related long non-coding RNAs (LncRNAs), as regulators of immune cell-specific gene expression that mediates immune stimulatory as well as suppression of immune response, indicating LncRNAs as targets to improve the efficacy of immunotherapy against tumours. Moreover, the immune-related LncRNAs acting as epigenetic modifiers are also under deep investigation. Thus, herein, is a summarised knowledge of LncRNAs and their regulation in the adaptive and innate immune system, considering their importance in autophagy and predicting putative immunotherapeutic responses.
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Affiliation(s)
- Krishnapriya M Varier
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou Province, People's Republic of China
| | - Hemavathi Dhandapani
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai, 600020, India
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Wuling Liu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China
| | - Jialei Song
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou Province, People's Republic of China
| | - Chunlin Wang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China
| | - Anling Hu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China
| | - Yaacov Ben-David
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China.
| | - Xiangchun Shen
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China.
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou Province, People's Republic of China.
| | - Yanmei Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China.
| | - Babu Gajendran
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, Guizhou Province, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, 550014, Guizhou Province, People's Republic of China.
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou Province, People's Republic of China.
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23
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Novikova EL, Kulakova MA. There and Back Again: Hox Clusters Use Both DNA Strands. J Dev Biol 2021; 9:28. [PMID: 34287306 PMCID: PMC8293171 DOI: 10.3390/jdb9030028] [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: 06/15/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 12/25/2022] Open
Abstract
Bilaterian animals operate the clusters of Hox genes through a rich repertoire of diverse mechanisms. In this review, we will summarize and analyze the accumulated data concerning long non-coding RNAs (lncRNAs) that are transcribed from sense (coding) DNA strands of Hox clusters. It was shown that antisense regulatory RNAs control the work of Hox genes in cis and trans, participate in the establishment and maintenance of the epigenetic code of Hox loci, and can even serve as a source of regulatory peptides that switch cellular energetic metabolism. Moreover, these molecules can be considered as a force that consolidates the cluster into a single whole. We will discuss the examples of antisense transcription of Hox genes in well-studied systems (cell cultures, morphogenesis of vertebrates) and bear upon some interesting examples of antisense Hox RNAs in non-model Protostomia.
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Affiliation(s)
- Elena L. Novikova
- Department of Embryology, St. Petersburg State University, Universitetskaya nab. 7–9, 199034 Saint Petersburg, Russia;
- Laboratory of Evolutionary Morphology, Zoological Institute RAS, Universitetskaya nab. 1, 199034 Saint Petersburg, Russia
| | - Milana A. Kulakova
- Department of Embryology, St. Petersburg State University, Universitetskaya nab. 7–9, 199034 Saint Petersburg, Russia;
- Laboratory of Evolutionary Morphology, Zoological Institute RAS, Universitetskaya nab. 1, 199034 Saint Petersburg, Russia
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24
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Sansonetti M, De Windt LJ. Non-coding RNAs in cardiac inflammation: key drivers in the pathophysiology of heart failure. Cardiovasc Res 2021; 118:2058-2073. [PMID: 34097013 DOI: 10.1093/cvr/cvab192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 06/04/2021] [Indexed: 12/15/2022] Open
Abstract
Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of the cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation.
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Affiliation(s)
- Marida Sansonetti
- Department of Molecular Genetics, Faculty of Science and Engineering; Faculty of Health, Medicine and Life Sciences; Maastricht University, Maastricht, The Netherlands
| | - Leon J De Windt
- Department of Molecular Genetics, Faculty of Science and Engineering; Faculty of Health, Medicine and Life Sciences; Maastricht University, Maastricht, The Netherlands
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25
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LncRNA HOXA-AS2 promotes the progression of prostate cancer via targeting miR-509-3p/PBX3 axis. Biosci Rep 2021; 40:225235. [PMID: 32519740 PMCID: PMC7426630 DOI: 10.1042/bsr20193287] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 05/22/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) act as crucial modulators during the development of diverse cancers. Although various types of lncRNAs in prostate cancer (PCa) have been explored, quantities of lncRNAs still wait to be exploited. The present study is to probe the functions and mechanism of lncRNA HOXA cluster antisense RNA 2 (HOXA-AS2) in PCa. In the present study, we discovered that HOXA-AS2 was highly expressed in PCa tissues and cells. HOXA-AS2 depletion obviously influenced cell proliferation, migration, invasion, as well as epithelial-to-mesenchymal transition (EMT) progression. In addition, miR-509-3p had low expression in PCa cells and inversely modulated by HOXA-AS2. Cutting down HOXA-AS2 expression was capable of up-regulating miR-509-3p expression. In addition, HOXA-AS2 served as a competing endogenous RNA (ceRNA) through sponging miR-509-3p to release pre-B-cell leukemia homeobox 3 (PBX3) expression. The expression of PBX3 was noticeably high in tumor tissues. And PBX3 expression level was down-regulated markedly with the knockdown of HOXA-AS2. Rescue experiments certified the facilitated role of HOXA-AS2-miR-509-3p-PBX3 axis in regulating the progress of PCa. The present study may provide clues for exploration of novel therapeutic targets for PCa patients.
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26
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Liu G, Liu B, Liu X, Xie L, He J, Zhang J, Dong R, Ma D, Dong K, Ye M. ARID1B/SUB1-activated lncRNA HOXA-AS2 drives the malignant behaviour of hepatoblastoma through regulation of HOXA3. J Cell Mol Med 2021; 25:3524-3536. [PMID: 33683826 PMCID: PMC8034473 DOI: 10.1111/jcmm.16435] [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: 01/12/2020] [Revised: 02/16/2021] [Accepted: 02/20/2021] [Indexed: 12/17/2022] Open
Abstract
It has been becoming increasingly evident that long non‐coding RNAs (lncRNAs) play important roles in various human cancers. However, the biological processes and clinical significance of most lncRNAs in hepatoblastoma (HB) remain unclear. In our previous study, genome‐wide analysis with a lncRNA microarray found that lncRNA HOXA‐AS2 was up‐regulated in HB. Stable transfected cell lines with HOXA‐AS2 knockdown or overexpression were constructed in HepG2 and Huh6 cells, respectively. Our data revealed knockdown of HOXA‐AS2 increased cell apoptosis and inhibited cell proliferation, migration and invasion in HB. Up‐regulation of HOXA‐AS2 promoted HB malignant biological behaviours. Mechanistic investigations indicated that HOXA‐AS2 was modulated by chromatin remodelling factor ARID1B and transcription co‐activator SUB1, thereby protecting HOXA3 from degradation. Therefore, HOXA‐AS2 positively regulates HOXA3, which might partly demonstrate the involvement of HOXA3 in HOXA‐AS2‐mediated HB carcinogenesis. In conclusion, HOXA‐AS2 is significantly overexpressed in HB and the ARID1B/HOXA‐AS2/HOXA3 axis plays a critical role in HB tumorigenesis and development. These results might provide a potential new target for HB diagnosis and therapy.
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Affiliation(s)
- Gongbao Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Baihui Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Xiangqi Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Lulu Xie
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jiajun He
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jingjing Zhang
- Department of Medical Imaging, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Duan Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, Collaborative Innovation Center of Genetics and Development, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Kuiran Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Mujie Ye
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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27
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García-Padilla C, Lozano-Velasco E, López-Sánchez C, Garcia-Martínez V, Aranega A, Franco D. Non-Coding RNAs in Retinoic Acid as Differentiation and Disease Drivers. Noncoding RNA 2021; 7:ncrna7010013. [PMID: 33671241 PMCID: PMC8005990 DOI: 10.3390/ncrna7010013] [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] [Received: 01/21/2021] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 12/12/2022] Open
Abstract
All-trans retinoic acid (RA) is the most active metabolite of vitamin A. Several studies have described a pivotal role for RA signalling in different biological processes such as cell growth and differentiation, embryonic development and organogenesis. Since RA signalling is highly dose-dependent, a fine-tuning regulatory mechanism is required. Thus, RA signalling deregulation has a major impact, both in development and disease, related in many cases to oncogenic processes. In this review, we focus on the impact of ncRNA post-transcriptional regulatory mechanisms, especially those of microRNAs and lncRNAs, in RA signalling pathways during differentiation and disease.
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Affiliation(s)
- Carlos García-Padilla
- Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (C.G.-P.); (E.L.-V.); (A.A.)
- Department of Human Anatomy and Embryology, University of Extremadura, 06006 Badajoz, Spain; (C.L.-S.); (V.G.-M.)
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
| | - Estefanía Lozano-Velasco
- Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (C.G.-P.); (E.L.-V.); (A.A.)
- Fundación Medina, 18016 Granada, Spain
| | - Carmen López-Sánchez
- Department of Human Anatomy and Embryology, University of Extremadura, 06006 Badajoz, Spain; (C.L.-S.); (V.G.-M.)
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
| | - Virginio Garcia-Martínez
- Department of Human Anatomy and Embryology, University of Extremadura, 06006 Badajoz, Spain; (C.L.-S.); (V.G.-M.)
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
| | - Amelia Aranega
- Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (C.G.-P.); (E.L.-V.); (A.A.)
- Fundación Medina, 18016 Granada, Spain
| | - Diego Franco
- Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (C.G.-P.); (E.L.-V.); (A.A.)
- Fundación Medina, 18016 Granada, Spain
- Correspondence:
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28
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Paço A, Aparecida de Bessa Garcia S, Leitão Castro J, Costa-Pinto AR, Freitas R. Roles of the HOX Proteins in Cancer Invasion and Metastasis. Cancers (Basel) 2020; 13:E10. [PMID: 33375038 PMCID: PMC7792759 DOI: 10.3390/cancers13010010] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Invasion and metastasis correspond to the foremost cause of cancer-related death, and the molecular networks behind these two processes are extremely complex and dependent on the intra- and extracellular conditions along with the prime of the premetastatic niche. Currently, several studies suggest an association between the levels of HOX genes expression and cancer cell invasion and metastasis, which favour the formation of novel tumour masses. The deregulation of HOX genes by HMGA2/TET1 signalling and the regulatory effect of noncoding RNAs generated by the HOX loci can also promote invasion and metastasis, interfering with the expression of HOX genes or other genes relevant to these processes. In this review, we present five molecular mechanisms of HOX deregulation by which the HOX clusters products may affect invasion and metastatic processes in solid tumours.
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Affiliation(s)
- Ana Paço
- BLC3—Biomassa Lenho-Celulósica de 3ª Geração, Campus of Technology and Innovation, 3405-169 Oliveira do Hospital, Portugal
| | - Simone Aparecida de Bessa Garcia
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Joana Leitão Castro
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Ana Rita Costa-Pinto
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
| | - Renata Freitas
- I3S—Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal; (S.A.d.B.G.); (J.L.C.); (A.R.C.-P.); (R.F.)
- ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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29
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Feng Y, Hu S, Li L, Peng X, Chen F. Long noncoding RNA HOXA-AS2 functions as an oncogene by binding to EZH2 and suppressing LATS2 in acute myeloid leukemia (AML). Cell Death Dis 2020; 11:1025. [PMID: 33268767 PMCID: PMC7710717 DOI: 10.1038/s41419-020-03193-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022]
Abstract
Acute myeloid leukemia (AML) is the most common hematological malignancy in the world. Long noncoding RNAs (lncRNAs) play an important role in the development of physiology and pathology. Many reports have shown that lncRNA HOXA cluster antisense RNA 2 (HOXA-AS2) is a carcinogen and plays an important role in many tumors, but little is known about its role in AML. The aim of this study was to explore the potential mechanism and role of HOXA-AS2 in AML. HOXA-AS2 was upregulated in AML cell lines and tissues, and the overexpression of HOXA-AS2 is negatively correlated with the survival of patients. Silencing HOXA-AS2 can inhibit the proliferation and induce differentiation of AML cells in vitro and in vivo. Overexpressing HOXA-AS2 showed the opposite result. Moreover, more in-depth mechanism studies showed that carcinogenicity of HOXA-AS2 exerted mainly through binding with the epigenetic inhibitor Enhancer of zeste homolog 2 (EZH2) and then inhibiting the expression of Large Tumor Suppressor 2 (LATS2). Taken together, our findings highlight the important role of HOXA-AS2 in AML, suggesting that HOXA-AS2 may be an effective therapeutic target for patients with AML.
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Affiliation(s)
- Yubin Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
| | - Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
| | - Lanlan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
| | - Xiaoqing Peng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. .,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China.
| | - Feihu Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China. .,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China.
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30
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Ooki A, Onodera S, Saito A, Oguchi A, Murakawa Y, Sakamoto T, Sueishi K, Nishii Y, Azuma T. CAGE-seq analysis of osteoblast derived from cleidocranial dysplasia human induced pluripotent stem cells. Bone 2020; 141:115582. [PMID: 32795676 DOI: 10.1016/j.bone.2020.115582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 10/23/2022]
Abstract
Non-coding RNAs (ncRNAs) comprise a major portion of transcripts and serve an essential role in biological processes. Although the importance of major transcriptomes in osteogenesis has been extensively studied, the function of ncRNAs in human osteogenesis remains unclear. Previously, we developed hiPSCs from patients with cleidocranial dysplasia (CCD) caused by runt-related transcription factor 2 (RUNX2) haploinsufficiency. To gain insight into ncRNAs in osteogenesis, we surveyed differential ncRNA expression profiling and promoter differences of RUNX2 using patient-specific iPSCs and cap analysis gene expression (CAGE) technology to define the promoter landscape. Revertant iPSCs (Rev1 iPSCs) edited by CRISPR/Cas9 system to harbor mutation-corrected RUNX2 exhibited increased proximal promoter expression of RUNX2, while CCD iPSCs did not. We identified 2271 ncRNA genes with altered expression levels before and after differentiation, 31 of which showed at least 20-fold higher expression in Rev1 iPSCs. Bioinformatic analysis also categorized AC007392.3, LINC00379, RP11-122D10.1, and RP11-90J7.2 as enhancer regulatory regions, and HOXA-AS2, MIR219-2, and RP11-834C11.3 as dyadic regulatory regions of these ncRNAs. In addition, two miRNAs, termed MIR199A2 and MIR152, were found to have high enrichment of osteogenic-related terms. Upon further examination of the role of MIR152 on osteoblast differentiation, we found that MIR152 knockdown induced upregulation of ALP and COL1A1 in Saos-2 cells. Thus, ncRNAs were found to regulate the osteogenic differentiation potentials of hiPSCs that are used for bone regeneration and repair owing to their differentiation potentials. These data allow understanding ncRNA profiles of hiPSCs during osteogenesis.
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Affiliation(s)
- Akio Ooki
- Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Shoko Onodera
- Department of Biochemistry, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Akiko Saito
- Department of Biochemistry, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Akiko Oguchi
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan
| | - Yasuhiro Murakawa
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan
| | - Teruo Sakamoto
- Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Kenji Sueishi
- Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Yasushi Nishii
- Department of Orthodontics, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Toshifumi Azuma
- Department of Biochemistry, Tokyo Dental College, Tokyo 101-0061, Japan; Oral Health Science Center, Tokyo Dental College, Tokyo 101-0061, Japan.
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31
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Rajabi A, Riahi A, Shirabadi-Arani H, Moaddab Y, Haghi M, Safaralizadeh R. Overexpression of HOXA-AS2 LncRNA in Patients with Gastric Cancer and Its Association with Helicobacter pylori Infection. J Gastrointest Cancer 2020; 53:72-77. [PMID: 33174119 DOI: 10.1007/s12029-020-00549-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE LncRNAs are regulatory factors that play a prominent role in the carcinogenesis processes and cancer cell ability to invade and metastasize. Hence, lncRNAs are considered as the potential diagnostic and therapeutic biomarkers in diverse malignancies. The present study was designed to assess the difference of HOXA-AS2 gene expression levels in cancerous tissues as compared to marginal noncancerous tissues of gastric cancer patients. METHODS Fifty pairs of cancerous and marginal noncancerous tissue of gastric cancer patients were collected in the present study. Then, RNA extraction and cDNA synthesis were performed for all specimens. The qRT-PCR was carried out to examine the difference of HOXA-AS2 gene expression. Furthermore, the association between HOXA-AS2 expression and the clinicopathological features as well as the function of HOXA-AS2 biomarkers was evaluated. RESULTS The HOXA-AS2 expression was significantly elevated in cancerous tissues as compared to marginal noncancerous tissues in gastric cancer patients (p < 0.0001). Analysis of gene expression data revealed that there was a significant association between an increased HOXA-AS2 gene expression and clinicopathological features such as tumor size ˃ 5 cm (p = 0.009), lymph node metastasis (p = 0.028), and H. pylori infection (p = 0.011). The results of ROC analysis indicated that HOXA-AS2 with AUC, sensitivity, and specificity of 0.816, 92%, and 70%, respectively, can act as a potential biomarker (CI 95% = 0.7297-0.9023). CONCLUSION With regard to the overexpression of HOXA-AS2 in gastric cancer tissues, the mentioned gene may serve as an oncogenic lncRNA in gastric cancer patients. Moreover, HOXA-AS2 can act as a potential biomarker in molecular targeted therapies to recognize and treat gastric cancer patients.
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Affiliation(s)
- Ali Rajabi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Atousa Riahi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Hanie Shirabadi-Arani
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Yaghoub Moaddab
- Liver and Gastroenterology Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mehdi Haghi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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Song N, Zhang Y, Kong F, Yang H, Ma X. HOXA-AS2 promotes type I endometrial carcinoma via miRNA-302c-3p-mediated regulation of ZFX. Cancer Cell Int 2020; 20:359. [PMID: 32760226 PMCID: PMC7393821 DOI: 10.1186/s12935-020-01443-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
Abstract
Background HOXA cluster antisense RNA2 (HOXA-AS2), a long-chain non-coding RNA, plays an important role in the behavior of various malignant tumors. The roles of HOXA-AS2 in endometrial cancer remain unclear. Methods We test expression levels of HOXA-AS2, miRNA-302c-3p, the transcription factor zinc finger X-chromosomal protein (ZFX), and the chitinase-like protein YKL-40 in endometrial carcinoma by qRT-PCR and western blotting. Luciferase reporter and qRT-PCR assays were conducted to identify potential binding sites of HOXA-AS2 to miRNA-302c-3p. Cell cycle, migration and invasion ability of endometrial cancer cells were investigated using flow-cytometric analysis, CCK-8 and transwell assays, respectively. Results HOXA-AS2 levels were significantly increased in endometrial cancer specimens compared to normal endometrial specimens. Upregulated HOXA-AS2 promoted invasion and proliferation of type I endometrial cancer cells. HOXA-AS2 silenced miRNA-302c-3p by binding to it. MiRNA-302c-3p negatively regulates ZFX and YKL-40. Thus HOXA-AS2 promotes the development of type I endometrial cancer via miRNA-302c-3p-mediated regulation of ZFX. Conclusions These findings suggest that HOXA-AS2 can act as a new therapeutic target for type I endometrial cancer.
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Affiliation(s)
- Ning Song
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Heping District Sanhao Street 36, Shenyang, 110004 China
| | - Ying Zhang
- Experimental technology center of China Medical University, Shenyang, China
| | - Fanfei Kong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Heping District Sanhao Street 36, Shenyang, 110004 China
| | - Hui Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Heping District Sanhao Street 36, Shenyang, 110004 China
| | - Xiaoxin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Heping District Sanhao Street 36, Shenyang, 110004 China
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Liu Y, Sun P, Zhao Y, Liu B. The role of long non-coding RNAs and downstream signaling pathways in leukemia progression. Hematol Oncol 2020; 39:27-40. [PMID: 32621547 DOI: 10.1002/hon.2776] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/22/2020] [Accepted: 06/25/2020] [Indexed: 01/17/2023]
Abstract
The study of long non-coding RNAs (lncRNA) is a newly established field and our knowledge about them is rapidly growing. These kinds of RNAs are unchanged parts of the genome throughout evolution, that modulate cell growth, differentiation, and apoptosis during diverse physiological and pathological processes including leukemia development. They have the capability to be useful biomarkers for the diagnosis, clinical typing, prognosis, as well as potential therapeutic targets. In this study, we summarized the role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia.
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Affiliation(s)
- Yadong Liu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Penghao Sun
- Department of Andrology, The First Hospital of Jilin University, Changchun, China
| | - Yuhao Zhao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
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Qu Y, Wang Y, Wang P, Lin N, Yan X, Li Y. Overexpression of long noncoding RNA HOXA-AS2 predicts an adverse prognosis and promotes tumorigenesis via SOX4/PI3K/AKT pathway in acute myeloid leukemia. Cell Biol Int 2020; 44:1745-1759. [PMID: 32369230 DOI: 10.1002/cbin.11370] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 04/26/2020] [Accepted: 04/27/2020] [Indexed: 01/13/2023]
Abstract
Long noncoding RNAs (lncRNAs) play important roles in diverse cellular processes and carcinogenesis. Homeobox A cluster antisense RNA 2 (HOXA-AS2) is a 1,048-basepairs lncRNA located between human HOXA3 and HOXA4 genes, whose overactivation was previously found to promote the proliferation and invasion of solid tumors. However, its clinical and biological roles in acute myeloid leukemia (AML) remain unclear. This study showed that HOXA-AS2 was overexpressed in AML patients. In addition, the increased HOXA-AS2 expression was correlated with higher white blood cell and bone marrow blast counts, unfavorable karyotype classification, more measurable residual disease positivity, and earlier death. There was also a tendency toward inferior survival in patients with high HOXA-AS2 expression, and HOXA-AS2 was an independent prognostic factor among the normal-karyotype AMLs. Furthermore, the results of in vitro study showed that silencing HOXA-AS2 significantly inhibited the growth of leukemic cells by inducing G1/G0-phase arrest and apoptosis. Further analysis demonstrated that silencing HOXA-AS2 suppressed the phosphorylation level of PI3K and AKT, which thereafter promoted the expression of P21 and P27. Moreover, it was suggested that the sex-determining region Y-box 4 (SOX4), which is closely involved in the PI3K/AKT pathway, might be one of the major downstream targets of HOXA-AS2. Silencing HOXA-AS2 decreased the expression of SOX4, whereas the upregulation of SOX4 partially abrogated the inhibitory effect of silencing HOXA-AS2 on leukemic cells. In conclusion, these findings suggest that HOXA-AS2 probably functions as an oncogene via SOX4/PI3K/AKT pathway and might be a useful biomarker for the prognostic prediction in AML patients, providing a potential therapeutic target for AML.
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Affiliation(s)
- Yi Qu
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yue Wang
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Pingping Wang
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Na Lin
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaojing Yan
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Li
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Gao J, Wang F, Wu P, Chen Y, Jia Y. Aberrant LncRNA Expression in Leukemia. J Cancer 2020; 11:4284-4296. [PMID: 32368311 PMCID: PMC7196264 DOI: 10.7150/jca.42093] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/31/2020] [Indexed: 02/05/2023] Open
Abstract
Leukemia is a common malignant cancer of the hematopoietic system, whose pathogenesis has not been fully elucidated. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides without protein-coding function. Recent studies report their role in cellular processes such as the regulation of gene expression, as well as in the carcinogenesis, occurrence, development, and prognosis of various tumors. Evidence indicating relationships between a variety of lncRNAs and leukemia pathophysiology has increased dramatically in the previous decade, with specific lncRNAs expected to serve as diagnostic biomarkers, novel therapeutic targets, and predictors of clinical outcomes. Furthermore, these lncRNAs might offer insight into disease pathogenesis and novel treatment options. This review summarizes progress in studies on the role(s) of lncRNAs in leukemia.
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Affiliation(s)
- Jie Gao
- Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Fujue Wang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Pengqiang Wu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yingying Chen
- Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yongqian Jia
- Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
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Bhat AA, Younes SN, Raza SS, Zarif L, Nisar S, Ahmed I, Mir R, Kumar S, Sharawat SK, Hashem S, Elfaki I, Kulinski M, Kuttikrishnan S, Prabhu KS, Khan AQ, Yadav SK, El-Rifai W, Zargar MA, Zayed H, Haris M, Uddin S. Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance. Mol Cancer 2020; 19:57. [PMID: 32164715 PMCID: PMC7069174 DOI: 10.1186/s12943-020-01175-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Ajaz A Bhat
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Salma N Younes
- Department of Biomedical Science, College of Health Sciences, Qatar University, Doha, Qatar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Lubna Zarif
- Department of Biomedical Science, College of Health Sciences, Qatar University, Doha, Qatar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Sabah Nisar
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Ikhlak Ahmed
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Rashid Mir
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Sachin Kumar
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Surender K Sharawat
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Sheema Hashem
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Michal Kulinski
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Santosh K Yadav
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, Florida, USA
| | - Mohammad A Zargar
- Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Hatem Zayed
- Department of Biomedical Science, College of Health Sciences, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
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Inferences of Individual Drug Response-Related Long Non-coding RNAs Based on Integrating Multi-omics Data in Breast Cancer. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 20:128-139. [PMID: 32163894 PMCID: PMC7066040 DOI: 10.1016/j.omtn.2020.01.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/19/2020] [Accepted: 01/31/2020] [Indexed: 12/25/2022]
Abstract
Differences in individual drug responses are obstacles in breast cancer (BRCA) treatment, so predicting responses would help to plan treatment strategies. The accumulation of cancer molecular profiling and drug response data provide opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs in BRCA. This study evaluated drug responses with a multi-omics integrated system that depended on long non-coding RNAs (lncRNAs). We identified drug response-related lncRNAs (DRlncs) by combining expression data of lncRNA, microRNA, messenger RNA, methylation levels, somatic mutations, and the survival data of cancer patients treated with drugs. We constructed an integrated and computational multi-omics approach to identify DRlncs for diverse chemotherapeutic drugs in BRCA. Some DRlncs were identified with Adriamycin, Cytoxan, Tamoxifen, and all samples for BRCA patients. These DRlncs showed specific features regarding both expression and computational accuracies. The DRlnc-gene co-expression networks were constructed and analyzed. Key DRlncs, such as HOXA-AS2 (Ensembl: ENSG00000253552), in the drug Adriamycin were characterized. The experimental analysis also suggested that HOXA-AS2 (Ensembl: ENSG00000253552) was a key DRlnc in Adriamycin drug resistance in BRCA patients. Some DRlncs were associated with survival and some specific functions. A possible mechanism of DRlnc HOXA-AS2 (Ensembl: ENSG00000253552) in the Adriamycin drug response for BRCA resistance was inferred. In summary, this study provides a framework for lncRNA-based evaluation of clinical drug responses in BRCA. Understanding the underlying molecular mechanisms of drug responses will facilitate improved responses to chemotherapy and outcomes of BRCA treatment.
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Identification of key protein-coding genes and lncRNAs in spontaneous neutrophil apoptosis. Sci Rep 2019; 9:15106. [PMID: 31641174 PMCID: PMC6805912 DOI: 10.1038/s41598-019-51597-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 10/04/2019] [Indexed: 01/17/2023] Open
Abstract
Polymorphonuclear leukocytes (PMNs) are the most abundant cells of the innate immune system in humans, and spontaneous PMN apoptosis plays crucial roles in maintaining neutrophil homeostasis and resolving inflammation. However, the detailed mechanisms of spontaneous PMN apoptosis remain to be elucidated. By analysis of the public microarray dataset GSE37416, we identified a total of 3050 mRNAs and 220 long non-coding RNAs (lncRNAs) specifically expressed during PMN apoptosis in a time-dependent manner. By short time-series expression miner (STEM) analysis, Gene Ontology analysis, and lncRNA-mRNA co-expression network analyses, we identified some key molecules specifically related to PMN apoptosis. STEM analysis identified 12 gene profiles with statistically significance, including 2 associated with apoptosis. Protein-protein interaction (PPI) network analysis of the genes from 2 profiles and lncRNA-mRNA co-expression network analysis identified a 12-gene hub (including NFκB1 and BIRC3) associated with apoptosis, as well as 2 highly correlated lncRNAs (THAP9-AS1, and AL021707.6). We experimentally examined the expression profiles of two mRNA (NFκB1 and BIRC3) and two lncRNAs (THAP9-AS1 andAL021707.6) by quantitative real-time polymerase chain reaction to confirm their time-dependent expressions. These data altogether demonstrated that these genes are involved in the regulation of spontaneous neutrophil apoptosis and the corresponding gene products could also serve as potential key regulatory molecules for PMN apoptosis and/or therapeutic targets for over-reactive inflammatory response caused by the abnormality in PMN apoptosis.
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Fallah H, Azari I, Neishabouri SM, Oskooei VK, Taheri M, Ghafouri-Fard S. Sex-specific up-regulation of lncRNAs in peripheral blood of patients with schizophrenia. Sci Rep 2019; 9:12737. [PMID: 31484957 PMCID: PMC6726592 DOI: 10.1038/s41598-019-49265-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/22/2019] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia as a common disabling psychiatric disorder has been associated with dysregulation of several genes and pathways among them are those being regulated by long non-coding RNAs (lncRNAs). Based on the acknowledged roles of lncRNAs in neurodevelopment, in the current study, we assessed expression of six lncRNAs namely HOXA-AS2, Linc-ROR, MALAT1, MEG3, SPRY4-IT1 and UCA1 in peripheral blood of 60 patients with schizophrenia and 60 healthy subjects. HOXA-AS2, Linc-ROR, MEG3, SPRY4-IT1 and UCA1 levels were significantly higher in total patients compared with total controls. However, when evaluating expression of genes in sex-based subgroups, the differences in the expression of these lncRNAs were significant only among females. Assessment of partial correlation between expression of lncRNAs and age of study participants after controlling the effect of sex, revealed significant correlations for HOXA-AS2, MALAT1 and UCA1 in both patients and controls. Besides, expressions of Linc-ROR and SPRY4-IT1 were correlated with age only in patients. Significant pairwise correlations were recognized between expression levels of lncRNAs in both patients with schizophrenia and controls. Based on the area under curve (AUC) values, SPRY4-IT1 had the best performance in differentiation of female patients with schizophrenia from female controls (AUC = 0.85, P < 0.0001). Combination of Linc-ROR, MEG3, SPRY4-IT1 and UCA1 expression levels could differentiate female patients with 95.2% sensitivity, 76.9% specificity and diagnostic power of 0.88 (P < 0.0001). The current study suggests the presence of a sex-based dysregulation of lncRNAs in patients with schizophrenia and their possible application as diagnostic biomarkers.
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Affiliation(s)
- Hamid Fallah
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Iman Azari
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Vahid Kholghi Oskooei
- Department of Laboratory Sciences, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ng M, Heckl D, Klusmann JH. The Regulatory Roles of Long Noncoding RNAs in Acute Myeloid Leukemia. Front Oncol 2019; 9:570. [PMID: 31338324 PMCID: PMC6629768 DOI: 10.3389/fonc.2019.00570] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/12/2019] [Indexed: 01/23/2023] Open
Abstract
In this post-genomic era, long noncoding RNAs (lncRNAs) are rapidly gaining recognition for their crucial roles across diverse biological processes and contexts. The human blood system is no exception, where dozens of lncRNAs have been established as regulators of normal and/or malignant hematopoiesis, and where ongoing works continue to uncover novel lncRNA functions. Our review focuses on lncRNAs that are involved in the pathogenesis of acute myeloid leukemia (AML) and the mechanisms through which they control gene expression in this disease context. We also comment on genome-wide sequencing or profiling studies that have implicated large sets of lncRNAs in AML pathophysiology.
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Affiliation(s)
- Michelle Ng
- Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Dirk Heckl
- Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Jan-Henning Klusmann
- Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
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Wu J, Li M, Zhang Y. Long noncoding RNA HOXA-AS2 regulates the expression of SCN3A by sponging miR-106a in breast cancer. J Cell Biochem 2019; 120:14465-14475. [PMID: 30993766 DOI: 10.1002/jcb.28706] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/01/2019] [Accepted: 03/15/2019] [Indexed: 12/14/2022]
Abstract
Breast cancer is the most commonly diagnosed cancer that affects women worldwide. This study aimed to investigate the competing endogenous RNAs (ceRNAs) mechanism in breast cancer. Microarray data were downloaded from the University of California Santa Cruz (UCSC) Xena database. The limma package was used to screen the differentially expressed messenger RNAs (DEMs) and differentially expressed long noncoding RNAs (DELs). Subsequently, functional analysis was performed using DAVID tool. After constructing the protein-protein interaction (PPI) network, we identified the major gene modules using the Cytoscape software. Univariate survival analysis in the survival package was performed. Finally, the ceRNA regulatory network was constructed to identify the critical genes. A total of 1380 DEMs and 345 DELs were identified in breast cancer samples compared with normal samples. Functional enrichment analysis showed that DEMs were mainly involved in cell division, and cell cycle. We screened four major gene modules and identified the hub nodes in these functional modules. Several DEMs (including FABP7, C4BPA, and LAMB3) and three long noncoding RNAs (lncRNAs) (LINC00092, SLC26A4.AS1, and COLCA1) exhibited significant correlation with patients' survival outcomes. In the ceRNA network, the lncRNA HOXA-AS2 regulated the expression level of SCN3A by interacting with hsa-miR-106a-5p. Thus, our study investigated the ceRNA mechanism in breast cancer. The results showed that lncRNA HOXA-AS2 might modulate the expression of SCN3A by sponging miR-106a in breast cancer.
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Affiliation(s)
- Jie Wu
- Key Laboratory of Hydrodynamics (Ministry of Education), School of Naval Architecture, Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Maolan Li
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yijian Zhang
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China.,Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
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Inhibition of the lncRNA SAF drives activation of apoptotic effector caspases in HIV-1-infected human macrophages. Proc Natl Acad Sci U S A 2019; 116:7431-7438. [PMID: 30918127 PMCID: PMC6462110 DOI: 10.1073/pnas.1818662116] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Tissue resident macrophages are long-lived, self-replenishing myeloid cells. They harbor and support HIV-1 replication, but unlike CD4+ T cells, do not succumb to virus-induced cell death. Here, we have screened a panel of 90 long noncoding RNAs (lncRNA) and identified a lncRNA, SAF, that plays a critical role in the resistance of HIV-1–infected macrophages to activation of apoptotic caspases. We have further shown that down-regulation of SAF expression with siRNA treatment can activate effector caspase-3/7 specifically in virus-infected macrophages without affecting the uninfected and bystander cells. Overall, our study describes the approach of modulating the lncRNA SAF for targeted elimination of HIV-1–infected macrophages that can lead to reduction and potential clearance of these viral reservoir cells. Long noncoding RNAs (lncRNAs) impart significant regulatory functions in a diverse array of biological pathways and manipulation of these RNAs provides an important avenue to modulate such pathways, particularly in disease. Our knowledge about lncRNAs’ role in determination of cellular fate during HIV-1 infection remains sparse. Here, we have identified the impact of the lncRNA SAF in regulating apoptotic effector caspases in macrophages, a long-lived cellular reservoir of HIV-1, that are largely immune to virus-induced cell death. Expression of SAF is significantly up-regulated in HIV-1–infected human monocyte-derived macrophages (MDM) compared with bystander and virus-nonexposed cells. A similar enhancement in SAF RNA expression is also detected in the HIV-1–infected airway macrophages obtained by bronchoalveolar lavage of HIV-1–infected individuals. Down-regulation of SAF with siRNA treatment increases caspase-3/7 activity levels in virus-infected MDMs. This induction of apoptotic caspases occurs exclusively in HIV-1–infected macrophages and not in bystander cells, leading to a significant reduction in HIV-1 replication and overall viral burden in the macrophage culture. This study identifies targeting of the lncRNA SAF as a potential means to specifically induce cell death in HIV-1–infected macrophages.
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Long Non-Coding RNA and Acute Leukemia. Int J Mol Sci 2019; 20:ijms20030735. [PMID: 30744139 PMCID: PMC6387068 DOI: 10.3390/ijms20030735] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 10/20/2018] [Accepted: 10/22/2018] [Indexed: 12/19/2022] Open
Abstract
Acute leukemia (AL) is the main type of cancer in children worldwide. Mortality by this disease is high in developing countries and its etiology remains unanswered. Evidences showing the role of the long non-coding RNAs (lncRNAs) in the pathophysiology of hematological malignancies have increased drastically in the last decade. In addition to the contribution of these lncRNAs in leukemogenesis, recent studies have suggested that lncRNAs could be used as biomarkers in the diagnosis, prognosis, and therapeutic response in leukemia patients. The focus of this review is to describe the functional classification, biogenesis, and the role of lncRNAs in leukemogenesis, to summarize the evidence about the lncRNAs which are playing a role in AL, and how these genes could be useful as potential therapeutic targets.
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Wang F, Wu D, Chen J, Chen S, He F, Fu H, Wu Q, Liu S, Li X, Wang W. Long non-coding RNA HOXA-AS2 promotes the migration, invasion and stemness of bladder cancer via regulating miR-125b/Smad2 axis. Exp Cell Res 2019; 375:1-10. [DOI: 10.1016/j.yexcr.2018.11.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 10/13/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023]
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Long noncoding RNAs in cancer cells. Cancer Lett 2019; 419:152-166. [PMID: 29414303 DOI: 10.1016/j.canlet.2018.01.053] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 12/11/2022]
Abstract
Long noncoding RNA (lncRNA) has recently been investigated as key modulators that regulate many biological processes in human cancers via diverse mechanisms. LncRNAs can interact with macromolecules such as DNA, RNA, or protein to exert cellular effects and to act as either tumor promoters or tumor suppressors in various malignancies. Moreover, the aberrant expression of lncRNAs may be detected in multiple cancer phenotypes by employing the rapidly developing modern gene chip technology and bioinformatics analysis. Herein, we highlight the mechanisms of action of lncRNAs, their functional cellular roles and their involvement in cancer progression. Finally, we provide an overview of recent progress in the lncRNA field and future potential for lncRNAs as cancer diagnostic markers and therapeutics.
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Li X, Zhong W, Xu Y, Yu B, Liu H. Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-204–3p/CDC23 axis. Biochem Biophys Res Commun 2019; 508:1145-1148. [DOI: 10.1016/j.bbrc.2018.12.051] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023]
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Collord G, Tarpey P, Kurbatova N, Martincorena I, Moran S, Castro M, Nagy T, Bignell G, Maura F, Young MD, Berna J, Tubio JMC, McMurran CE, Young AMH, Sanders M, Noorani I, Price SJ, Watts C, Leipnitz E, Kirsch M, Schackert G, Pearson D, Devadass A, Ram Z, Collins VP, Allinson K, Jenkinson MD, Zakaria R, Syed K, Hanemann CO, Dunn J, McDermott MW, Kirollos RW, Vassiliou GS, Esteller M, Behjati S, Brazma A, Santarius T, McDermott U. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures. Sci Rep 2018; 8:13537. [PMID: 30202034 PMCID: PMC6131140 DOI: 10.1038/s41598-018-31659-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/16/2018] [Indexed: 12/21/2022] Open
Abstract
Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
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Affiliation(s)
- Grace Collord
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Patrick Tarpey
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Natalja Kurbatova
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
| | - Inigo Martincorena
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Sebastian Moran
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Manuel Castro
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Tibor Nagy
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Graham Bignell
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Francesco Maura
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Matthew D Young
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Jorge Berna
- Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, 15706, Spain
| | - Jose M C Tubio
- Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, 15706, Spain
| | - Chris E McMurran
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Adam M H Young
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Mathijs Sanders
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Erasmus University Medical Center, Department of Hematology, Rotterdam, The Netherlands
| | - Imran Noorani
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Stephen J Price
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Colin Watts
- Department of Neurosurgery, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Elke Leipnitz
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Matthias Kirsch
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Gabriele Schackert
- Klinik und Poliklink für Neurochirurgie, "Carl Gustav Carus" Universitätsklinikum, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Danita Pearson
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Abel Devadass
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Zvi Ram
- Department of Neurosurgery, Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - V Peter Collins
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Kieren Allinson
- Department of Pathology, Cambridge University Hospital, CB2 0QQ, Cambridge, UK
| | - Michael D Jenkinson
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, L9 7LJ, UK
| | - Rasheed Zakaria
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Integrative Biology, University of Liverpool, Liverpool, L9 7LJ, UK
| | - Khaja Syed
- Department of Neurosurgery, The Walton Centre, Liverpool, L9 7LJ, UK
- Institute of Integrative Biology, University of Liverpool, Liverpool, L9 7LJ, UK
| | - C Oliver Hanemann
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK
| | - Jemma Dunn
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK
| | - Michael W McDermott
- Department of Neurosurgery, UCSF Medical Center, San Francisco, CA, 94143-0112, USA
| | - Ramez W Kirollos
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - George S Vassiliou
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Sam Behjati
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Alvis Brazma
- European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
| | - Thomas Santarius
- Department of Neurosurgery, Department of Clinical Neuroscience, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
| | - Ultan McDermott
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
- Institute of Translational Medicine, University of Liverpool, Liverpool, L9 7LJ, UK.
- AstraZeneca, CRUK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
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Botti G, De Chiara A, Di Bonito M, Cerrone M, Malzone MG, Collina F, Cantile M. Noncoding RNAs within the
HOX
gene network in tumor pathogenesis and progression. J Cell Physiol 2018; 234:395-413. [DOI: 10.1002/jcp.27036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/25/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Gerardo Botti
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Anna De Chiara
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maurizio Di Bonito
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Margherita Cerrone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Maria Gabriella Malzone
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Francesca Collina
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
| | - Monica Cantile
- Department of Support for Oncological Pathways Diagnostic Area, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. Pascale” Napoli Italy
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Wang Y, Zhang R, Cheng G, Xu R, Han X. Long non-coding RNA HOXA-AS2 promotes migration and invasion by acting as a ceRNA of miR-520c-3p in osteosarcoma cells. Cell Cycle 2018; 17:1637-1648. [PMID: 30081707 PMCID: PMC6133314 DOI: 10.1080/15384101.2018.1489174] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 06/01/2018] [Indexed: 01/08/2023] Open
Abstract
Osteosarcoma (OS) is the commonest primary malignant tumour originating from bone. Previous studies demonstrated that long non-coding RNAs (lncRNAs) could participate in both oncogenic and tumor suppressing pathways in various cancer, including OS. The HOXA cluster antisense RNA2 (HOXA-AS2) plays an important role in carcinogenesis, however, the underlying role of HOXA-AS2 in OS progression remains unknown. The aim of the present study was to evaluate the expression and function of HOXA-AS2 in OS. The qRT-PCR analysis was to investigate the expression pattern of HOXA-AS2 in OS tissues. Then, the effects of HOXA-AS2 on cell proliferation, cell cycle, apoptosis, migration, and invasion were assessed in OS in vitro. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in OS cells. We observed that HOXA-AS2 was up-regulated in OS tissues. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited OS cells proliferation by promoting apoptosis and causing G1 arrest, whereas HOXA-AS2 overexpression promoted cell proliferation. Further functional assays indicated that HOXA-AS2 significantly promoted OS cell migration and invasion by promoting epithelial-mesenchymal transition (EMT). Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in OS cells. In conclusion, our study suggests that HOXA-AS2 acts as a functional oncogene in OS.
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Affiliation(s)
- Yihan Wang
- Department of Orthopaedics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Department of Orthopaedics, Renji Hospital Southern Division, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
| | - Rui Zhang
- Department of Orthopaedics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Department of Orthopaedics, Renji Hospital Southern Division, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
| | - Guangqi Cheng
- Department of Orthopaedics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Department of Orthopaedics, Renji Hospital Southern Division, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
| | - Ruida Xu
- Department of Orthopaedics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Department of Orthopaedics, Renji Hospital Southern Division, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
| | - Xiaofeng Han
- Department of Orthopaedics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Department of Orthopaedics, Renji Hospital Southern Division, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
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50
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Wang J, Su Z, Lu S, Fu W, Liu Z, Jiang X, Tai S. LncRNA HOXA-AS2 and its molecular mechanisms in human cancer. Clin Chim Acta 2018; 485:229-233. [PMID: 29981289 DOI: 10.1016/j.cca.2018.07.004] [Citation(s) in RCA: 188] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 06/28/2018] [Accepted: 07/03/2018] [Indexed: 12/21/2022]
Abstract
Long non-coding RNAs (lncRNAs), a novel class of noncoding RNAs, are commonly defined as RNA molecules more than 200 nucleotides in length. Emerging research indicated that lncRNA played a vital role in human tumorigenesis and progression by serving as tumor oncogenes or suppressors. LncRNA has been shown to get involved in participate various biological processes, such as cell growth, anti-apoptosis, migration and invasion. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) is a novel cancer-related lncRNA. It was recently found to exhibit aberrant expression in a variety of malignancies, including breast cancer, gastric cancer, gallbladder carcinoma, hepatocellular carcinoma and pancreatic cancer. The oncogenicity of lncRNA HOXA-AS2 mainly inhibits or promotes the expression of related genes through direct or indirect pathways, suggesting that HOXA-AS2 likely represents a feasible biomarker or therapeutic target in human cancers. In this review, we summarize current evidences concerning the biological functions and mechanisms of HOXA-AS2 during tumor development.
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Affiliation(s)
- Jicai Wang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
| | - Zhilei Su
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
| | - Shounan Lu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
| | - Wen Fu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
| | - Zhifa Liu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China
| | - Xingming Jiang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China.
| | - Sheng Tai
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No.246 XueFu Avenue, Harbin 150086, China.
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