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1
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Wan M, Wang Y, Liu X, Li Y, Deng C, Sun C. Identification of RAD51AP1 as a key gene in hepatitis B virus-associated hepatocellular carcinoma. Heliyon 2025; 11:e41594. [PMID: 39850418 PMCID: PMC11755046 DOI: 10.1016/j.heliyon.2024.e41594] [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: 08/18/2024] [Revised: 11/25/2024] [Accepted: 12/30/2024] [Indexed: 01/25/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a significant global health concern, with chronic hepatitis B virus (HBV) infection being a major contributor. Understanding the mechanisms of HBV-associated HCC is crucial to improving the prognosis and developing effective treatments. Methods HBV-associated HCC datasets (GSE19665, GSE121248, GSE55092, GSE94660, and TCGA-LIHC) acquired from public databases were mined to identify key driver genes by differentially expressed gene analysis, weighted gene co-expression network analysis (WGCNA), followed by protein-protein interaction network analysis, Lasso-Cox regression analysis, and randomforestSRC algorithm. Then, in vitro experiments including CCK-8 assay, wound healing, and Transwell assay were performed to explore the functions and mechanisms. Results RAD51AP1 was identified as a specific key gene linked to the progression of HBV-associated HCC. High expression of RAD51AP1 was associated with worse overall survival (OS) in patients with HBV-associated HCC, but not in patients with non-HBV-associated HCC. Mechanistically, RAD51AP1 forms a potential ceRNA axis with LINC01419 and miR-8070, where LINC01419 acts as a molecular sponge for miR-8070 to upregulate RAD51AP1. HBV infection can enhance the LINC01419/miR-8070/RAD51AP1 axis, and LINC01419 overexpression conversely promotes HBV replication. The ceRNA axis and HBV synergistically promote the proliferation and metastasis of HBV-associated HCC cells. Furthermore, LINC01419 or RAD51AP1 knockdown, and miR-8070 overexpression in HepG2.2.15 cells significantly attenuated the Wnt/β-catenin signaling. Conclusions The LINC01419/miR-8070/RAD51AP1 axis promotes the HBV-associated HCC progression through an HBV-boosted positive feedback loop and Wnt/β-catenin signaling. These findings provide novel insights into the underlying mechanisms and may offer potential diagnostic and therapeutic targets in HBV-associated HCC.
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Affiliation(s)
- Meiling Wan
- Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yonghong Wang
- Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Xiaoling Liu
- Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yaling Li
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Cunliang Deng
- Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Changfeng Sun
- Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
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Żychowska J, Ćmil M, Skórka P, Olejnik-Wojciechowska J, Plewa P, Bakinowska E, Kiełbowski K, Pawlik A. The Role of Epigenetic Mechanisms in the Pathogenesis of Hepatitis C Infection. Biomolecules 2024; 14:986. [PMID: 39199374 PMCID: PMC11352264 DOI: 10.3390/biom14080986] [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: 07/11/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.
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Affiliation(s)
- Justyna Żychowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Maciej Ćmil
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Patryk Skórka
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | | | - Paulina Plewa
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland;
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Milosevic I, Todorovic N, Filipovic A, Simic J, Markovic M, Stevanovic O, Malinic J, Katanic N, Mitrovic N, Nikolic N. HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article. Int J Mol Sci 2023; 24:16048. [PMID: 38003240 PMCID: PMC10671156 DOI: 10.3390/ijms242216048] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Nevena Todorovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Ana Filipovic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jelena Simic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Marko Markovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Olja Stevanovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Jovan Malinic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Katanic
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
- Faculty of Medicine, University of Pristina Situated in Kosovska Mitrovica, 28000 Kosovska Mitrovica, Serbia
| | - Nikola Mitrovic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
| | - Natasa Nikolic
- Faculty of Medicine, Department for Infectious Diseases, University of Belgrade, 11000 Belgrade, Serbia; (I.M.); (M.M.); (O.S.); (J.M.); (N.M.)
- University Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Bulevar Oslobodjenja 16, 11000 Belgrade, Serbia; (N.T.); (A.F.); (J.S.); (N.K.)
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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Abdelsattar S, Fahim SA, Kamel HFM, Al-Amodi H, Kasemy ZA, Khalil FO, Abdallah MS, Bedair HM, Gadallah ANAA, Sabry A, Sakr MA, Selim M, Gayed EMAE. The Potential Role of Circulating Long Miscellaneous RNAs in the Diagnosis and Prognosis of Hepatitis C Related Hepatocellular Carcinoma. Noncoding RNA 2023; 9:62. [PMID: 37888208 PMCID: PMC10609931 DOI: 10.3390/ncrna9050062] [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: 08/27/2023] [Revised: 10/04/2023] [Accepted: 10/08/2023] [Indexed: 10/28/2023] Open
Abstract
Ribonucleic acids (RNAs) are important regulators of gene expression and crucial for the progression of hepatocellular carcinoma (HCC). This study was designed to determine the diagnostic and prognostic utility of the circulating long miscellaneous RNAs; LINC01419, AK021443, and AF070632 in HCV-related HCC patients. Real-time PCR was used to measure their relative expression levels in the plasma of 194 HCV patients, 120 HCV-related HCC patients and 120 healthy controls. LINC01419 and AK021443 expression levels had significantly increasing linear trend estimates while AF070632 was dramatically downregulated in HCC compared to HCV. Interestingly, LINC01419 and AK021443 served as more significant diagnostic biomarkers for HCC than AF070632 and AFP. Multivariate analysis with cox regression revealed that the high expression of AK021443 [HR = 10.06, CI95%: 3.36-30.07], the high expression of LINC01419 [HR 4.13, CI95%: 1.32-12.86], and the low expression of AF070632 [HR = 2.70, CI95%: 1.07-6.81] were significant potential prognostic factors for HCC. Besides, the Kaplan-Meier analysis showed that HCC patients with high LIN01419 and AK021443 and low AF070632 expression levels had shorter OS. The circulating LINC01419 and AK021443 can be used as noninvasive potential biomarkers for diagnosis and prognosis of HCV-related HCC patients than AF070632 providing new targets for limiting the progression of the disease.
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Affiliation(s)
- Shimaa Abdelsattar
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Sally A. Fahim
- Biochemistry Department, School of Pharmacy, Newgiza University (NGU), Cairo 94114, Egypt;
| | - Hala F. M. Kamel
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt;
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Hiba Al-Amodi
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Zeinab A. Kasemy
- Department of Public Health and Community Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Fatma O. Khalil
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Mahmoud S. Abdallah
- Clinical Pharmacy Department, Faculty of Pharmacy, University of Sadat City (USC), Sadat City 32897, Egypt;
| | - Hanan M. Bedair
- Clinical Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | | | - Aliaa Sabry
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt;
| | - Mohamed A. Sakr
- Medical Microbiology and Immunology Department, Faculty of Medicine, Suez University, Suez 43512, Egypt;
| | - Mahmoud Selim
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta 31111, Egypt;
| | - Eman M. Abd El Gayed
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Shebin El-Kom 32511, Egypt;
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Malekshahi A, Alamdary A, Safarzadeh A, Khavandegar A, Nikoo HR, Safavi M, Ajorloo M, Bahavar A, Ajorloo M. Potential roles of core and core+1 proteins during the chronic phase of hepatitis C virus infection. Future Virol 2023. [DOI: 10.2217/fvl-2022-0117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
The HCV Core protein is a multifunctional protein that interacts with many viral and cellular proteins. In addition to the encapsidation of the viral genome, it can disturb various cellular pathways and impede antiviral cellular responses such as interferon (IFN) production. The Core protein can also disrupt the functions of immune cells against HCV. The Core protein helps viral infection persistency by interfering with apoptosis. The Core+1 protein plays a significant role in inducing chronic HCV infection through diverse mechanisms. We review some of the mechanisms by which Core and Core+1 proteins facilitate HCV infection to chronic infection. These proteins could be considered for designing more sufficient treatments and effective vaccines against HCV.
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Affiliation(s)
- Asra Malekshahi
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ashkan Alamdary
- Department of Biology, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Safarzadeh
- Department of Biology, University of Padova, Padova, Italy
| | - Armin Khavandegar
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Hadi Razavi Nikoo
- Infectious Disease Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mahshid Safavi
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Mobina Ajorloo
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Atefeh Bahavar
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehdi Ajorloo
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Tanvir I, Hassan A, Albeladi F. DNA Methylation and Epigenetic Events Underlying Renal Cell Carcinomas. Cureus 2022; 14:e30743. [DOI: 10.7759/cureus.30743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2022] [Indexed: 11/05/2022] Open
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9
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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10
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Suhail M, Sohrab SS, Kamal M, Azhar EI. Role of hepatitis c virus in hepatocellular carcinoma and neurological disorders: an overview. Front Oncol 2022; 12:913231. [PMID: 35965577 PMCID: PMC9372299 DOI: 10.3389/fonc.2022.913231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
The hepatitis C virus (HCV) causes serious issues, affecting 71 million people globally. The most common manifestations range from chronic hepatitis to liver cirrhosis, leading to hepatocellular carcinoma. Many mechanisms are known to play an important role in HCV-induced HCC. The interaction of viral proteins with host cells results in oxidative stress damage, liver inflammation, and irregularities in signaling pathways. These results in the activation of oncogenes and metabolic disturbances, liver fibrosis, and angiogenesis. Additionally, some non-coding RNAs (ncRNAs) and toll-like receptors have been identified and play a significant role in HCC development. This virus is also associated with impairment of the central nervous system, resulting in acute or sub-acute encephalopathy and inflammatory disorders. Neurological disorders are associated with the inflammatory responses of many cells, including microglia and astrocytes. Additionally, there are many other extrahepatic manifestations, including neurological disorders such as depression and fatigue, in 50% of infected patients. These manifestations include neuro-invasion, immune-mediated damage, neurotransmitter alterations, sensory-motor polyneuropathy, sensitivity loss, weakness of the leg, and cryoglobulinemia, which significantly results in a reduced quality of life. HCV infection may be improved using an appropriate diagnosis and direct antiviral therapy for sustained virological response. However, the success of therapy depends on the symptoms and organ damage, diagnosis, and therapeutic strategies applied. Some published reports have discussed that HCV is associated with both HCC and neurological disorders. Additionally, it has also been observed that individuals with HCC also develop neurological disorders compared with individuals with HCV alone. This review aims to provide an overview of the latest information about the relationship between HCV-induced HCC and their role in neurological disorders. Additionally, we have also discussed the progress made in the diagnosis, physio-pathological mechanisms, and strong antiviral therapies developed for HCV infection and HCC, as well as the latest advancements made in the study of the neurological disorders associated with HCV infection.
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Affiliation(s)
- Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sayed Sartaj Sohrab
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- *Correspondence: Sayed Sartaj Sohrab,
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Enzymoics Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | - Esam Ibraheem Azhar
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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11
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Sun ZP, Tan ZG, Peng C. Long noncoding RNA LINC01419 promotes hepatocellular carcinoma malignancy by mediating miR-485-5p/LSM4 axis. Kaohsiung J Med Sci 2022; 38:826-838. [PMID: 35748489 DOI: 10.1002/kjm2.12566] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 12/29/2022] Open
Abstract
To investigate the effect of long noncoding RNA (LINC01419)/miR-485-5p/LSM4 on the malignant behavior of hepatocellular carcinoma (HCC) cells. The expressions of LINC01419, miR-485-5p, and LSM4 were determined in HCC at the cellular and clinical levels, and cell biological behavior was evaluated. The relationships between LINC01419, miR-485-5p, and LSM4 were predicted and verified. Additionally, the subcellular localization of LINC01419 in HCC cells was analyzed. Finally, an animal experiment was conducted to confirm the effect of LINC01419 silencing on tumor growth. in HCC tissues and cells, LINC01419 and LSM4 were increasingly expressed, but miR-485-5p was decreasingly expressed. LINC01419 negatively regulated miR-485-5p- and miR-485-5p-targeted LSM4. LINC01419 was localized in the cytoplasm of HCC cells. Downregulation of miR-485-5p or upregulation of LSM4 reversed the inhibition of HCC cell malignant behavior by LINC01419 interference. LINC01419 sponges miR-485-5p to upregulate LSM4 expression, thereby facilitating the biological behavior of HCC cells.
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Affiliation(s)
- Zeng-Peng Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, People's Republic of China
| | - Zhi-Guo Tan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, People's Republic of China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, People's Republic of China
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12
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Li D, Fan X, Li Y, Yang J, Lin H. The paradoxical functions of long noncoding RNAs in hepatocellular carcinoma: Implications in therapeutic opportunities and precision medicine. Genes Dis 2022; 9:358-369. [PMID: 35224152 PMCID: PMC8843871 DOI: 10.1016/j.gendis.2020.11.014] [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: 06/03/2020] [Revised: 10/22/2020] [Accepted: 11/24/2020] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being "transcriptional noise," they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.
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Affiliation(s)
- Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
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13
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Yao Y, Shu F, Wang F, Wang X, Guo Z, Wang H, Li L, Lv H. Long noncoding RNA LINC01189 is associated with HCV-hepatocellular carcinoma and regulates cancer cell proliferation and chemoresistance through hsa-miR-155-5p. Ann Hepatol 2021; 22:100269. [PMID: 33059056 DOI: 10.1016/j.aohep.2020.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) may be closely associated with Hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC). In this study, we investigated the expression and functions of a lncRNA, LINC01189, in HCV-associated HCC. PATIENTS OR MATERIALS AND METHODS LINC01189 expression was measured in HCC tumors, HCV-infected HCC tumors and HCV-infected HCC cells. LINC01189 was overexpressed in HCV-infected HepG2 cells to measure its function on HCV-correlated cancer proliferation. In HCC cell lines of Huh7 and Hep3B, LINC01189 was upregulated to investigate its effects on cancer cell proliferation and 5-FU chemoresistance. The competing endogenous RNA (ceRNA) target of LINC01189, human microRNA-155-5p (hsa-miR-155-5p) was probed by dual-luciferase assay and qRT-PCR. Hsa-miR-155-5p was upregulated in LINC01189-overexpessed Huh7 and Hep3B cells to investigate their epigenetic correlation on HCC development regulation. RESULTS LINC01189 is downregulated in HCV-infected HCC tumors and cell lines. LINC01189 overexpression inhibited HCC cancer cell proliferation and 5-FU chemoresistance. Hsa-miR-155-5p was confirmed to be a ceRNA target of LINC01189 in HCC. Upregulating hsa-miR-155-5p reversed the LINC01189-mediated inhibition on HCC proliferation and 5-FU chemoresistance. CONCLUSIONS LINC01189 downregulation is associated with HCV infection in HCC, and it has tumor-suppressing effects on HCC development through hsa-miR-155-5p.
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Affiliation(s)
- Ying Yao
- Clinical laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054 Shaanxi, China
| | - Fang Shu
- Clinical laboratory, Third Hospital of Xi'an, 710000, Shaanxi, China
| | - Fang Wang
- Anaesthesiology department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Xiaoqiang Wang
- Department of Cancer Biology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Zhengshe Guo
- Anaesthesiology department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Haili Wang
- Anaesthesiology department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Lu Li
- Anaesthesiology department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Haigang Lv
- Anaesthesiology department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
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14
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Zhao P, Malik S, Xing S. Epigenetic Mechanisms Involved in HCV-Induced Hepatocellular Carcinoma (HCC). Front Oncol 2021; 11:677926. [PMID: 34336665 PMCID: PMC8320331 DOI: 10.3389/fonc.2021.677926] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC), is the third leading cause of cancer-related deaths, which is largely caused by virus infection. About 80% of the virus-infected people develop a chronic infection that eventually leads to liver cirrhosis and hepatocellular carcinoma (HCC). With approximately 71 million HCV chronic infected patients worldwide, they still have a high risk of HCC in the near future. However, the mechanisms of carcinogenesis in chronic HCV infection have not been still fully understood, which involve a complex epigenetic regulation and cellular signaling pathways. Here, we summarize 18 specific gene targets and different signaling pathways involved in recent findings. With these epigenetic alterations requiring histone modifications and DNA hyper or hypo-methylation of these specific genes, the dysregulation of gene expression is also associated with different signaling pathways for the HCV life cycle and HCC. These findings provide a novel insight into a correlation between HCV infection and HCC tumorigenesis, as well as potentially preventable approaches. Hepatitis C virus (HCV) infection largely causes hepatocellular carcinoma (HCC) worldwide with 3 to 4 million newly infected cases diagnosed each year. It is urgent to explore its underlying molecular mechanisms for therapeutic treatment and biomarker discovery. However, the mechanisms of carcinogenesis in chronic HCV infection have not been still fully understood, which involve a complex epigenetic regulation and cellular signaling pathways. Here, we summarize 18 specific gene targets and different signaling pathways involved in recent findings. With these epigenetic alterations requiring histone modifications and DNA hyper or hypo-methylation of these specific genes, the dysregulation of gene expression is also associated with different signaling pathways for the HCV life cycle and HCC. These findings provide a novel insight into a correlation between HCV infection and HCC tumorigenesis, as well as potentially preventable approaches.
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Affiliation(s)
- Pin Zhao
- Guandong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China
| | - Samiullah Malik
- Department of Pathogen Biology, Shenzhen University Health Science Center, Shenzhen, China
| | - Shaojun Xing
- Department of Pathogen Biology, Shenzhen University Health Science Center, Shenzhen, China
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15
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Hou Y, Chen K, Liao R, Li Y, Yang H, Gong J. LINC01419-mediated epigenetic silencing of ZIC1 promotes metastasis in hepatocellular carcinoma through the PI3K/Akt signaling pathway. J Transl Med 2021; 101:570-587. [PMID: 33772101 DOI: 10.1038/s41374-021-00539-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a rapidly growing tumor characterized by a high potential for vascular invasion and metastasis. The purpose of our study is to explore the regulation mechanism of long noncoding RNA (lncRNA) LINC01419 on cell-cycle distribution and metastasis in hepatocellular carcinoma (HCC) by regulating zinc finger of the cerebellum (ZIC1) through PI3K/Akt signaling pathway. Bioinformatics analysis and dual-luciferase reporter assay were used to analyze LINC01419 and related genes in HCC, and their expression in HCC tissues and adjacent normal tissues were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Then, HCC cell lines were subjected to the construction of LINC01419/ZIC1 overexpression/knockdown cells utilizing lentiviral vectors. RIP and ChIP assays were applied to identify the LINC01419-binding protein. BSP and MSP assays were used to determine gene methylation. According to the results, LINC01419 was highly expressed in HCC tissues and cells, while ZIC1 was poorly expressed. LINC01419 targeted and downregulated ZIC1 expression. Furthermore, LINC01419 increased the methylation of ZIC1 promoter and repressed ZIC1 expression. PI3K/Akt signaling pathway was activated by LINC01419 overexpression and ZIC1 knockdown, under which conditions, the HCC cell self-renewal and proliferation were promoted while cell apoptosis was attenuated, accompanied by accelerated formation and metastasis of xenografted tumors in mice. In conclusion, LINC01419 enhances the methylation of ZIC1 promoter, inhibits ZIC1 expression, and activates the PI3K/Akt signaling pathway, thereby enhancing the malignant phenotypes of HCC cells in vitro as well as tumor formation and metastasis in vivo.
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Affiliation(s)
- Yifu Hou
- Organ Transplant Center and Third Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, PR China
| | - Kai Chen
- Organ Transplant Center and Third Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, PR China
| | - Rui Liao
- Department of Hepatobiliary, Southwest Medical University, Luzhou, PR China
| | - Youzan Li
- Department of Hepatobiliary, Southwest Medical University, Luzhou, PR China
| | - Hongji Yang
- Organ Transplant Center and Third Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China.
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, PR China.
| | - Jun Gong
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, PR China.
- Second Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, PR China.
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16
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Hull R, Mbita Z, Dlamini Z. Long non-coding RNAs (LncRNAs), viral oncogenomics, and aberrant splicing events: therapeutics implications. Am J Cancer Res 2021; 11:866-883. [PMID: 33791160 PMCID: PMC7994164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/21/2020] [Indexed: 06/12/2023] Open
Abstract
It has been estimated that worldwide up to 10% of all human cancers are the result of viral infection, with 7.2% of all cancers in the developed world have a viral aetiology. In contrast, 22.9% of infections in the developing world are the result of viral infections. This number increases to 30% in Sub-Saharan Africa. The ability of viral infections to induce the transformation of normal cells into cancerous cells is well documented. These viruses are mainly Hepatitis B and C viruses, Epstein Barr virus, Human papillomavirus and Human Cytomegalovirus. They can induce the transformation of normal cells into cancer cells and this may be the underlying cause of carcinogenesis in many different types of cancer. These include liver cancer, lymphoma, nasopharyngeal cancer, cervical cancer, gastric cancer and even glioblastoma. Long non-coding RNAs (LncRNAs) can function by regulating the expression of their target genes by controlling the stability of the target mRNAs or by blocking translation of the target mRNA. They can control transcription by regulating the recruitment of transcription factors or chromatin modification complexes. Finally, lncRNAs can control the phosphorylation, acetylation, and ubiquitination of proteins at the post-translation level. Thus, altering protein localisation, function, folding, stability and ultimately expression. In addition to these functions, lncRNA also regulate alternate pre-mRNA splicing in ways that contribute to the formation of tumours. This mainly involves the interaction of lncRNAs with splicing factors, which alters their activity and function. The ability of lncRNAs to regulate the stability, expression and function of tumour suppressor proteins is important in the development and progression of cancers. LncRNAs also regulate viral replication and latency, leading to carcinogenesis. These factors all make lncRNAs ideal targets for the development of biomarker arrays that can be based on secreted lncRNAs leading to the development of affordable non-invasive biomarker tests for the stage specific diagnosis of tumours. These lncRNAs can also serve as targets for the development of new anticancer drug treatments.
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Affiliation(s)
- Rodney Hull
- SA-MRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute, University of Pretoria Hatfield0028, South Africa
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biochemistry, University of LimpopoSovenga 0727, South Africa
| | - Zodwa Dlamini
- SA-MRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute, University of Pretoria Hatfield0028, South Africa
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17
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Lu X, Ge G, Ji F, Wang J. LncRNA MORT Overexpression Inhibits Cancer Cell Migration and Invasion in Hepatocellular Carcinoma by Downregulating NOTCH1. Cancer Biother Radiopharm 2021; 37:537-543. [PMID: 33493420 DOI: 10.1089/cbr.2020.4020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background: Long noncoding RNA (lncRNA) MORT is silenced in many malignancies, but its role in cancer remains hardly known. Methods: The expression of MORT and NOTCH1 was determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Correlation between MORT and NOTCH1 was analyzed by Pearson's correlation analysis. To further investigate the interaction between MORT and NOTCH1, overexpression experiments were performed. Results: In our study, MORT expression was downregulated in hepatocellular carcinoma (HCC), while NOTCH1 expression was upregulated in HCC patients. Hepatitis B virus and hepatitis C virus infection and tumor size did not significantly affect MORT expression, but MORT expression was lower in metastatic HCC patients compared with nonmetastatic HCC patients. MORT and NOTCH1 were inversely correlated across HCC tissues. MORT overexpression decreased NOTCH1 expression, while NOTCH1 overexpression did not significantly affect MORT. MORT overexpression inhibited the migration and invasion of HCC cells, while NOTCH1 overexpression promoted the migration and invasion of HCC cells. In addition, NOTCH1 overexpression attenuated the effects of MORT overexpression on cell migration and invasion. Conclusion: Therefore, MORT overexpression may inhibit HCC by downregulating NOTCH1.
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Affiliation(s)
- Xiuqin Lu
- Shanghai University of Medicine & Health Sciences, Shanghai, P.R. China
| | - Guohong Ge
- The Third People's Hospital of Zhenjiang, Zhenjiang City, P.R. China
| | - Fang Ji
- The Third People's Hospital of Zhenjiang, Zhenjiang City, P.R. China
| | - Jian Wang
- Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
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18
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Pea A, Jamieson NB, Braconi C. Biology and Clinical Application of Regulatory RNAs in Hepatocellular Carcinoma. Hepatology 2021; 73 Suppl 1:38-48. [PMID: 32160335 DOI: 10.1002/hep.31225] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/03/2020] [Accepted: 03/05/2020] [Indexed: 12/14/2022]
Abstract
Most of the human genome consists of DNA genes that are translated into RNAs but not into proteins. These RNA molecules are named noncoding RNAs (ncRNA). While in the past it was thought that ncRNAs would be redundant without relevant functions, it is now well established that ncRNAs identify a class of regulatory molecules that finely tune cell homeostasis and are deregulated in disease states, including hepatocellular carcinoma (HCC). Of note, the number of ncRNAs within a cell increases progressively, with the complexity of the species indicating their essential role in the maintenance of regulatory networks that affect the intricacy of the organism. ncRNAs have been demonstrated to mediate HCC development and progression by affecting intrinsic cancer cell signaling and crosstalk between malignant cells and the microenvironment. Moreover, ncRNAs hold promise as clinical biomarkers, but further evidence is warranted before their translation and integration within clinical practice.
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Affiliation(s)
- Antonio Pea
- The Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.,West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Nigel B Jamieson
- The Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.,West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Chiara Braconi
- The Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.,Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
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19
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Mungamuri SK, Nagasuryaprasad K. Epigenetic mechanisms of hepatocellular carcinoma progression: Potential therapeutic opportunities. EPIGENETICS AND METABOLOMICS 2021:279-296. [DOI: 10.1016/b978-0-323-85652-2.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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20
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Abstract
Liver cancer is a global problem and hepatocellular carcinoma (HCC) accounts for about 85% of this cancer. In the USA, etiologies and risk factors for HCC include chronic hepatitis C virus (HCV) infection, diabetes, non-alcoholic steatohepatitis (NASH), obesity, excessive alcohol drinking, exposure to tobacco smoke, and genetic factors. Chronic HCV infection appears to be associated with about 30% of HCC. Chronic HCV infection induces multistep changes in liver, involving metabolic disorders, steatosis, cirrhosis and HCC. Liver carcinogenesis requires initiation of neoplastic clones, and progression to clinically diagnose malignancy. Tumor progression associates with profound exhaustion of tumor-antigen-specific CD8+T cells, and accumulation of PD-1hi CD8+T cells and Tregs. In this chapter, we provide a brief description of HCV and environmental/genetic factors, immune regulation, and highlight mechanisms of HCV associated HCC. We also underscore HCV treatment and recent paradigm of HCC progression, highlighted the current treatment and potential future therapeutic opportunities.
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21
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Zhou L, Zhang Z, Huang Z, Nice E, Zou B, Huang C. Revisiting cancer hallmarks: insights from the interplay between oxidative stress and non-coding RNAs. MOLECULAR BIOMEDICINE 2020; 1:4. [PMID: 35006436 PMCID: PMC8603983 DOI: 10.1186/s43556-020-00004-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/21/2020] [Indexed: 02/08/2023] Open
Abstract
Cancer is one of the most common disease worldwide, with complex changes and certain traits which have been described as “The Hallmarks of Cancer.” Despite increasing studies on in-depth investigation of these hallmarks, the molecular mechanisms associated with tumorigenesis have still not yet been fully defined. Recently, accumulating evidence supports the observation that microRNAs and long noncoding RNAs (lncRNAs), two main classes of noncoding RNAs (ncRNAs), regulate most cancer hallmarks through their binding with DNA, RNA or proteins, or encoding small peptides. Reactive oxygen species (ROS), the byproducts generated during metabolic processes, are known to regulate every step of tumorigenesis by acting as second messengers in cancer cells. The disturbance in ROS homeostasis leads to a specific pathological state termed “oxidative stress”, which plays essential roles in regulation of cancer progression. In addition, the interplay between oxidative stress and ncRNAs is found to regulate the expression of multiple genes and the activation of several signaling pathways involved in cancer hallmarks, revealing a potential mechanistic relationship involving ncRNAs, oxidative stress and cancer. In this review, we provide evidence that shows the essential role of ncRNAs and the interplay between oxidative stress and ncRNAs in regulating cancer hallmarks, which may expand our understanding of ncRNAs in the cancer development from the new perspective.
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Affiliation(s)
- Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Edouard Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia
| | - Bingwen Zou
- Department of Thoracic Oncology and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China. .,School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P.R. China.
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22
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Shen C, Wang Y, Wu Z, Da L, Gao S, Xie L, Qie Y, Wang Y, Zhang Z, Tian D, Hu H. Long noncoding RNAs, ENST00000598996 and ENST00000524265, are correlated with favorable prognosis and act as potential tumor suppressors in bladder cancer. Oncol Rep 2020; 44:1831-1850. [PMID: 33000254 PMCID: PMC7550980 DOI: 10.3892/or.2020.7733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 06/04/2020] [Indexed: 12/24/2022] Open
Abstract
Bladder cancer (BC) is a serious malignancy worldwide due to its distant metastasis and high recurrence rates. Increasing evidence has indicated that dysregulated long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression in multiple malignancies. However, their clinical significances, biological functions and molecular mechanisms in BC remain poorly understood. Hence, the present study investigated the expression profile of lncRNAs and mRNAs in five BC tissues and the corresponding adjacent normal specimens using high-throughput RNA sequencing (RNA-seq). A total of 103 differentially expressed (DE) lncRNAs were identified, including 35 upregulated and 68 downregulated ones in BC tissues. Similarly, a total of 2,756 DE-mRNAs were detected, including 1,467 upregulated and 1,289 downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, and lncRNA-miRNA-mRNA network analyses suggested that these dysregulated lncRNAs are potentially implicated in the onset and progression of BC. Subsequently, four lncRNAs (upregulated ENST00000433108; downregulated ENST00000598996, ENST00000524265 and ENST00000398461) and two mRNAs (upregulated CCNB1 and CDK1) in 64 pairs of BC and adjacent normal tissues and four BC cell lines were detected using reverse transcription-quantitative PCR and these results were consistent with the sequencing data. Additionally, Fisher's exact test, Kaplan-Meier plots, and Cox regression analyses were used for elucidating the clinical values of ENST00000598996 and ENST00000524265. Furthermore, a receiver operating characteristic curve was constructed to assess their diagnostic values. The low expression level of ENST00000598996 and ENST00000524265 was correlated with unfavorable clinicopathological parameters, and shorter progression-free and overall survival time, whereas, ENST00000433108 was not associated with either. The in vitro functional experiments also revealed that the overexpression of ENST00000598996 and ENST00000524265 decreased the proliferation, migration, and invasion abilities of BC cells. Collectively, the results of the present study provide a novel landscape of lncRNA and mRNA expression profiles in BC. In addition, the results also indicated that ENST00000598996 and ENST00000524265 may serve as tumor suppressors, potential diagnostic biomarkers and prognostic predictors for patients with BC.
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Affiliation(s)
- Chong Shen
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Yujie Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Zhouliang Wu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - La Da
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Shen Gao
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Linguo Xie
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Yunkai Qie
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Yinlei Wang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Zhe Zhang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Dawei Tian
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Hailong Hu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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Dang H, Chen L, Tang P, Cai X, Zhang W, Zhang R, Huang A, Tang H. LINC01419 promotes cell proliferation and metastasis in hepatocellular carcinoma by enhancing NDRG1 promoter activity. Cell Oncol (Dordr) 2020; 43:931-947. [PMID: 32557341 DOI: 10.1007/s13402-020-00540-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2020] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Emerging evidence indicates that dysfunction of long non-coding RNAs (lncRNAs) plays an essential role in the initiation and progression of hepatocellular carcinoma (HCC). In this study we investigated the potential roles and molecular mechanisms involving LINC01419 in HCC. METHODS The expression of LINC01419 in 40 pairs of HCC/normal tissues and 6 HCC cell lines was detected by qRT-PCR. MTS, EdU, colony formation, scratch wound-healing and transwell assays were performed to assess the role of LINC01419 in HCC cell (SMMC7721 and SK-Hep1) proliferation, migration and invasion in vitro. Artificial modulation of LINC01419 (up- and downregulation) was performed to explore the role of LINC01419 in tumor growth and metastasis in vivo. Interaction of LINC01419 with NDRG1 was assessed using qRT-PCR, RNA sequencing, Western blotting and immunohistochemistry. Physical interaction of LINC01419 with the NDRG1 promoter was assessed using a dual-luciferase reporter assay. RESULTS We observed LINC01419 overexpression in primary HCC tissues and HCC cell lines and that this overexpression positively correlated with large tumor size, increased vascular invasion and advanced TNM stage in 40 HCC patients. Exogenous LINC01419 expression significantly promoted HCC cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, we found that LINC01419 expression knockdown elicited opposite effects. Mechanistic investigations revealed that LINC01419 exerted its biological effects by regulating NDRG1. A dual-luciferase reporter assay revealed that LINC01419 interacts with a specific region within the NDRG1 promoter, resulting in its activation. CONCLUSIONS From our data we conclude that LINC01419 acts clinically, functionally and mechanistically oncogenic in HCC. LINC01419 may, therefore, serve as a promising prognostic indicator and therapeutic target for HCC.
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Affiliation(s)
- Hao Dang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China.,Department of Clinical Laboratory, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Ling Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Ping Tang
- Department of Head and Neck Surgery, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Renfei Zhang
- Department of Clinical Laboratory, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China.
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Zhang G, Chen X, Ma L, Ding R, Zhao L, Ma F, Deng X. LINC01419 facilitates hepatocellular carcinoma growth and metastasis through targeting EZH2-regulated RECK. Aging (Albany NY) 2020; 12:11071-11084. [PMID: 32522890 PMCID: PMC7346057 DOI: 10.18632/aging.103321] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/28/2020] [Indexed: 12/24/2022]
Abstract
Long non-coding RNAs (lncRNAs) have been reported to play significant roles in human tumorigenesis, for example, in hepatocellular carcinoma (HCC). This study explored the role of LINC01419, a new lncRNA, in HCC. In vitro study revealed that LINC01419 promotes growth and migration of HCC cells. Genes that affected cell proliferation and cell migration were identified using RNA-sequence. Subsequently, it was confirmed that LINC01419 binds to EZH2, leading to histone methylation of the RECK promoter. Interaction between LINC01419 and FUS stabilized EZH2 mRNA thereby enhancing EZH2 expression. Conclusively, the results of this study confirm that LINC01419 may serve as a potential target for HCC diagnosis and treatment.
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Affiliation(s)
- Gong Zhang
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, China
| | - Ximin Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Lei Ma
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Rui Ding
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, China
| | - Lihong Zhao
- Department of Radiotherapy, People's Hospital of Shanxi Province, Taiyuan, China
| | - Feng Ma
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xubin Deng
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. Int J Mol Sci 2020; 21:ijms21093057. [PMID: 32357520 PMCID: PMC7246584 DOI: 10.3390/ijms21093057] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.
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Affiliation(s)
- Kaku Goto
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Florian Wrensch
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Pôle Hépato-digestif, Institut Hopitalo-Universitaire, F-67000 Strasbourg, France
- Institut Universitaire de France, F-75231 Paris, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
| | - Joachim Lupberger
- Université de Strasbourg, F-67000 Strasbourg, France
- Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), F-67000 Strasbourg, France
- Correspondence: (T.F.B.); (J.L.); Tel.: +33-3-68-85-37-03 (T.F.B. & J.L.); Fax: +33-3-68-85-37-24 (T.F.B. & J.L.)
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Unfried JP, Fortes P. LncRNAs in HCV Infection and HCV-Related Liver Disease. Int J Mol Sci 2020; 21:ijms21062255. [PMID: 32214045 PMCID: PMC7139329 DOI: 10.3390/ijms21062255] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are transcripts with poor coding capacity that may interact with proteins, DNA, or other RNAs to perform structural and regulatory functions. The lncRNA transcriptome changes significantly in most diseases, including cancer and viral infections. In this review, we summarize the functional implications of lncRNA-deregulation after infection with hepatitis C virus (HCV). HCV leads to chronic infection in many patients that may progress to liver cirrhosis and hepatocellular carcinoma (HCC). Most lncRNAs deregulated in infected cells that have been described function to potentiate or block the antiviral response and, therefore, they have a great impact on HCV viral replication. In addition, several lncRNAs upregulated by the infection contribute to viral release. Finally, many lncRNAs have been described as deregulated in HCV-related HCC that function to enhance cell survival, proliferation, and tumor progression by different mechanisms. Interestingly, some HCV-related HCC lncRNAs can be detected in bodily fluids, and there is great hope that they could be used as biomarkers to predict cancer initiation, progression, tumor burden, response to treatment, resistance to therapy, or tumor recurrence. Finally, there is high confidence that lncRNAs could also be used to improve the suboptimal long-term outcomes of current HCC treatment options.
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Affiliation(s)
| | - P. Fortes
- Correspondence: ; Tel.: +34-948194700
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27
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Machida K. Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol. Chem Biol Interact 2020; 323:109055. [PMID: 32171851 DOI: 10.1016/j.cbi.2020.109055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/13/2019] [Accepted: 03/10/2020] [Indexed: 12/15/2022]
Abstract
Alcoholism synergizes the development of the hepatocellular carcinoma (HCC) in patients infected with hepatitis B or C virus (HBV or HCV). Tumor-initiating stem-like cells (TICs) are refractory to therapy and have expression of stemness transcription factors. Leaky-gut-derived endotoxin stimulates TLR4-NANOG pathway that skews asymmetric cell division and that metabolically reprograms hepatocytes/liver progenitor cells, leading to self-renewal. TICs isolated from mouse HCC models or human HCCs are tumorigenic and have p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncofetal protein TBC1D15. Furthermore, dysregulation of lncRNA promotes genesis of TICs, leading to HCC development. This review describes roles of cell fate decision, metabolic reprogramming and lncRNA for TIC genesis and liver oncogenesis. This project was supported by NIH grants 1R01AA018857-01, 5R21AA025470, P50AA11999 (Animal Core, Morphology Core, and Pilot Project Program), R24AA012885 (Non-Parenchymal Liver Cell Core) and pilot project funding (5P30DK048522-13).
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA; Department of Molecular Microbiology and Immunology, Los Angeles, CA, USA.
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Sun X, Ge X, Xu Z, Chen D. Identification of circular RNA-microRNA-messenger RNA regulatory network in hepatocellular carcinoma by integrated analysis. J Gastroenterol Hepatol 2020; 35:157-164. [PMID: 31222831 DOI: 10.1111/jgh.14762] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/03/2019] [Accepted: 06/09/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is the most common types of hepatic malignancies. This study aimed to better understand the pathogenesis of HCC and may help facilitate the improvement of the diagnostic of HCC. METHODS The mRNA and miRNA expression profiles of HCC, which was retrieved from The Cancer Genome Atlas database, and the circRNA expression profiles of HCC, which was retrieved from Gene Expression Omnibus database, were included in this study to perform an integrated analysis. The differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed circRNAs (DEcircRNAs) were identified, and competing endogenous RNA (ceRNA) (DEcircRNA-DEmiRNA-DEmRNA) regulatory network was conducted. Functional annotation of host gene of DEcircRNAs and DEmRNAs in ceRNA regulatory network was performed. Quantitative real-time polymerase chain reaction validation of the expression of the selected DEmRNAs, DEmiRNAs, and DEcircRNAs was performed. RESULTS A total of 2982 DEmRNAs, 144 DEmiRNAs, and 264 DEcircRNAs were obtained. The ceRNA network contained 61 circRNA-miRNA pairs and 1149 miRNA-mRNA pairs, including 48 circRNAs, 30 miRNAs, and 1149 mRNAs. Functional annotation of DEmRNAs in ceRNA regulatory network revealed that these DEmRNAs were significantly enriched in tryptophan metabolism, fatty acid metabolism, and pathways in cancer. Except for ARNT2 and hsa-miR-214-3p, expression of the others in the quantitative real-time polymerase chain reaction results was consistent with that in our integrated analysis, generally. CONCLUSION We speculate that hsa_circRNA_104268/hsa-miR-214-3p/E2F2, hsa_circRNA_104168/hsa-miR-139-5p/HRAS, and hsa_circRNA_104769/hsa-miR-93-5p/JUN interaction pairs may play a vital role in HCC. This study expected to provide a novel insight into the pathogenesis and therapy of HCC from the circRNA-miRNA-mRNA network view.
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Affiliation(s)
- Xiangjun Sun
- Department of Hepatobiliary Surgery, Linyi People's Hospital, Linyi, China
| | - Xinfeng Ge
- Department of General Surgery, The People's Hospital of Linshu, Linshu County, China
| | - Zhiyong Xu
- Department of General Surgery, The People's Hospital of Linshu, Linshu County, China
| | - Dongfeng Chen
- Department of General Surgery, Linyi People's Hospital, Linyi, China
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Involvement and Roles of Long Noncoding RNAs in the Molecular Mechanisms of Emerging and Reemerging Viral Infections. EMERGING AND REEMERGING VIRAL PATHOGENS 2020. [PMCID: PMC7150007 DOI: 10.1016/b978-0-12-814966-9.00006-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Cheng Z, Hou S, Wu Y, Wang X, Sun Y, Liu B, Yuan M. LINC01419 promotes cell proliferation and metastasis in lung adenocarcinoma via sponging miR-519b-3p to up-regulate RCCD1. Biochem Biophys Res Commun 2019; 520:107-114. [PMID: 31582214 DOI: 10.1016/j.bbrc.2019.09.090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 09/21/2019] [Indexed: 12/19/2022]
Abstract
Lung adenocarcinoma (LUAD) is one of the most common type of lung cancer notorious for the high incidence and mortality around the world. Long non-coding RNAs (LncRNAs) are defined as a class of RNAs with length more than 200 nucleotides. Mounting studies have proved that lncRNAs are related closely to incidence of diseases and play crucial roles in cancer progression. Although LINC01419 has been studied in several cancers, the function and mechanism of LINC01419 in LUAD remains a mystery. Our findings showed that LINC01419 level was high in LUAD cells, and LINC01419 knockdown inhibited carcinogenesis via suppressing cell proliferation, migration as well as invasion. Moreover, bioinformatics prediction, luciferase reporter experiments and RIP assay were used to confirm miR-519-3p was sequestered and negatively regulated by LINC01419. Subsequently, RCCD1 was identified as a miR-519b-3p target and had inverse relationship with miR-519b-3p. LINC01419 was positively related to RCCD1. Furthermore, rescue assays confirmed that miR-519b-3p inhibitor or RCCD1 overexpression could neutralize the effect of LINC01419 silenced in cell proliferation, migration and invasion. Taken together, all the results indicated that LINC01419 exhibited oncogenic behaviors LUAD via binding to miR-519b-3p to enhance the expression of RCCD1, manifesting the underlying therapy values of LINC01419 in LUAD.
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Affiliation(s)
- Ziming Cheng
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
| | - Shizhen Hou
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China.
| | - Yubing Wu
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
| | - Xiangdong Wang
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
| | - Yi Sun
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
| | - Bing Liu
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
| | - Maoxi Yuan
- Department of Thoracic Surgery, Linyi Central Hospital. No.17, Health Road, Linyi, Shandong, 276400, China
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Wang LL, Zhang L, Cui XF. Downregulation of long noncoding RNA LINC01419 inhibits cell migration, invasion, and tumor growth and promotes autophagy via inactivation of the PI3K/Akt1/mTOR pathway in gastric cancer. Ther Adv Med Oncol 2019; 11:1758835919874651. [PMID: 31579114 PMCID: PMC6759708 DOI: 10.1177/1758835919874651] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 07/25/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Accumulating evidence has highlighted the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis of gastric cancer (GC), which is the most common gastrointestinal malignancy. The present study aimed to identify the capacity of lncRNA LINC01419 (LINC01419) in GC progression, with the potential mechanism explored. Methods: Highly expressed lncRNAs were identified by in silico analysis, with the LINC01419 expression in GC tissues measured using reverse transcription-quantitative PCR (RT-qPCR). The GC cells were subsequently transfected with siRNA against LINC01419 or Rapamycin (the inhibitor of the mTOR pathway), or both, in order to measure cell migration and invasion in vitro as well as tumor growth and metastasis in vivo. Moreover, the expression of PI3K/Akt1/mTOR pathway-associated factors was determined. Results: LINC01419, highly expressed in GC samples of the Gene Expression Omnibus database, was observed to be markedly upregulated in GC tissues. Moreover, LINC01419 silencing, or PI3K/Akt1/mTOR pathway inhibition, exhibited an inhibitory role in GC cell migration and invasion in vitro, coupled with promoted cell autophagy in vitro, and inhibited tumor growth and metastasis in vivo. It was also revealed that LINC01419 silencing blocked the PI3K/Akt1/mTOR pathway, as proved by decreased extents of Akt1 and mTOR phosphorylation. Conclusions: In conclusion, LINC01419 inhibition may suppress GC cell invasion and migration, and promote autophagy via inhibition of the PI3K/Akt1/mTOR pathway. This provides significant theoretical basis and possibilities for further elucidation of the molecular mechanism of GC and finding new molecular-targeted therapeutic regimens.
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Affiliation(s)
- Lin-Lin Wang
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Lei Zhang
- Department of Neurology, the Second Hospital of Jilin University, Changchun, China
| | - Xiao-Feng Cui
- Department of Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, Jilin Province 130033, China
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Deng B, Xu W, Wang Z, Liu C, Lin P, Li B, Huang Q, Yang J, Zhou H, Qu L. An LTR retrotransposon-derived lncRNA interacts with RNF169 to promote homologous recombination. EMBO Rep 2019; 20:e47650. [PMID: 31486214 DOI: 10.15252/embr.201847650] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 08/10/2019] [Accepted: 08/14/2019] [Indexed: 01/10/2023] Open
Abstract
LTR retrotransposons are abundant repetitive elements in the human genome, but their functions remain poorly understood. Here, we report the function and regulatory mechanism of an ERV-9 LTR retrotransposon-derived lncRNA called p53-regulated lncRNA for homologous recombination (HR) repair 1 (PRLH1) in human cells. PRLH1 is highly expressed in p53-mutated hepatocellular carcinoma (HCC) samples and promotes cell proliferation in p53-mutated HCC cells, and its transcription is promoted by NF-Y and suppressed by p53. Mechanistically, PRLH1 specifically binds to an uncharacterized domain of RNF169 through two GCUUCA boxes in its 5' terminal region to form a DNA repair complex that supplants 53BP1 at double-strand break (DSB) sites and then promotes the initiation of HR repair. Notably, PRLH1 is essential for the stabilization of RNF169, acting as an RNA platform to recruit and assemble HR protein factors. This study characterizes PRLH1 as a novel HR-promoting factor and provides new insights into the function and mechanism of LTR retrotransposon-derived lncRNAs.
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Affiliation(s)
- Bing Deng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Wenli Xu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Zelin Wang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Chang Liu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Penghui Lin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Bin Li
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Qiaojuan Huang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Jianhua Yang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Hui Zhou
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
| | - Lianghu Qu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China
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Zhou Y, Zheng X, Xu B, Hu W, Huang T, Jiang J. The Identification and Analysis of mRNA-lncRNA-miRNA Cliques From the Integrative Network of Ovarian Cancer. Front Genet 2019; 10:751. [PMID: 31497032 PMCID: PMC6712160 DOI: 10.3389/fgene.2019.00751] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 07/17/2019] [Indexed: 12/11/2022] Open
Abstract
Ovarian cancer is one of the leading causes of cancer mortality in women. Since little clinical symptoms were shown in the early period of ovarian cancer, most patients were found in phases III-IV or with abdominal metastasis when diagnosed. The lack of effective early diagnosis biomarkers makes ovarian cancer difficult to screen. However, in essence, the fundamental problem is we know very little about the regulatory mechanisms during tumorigenesis of ovarian cancer. There are emerging regulatory factors, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), which have played important roles in cancers. Therefore, we analyzed the RNA-seq profiles of 407 ovarian cancer patients. An integrative network of 20,424 coding RNAs (mRNAs), 10,412 lncRNAs, and 742 miRNAs were construed with variance inflation factor (VIF) regression method. The mRNA-lncRNA-miRNA cliques were identified from the network and analyzed. Such promising cliques showed significant correlations with survival and stage of ovarian cancer and characterized the complex sponge regulatory mechanism, suggesting their contributions to tumorigenicity. Our results provided novel insights of the regulatory mechanisms among mRNAs, lncRNAs, and miRNAs and highlighted several promising regulators for ovarian cancer detection and treatment.
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Affiliation(s)
- You Zhou
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Bin Xu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute of Cell Therapy, Soochow University, Changzhou, China
| | - Wenwei Hu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (CAS), Shanghai, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute of Cell Therapy, Soochow University, Changzhou, China
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Sharma G, Tripathi SK, Das S. lncRNA HULC facilitates efficient loading of HCV-core protein onto lipid droplets and subsequent virus-particle release. Cell Microbiol 2019; 21:e13086. [PMID: 31290220 DOI: 10.1111/cmi.13086] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 06/29/2019] [Accepted: 07/07/2019] [Indexed: 12/11/2022]
Abstract
The cellular lipid pool plays a central role in hepatitis C virus (HCV) life cycle, from establishing infection to virus propagation. Here, we show that a liver abundant long noncoding RNA, highly upregulated in liver carcinoma (HULC), is upregulated during HCV infection and manipulates the lipid pool to favour virus life cycle. Interestingly, HULC was found to be crucial for the increase in number of lipid droplets in infected cells. This effect was attributed to the role of HULC in lipid biogenesis. Further, we demonstrated that HULC knockdown decreases the association of HCV-core protein with lipid droplets. This exhibited a direct consequence on the release of HCV particles. The role of HULC in HCV-particle release was further substantiated by additional knockdown and mutation experiments. Additionally, we found that increased level of HULC in HCV-infected cells was a result of Retinoid X Receptor Alpha (RXRA)-mediated transcription, which seemed to be aided by HCV-core protein. Taken together, the results identify a distinct role of long noncoding RNA HULC in lipid dynamics during HCV infection, which provides new insights into the complex process of HCV propagation and pathogenesis.
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Affiliation(s)
- Geetika Sharma
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Sachin Kumar Tripathi
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.,National Institute of Biomedical Genomics, Kalyani, India
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Zheng Y, Lv P, Wang S, Cai Q, Zhang B, Huo F. LncRNA PLAC2 upregulates p53 to induce hepatocellular carcinoma cell apoptosis. Gene 2019; 712:143944. [PMID: 31233763 DOI: 10.1016/j.gene.2019.143944] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/25/2019] [Accepted: 06/20/2019] [Indexed: 01/07/2023]
Abstract
It is known that lncRNA PLAC2 can inhibit glioma. This study explored the function of PLAC2 in hepatocellular carcinoma (HCC). Our data showed that PLAC2 expression in HCC was not affect by HCV and HBV infection, while PLAC2 levels were significantly lower in HCC tissues comparing to non-cancer tissues. Low PLAC2 levels in HCC tissues were associated with low overall 5-year survival rate. P53 mRNA was also downregulated in HCC and positively correlated with PLAC2. PLAC2 overexpression caused upregulated p53 and increase cancer cell apoptosis. P53 overexpression failed to affect PLAC2. In addition, p53 silencing reduced the effects of PLAC2 overexpression. Therefore, PLAC2 upregulated p53 to mediate cancer cell apoptosis.
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Affiliation(s)
- Yujian Zheng
- Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou City, Guangdong Province 510010, China.
| | - Pengxiang Lv
- Department of Hepatobiliary Surgery, The 1st People's Hospital of Baiyin, Baiyin, Gansu Province 730900, China
| | - Shaoping Wang
- Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou City, Guangdong Province 510010, China
| | - Qing Cai
- Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou City, Guangdong Province 510010, China
| | - Bao Zhang
- Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou City, Guangdong Province 510010, China
| | - Feng Huo
- Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou City, Guangdong Province 510010, China
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Mao BDI, Xu P, Xu P, Zhong Y, Ding WW, Meng QZ. LINC00511 knockdown prevents cervical cancer cell proliferation and reduces resistance to paclitaxel. J Biosci 2019; 44:44. [PMID: 31180057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cervical cancer (CC) is one of the most common female malignancies in the world. Although paclitaxel (PTX) is a critical chemotherapy agent for the treatment of CC, its treatment outcome is limited by the development of drug resistance. The present study aims to define the role of long non-coding RNA (lncRNA) LINC00511 in the progression of CC with the involvement of cell proliferation, apoptosis and resistance to PTX in Hela/PTX cells. CC and adjacent normal tissue samples were collected from 84 patients with CC, and used to determine LINC0051 expression. PTX-resistant Hela/PTX cell line was constructed, in which LINC0051 was overexpressed or silenced to further investigate the effect of LINC00511 on PTX-resistant Hela/PTX cell viability, proliferation, migration, invasion, cell cycle, apoptosis and resistance of CC cells to PTX. The expression of Bcl-2, Bax, cleaved-caspase-3, matrix metalloproteinase (MMP)-2, MMP-9, multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-GP) was also assessed. High-expression of LINC00511 was found in CC with its close association with the tumor stage, tumor size and lymph node metastasis. After silencing LINC00511 expression, the expression of MRP1, P-GP, Bcl-2, MMP-2 and MMP-9 was decreased, while Bax and cleaved-caspase-3 increased with more CC cells arrested at G1 phase. Furthermore, silencing of LINC00511 could suppress cell resistance to PTX, cell viability, cell proliferation, migration and invasion yet promoted cell apoptosis in PTX-resistant Hela/PTX cells. Collectively, our findings demonstrate that silencing of LINC00511 could inhibit CC cell resistance to PTX, cell proliferation, migration and invasion, and promote cell apoptosis in CC. Silencing of LINC00511 provides a novel therapeutic target for CC.
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MESH Headings
- Adenocarcinoma/drug therapy
- Adenocarcinoma/genetics
- Adenocarcinoma/mortality
- Adenocarcinoma/surgery
- Adult
- Aged
- Antineoplastic Agents/therapeutic use
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/surgery
- Caspase 3/genetics
- Caspase 3/metabolism
- Cell Differentiation/drug effects
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Female
- Gene Expression Regulation, Neoplastic
- HeLa Cells
- Humans
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Middle Aged
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- Neoplasm Staging
- Oligoribonucleotides/genetics
- Oligoribonucleotides/metabolism
- Paclitaxel/therapeutic use
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- RNA, Long Noncoding/antagonists & inhibitors
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Signal Transduction
- Survival Analysis
- Tumor Burden/drug effects
- Uterine Cervical Neoplasms/drug therapy
- Uterine Cervical Neoplasms/genetics
- Uterine Cervical Neoplasms/mortality
- Uterine Cervical Neoplasms/surgery
- bcl-2-Associated X Protein/genetics
- bcl-2-Associated X Protein/metabolism
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Affiliation(s)
- Ben-DI Mao
- Department of Gynecology, Linyi Cancer Hospital, Linyi 276000, People's Republic of China
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LncRNAs with miRNAs in regulation of gastric, liver, and colorectal cancers: updates in recent years. Appl Microbiol Biotechnol 2019; 103:4649-4677. [PMID: 31062053 DOI: 10.1007/s00253-019-09837-5] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Long noncoding RNA (lncRNA) is a kind of RNAi molecule composed of hundreds to thousands of nucleotides. There are several major types of functional lncRNAs which participate in some important cellular pathways. LncRNA-RNA interaction controls mRNA translation and degradation or serves as a microRNA (miRNA) sponge for silencing. LncRNA-protein interaction regulates protein activity in transcriptional activation and silencing. LncRNA guide, decoy, and scaffold regulate transcription regulators of enhancer or repressor region of the coding genes for alteration of expression. LncRNA plays a role in cellular responses including the following activities: regulation of chromatin structural modification and gene expression for epigenetic and cell function control, promotion of hematopoiesis and maturation of immunity, cell programming in stem cell and somatic cell development, modulation of pathogen infection, switching glycolysis and lipid metabolism, and initiation of autoimmune diseases. LncRNA, together with miRNA, are considered the critical elements in cancer development. It has been demonstrated that tumorigenesis could be driven by homeostatic imbalance of lncRNA/miRNA/cancer regulatory factors resulting in biochemical and physiological alterations inside the cells. Cancer-driven lncRNAs with other cellular RNAs, epigenetic modulators, or protein effectors may change gene expression level and affect the viability, immortality, and motility of the cells that facilitate cancer cell cycle rearrangement, angiogenesis, proliferation, and metastasis. Molecular medicine will be the future trend for development. LncRNA/miRNA could be one of the potential candidates in this category. Continuous studies in lncRNA functional discrepancy between cancer cells and normal cells and regional and rational genetic differences of lncRNA profiles are critical for clinical research which is beneficial for clinical practice.
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Mao BD, Xu P, Zhong Y, Ding WW, Meng QZ. LINC00511 knockdown prevents cervical cancer cell proliferation and reduces resistance to paclitaxel. J Biosci 2019. [DOI: 10.1007/s12038-019-9851-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 190] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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41
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Chen JL, Lin ZX, Qin YS, She YQ, Chen Y, Chen C, Qiu GD, Zheng JT, Chen ZL, Zhang SY. Overexpression of long noncoding RNA LINC01419 in esophageal squamous cell carcinoma and its relation to the sensitivity to 5-fluorouracil by mediating GSTP1 methylation. Ther Adv Med Oncol 2019; 11:1758835919838958. [PMID: 31019568 PMCID: PMC6463338 DOI: 10.1177/1758835919838958] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 01/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Genome-wide sequencing investigations have identified numerous long noncoding RNAs (lncRNAs) among mammals, many of which exhibit aberrant expression in cancers, including esophageal squamous cell carcinoma (ESCC). Herein, this study elucidates the role and mechanism by which LINC01419 regulates the DNA methylation of glutathione S-transferase pi 1 (GSTP1) in relation to ESCC progression and the sensitivity of ESCC cells to 5-fluorouracil (5-FU). METHODS LINC01419 and GSTP1 levels were quantified among 38 paired ESCC and adjacent tissue samples collected from patients with ESCC. To ascertain the contributory role of LINC01419 in the progression of ESCC and identify the interaction between LINC01419 and GSTP1 promoter methylation, LINC01419 was overexpressed or silenced, and the DNA methyltransferase inhibitor 5-Aza-CdR was treated. RESULTS Data from the GEO database (GSE21362) and the Cancer Genome Atlas displayed elevated levels of LINC01419 and downregulated levels of GSTP1 in the ESCC tissues and cells. The silencing of LINC01419 led to decreased proliferation, increased apoptosis, and enhanced sensitivity to 5-FU in ESCC cells. Notably, LINC01419 could bind to the promoter region of the GSTP1 gene, resulting in elevated GSTP1 methylation and reduced GSTP1 levels via the recruitment of DNA methyltransferase among ESCC cells, whereby ESCC progression was stimulated accompanied by reduced ESCC cell sensitivity to 5-FU. GSTP1 demethylation by 5-Aza-CdR was observed to reverse the effects of LINC01419 overexpression in ESCC cells and the response to 5-FU. CONCLUSION Highly expressed LINC01419 in ESCC promotes GSTP1 methylation, which ultimately acts to promote the event of ESCC and diminish the sensitivity of ESCC cells to 5-FU, highlighting a novel potential strategy to improve 5-FU-based chemotherapy in ESCC.
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Affiliation(s)
- Jian-Liang Chen
- Clinical Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Zhi-Xiong Lin
- Radiotherapy Department, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yun-Sheng Qin
- Chest Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yu-Qi She
- Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yun Chen
- Clinical Pharmacy Research Center, Shantou University Medical College, Shantou, China
| | - Chen Chen
- Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Guo-Dong Qiu
- Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Jie-Ting Zheng
- Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Zhong-Lin Chen
- Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, China
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Porcine endemic diarrhea virus infection regulates long noncoding RNA expression. Virology 2018; 527:89-97. [PMID: 30471453 PMCID: PMC7112091 DOI: 10.1016/j.virol.2018.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/09/2018] [Accepted: 11/12/2018] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (lncRNAs) have been implicated in various life processes. However, the lncRNA expression and potential functions in porcine endemic diarrhea virus (PEDV) infection and host defense are still poorly understood. In this study, we investigated the lncRNA expression profiles during PEDV infection in intestinal porcine epithelial cell-jejunum 2 (IPEC-J2) cell lines by next-generation sequencing and identified 6188 novel lncRNAs. The functional annotation analysis revealed that these lncRNAs might be associated with many immunity-related genes. We next selected candidate lncRNAs related to immune response pathways and further identified their differential expression in PEDV-infected IPEC-J2 cells and newborn piglets. Our results demonstrated that PEDV infection regulated lncRNA expression patterns in both the IPEC-J2 cell line and piglet ileum. These findings provide the first large-scale survey of lncRNAs associated with PEDV infection, specifically the lncRNAs responsible for the activation of the immune system within the ileum.
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Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma. Viruses 2018; 10:v10110591. [PMID: 30380697 PMCID: PMC6265700 DOI: 10.3390/v10110591] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 10/27/2018] [Accepted: 10/29/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC.
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Xia CQ, Han K, Qi Y, Zhang Y, Yu DJ. A Self-Training Subspace Clustering Algorithm under Low-Rank Representation for Cancer Classification on Gene Expression Data. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2018; 15:1315-1324. [PMID: 28600258 PMCID: PMC5986621 DOI: 10.1109/tcbb.2017.2712607] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Accurate identification of the cancer types is essential to cancer diagnoses and treatments. Since cancer tissue and normal tissue have different gene expression, gene expression data can be used as an efficient feature source for cancer classification. However, accurate cancer classification directly using original gene expression profiles remains challenging due to the intrinsic high-dimension feature and the small size of the data samples. We proposed a new self-training subspace clustering algorithm under low-rank representation, called SSC-LRR, for cancer classification on gene expression data. Low-rank representation (LRR) is first applied to extract discriminative features from the high-dimensional gene expression data; the self-training subspace clustering (SSC) method is then used to generate the cancer classification predictions. The SSC-LRR was tested on two separate benchmark datasets in control with four state-of-the-art classification methods. It generated cancer classification predictions with an overall accuracy 89.7 percent and a general correlation 0.920, which are 18.9 and 24.4 percent higher than that of the best control method respectively. In addition, several genes (RNF114, HLA-DRB5, USP9Y, and PTPN20) were identified by SSC-LRR as new cancer identifiers that deserve further clinical investigation. Overall, the study demonstrated a new sensitive avenue to recognize cancer classifications from large-scale gene expression data.
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45
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Sang L, Wang XM, Xu DY, Zhao WJ. Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma. World J Gastroenterol 2018; 24:2605-2616. [PMID: 29962817 PMCID: PMC6021769 DOI: 10.3748/wjg.v24.i24.2605] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/02/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To discover methylated-differentially expressed genes (MDEGs) in hepatocellular carcinoma (HCC) and to explore relevant hub genes and potential pathways.
METHODS The data of expression profiling GSE25097 and methylation profiling GSE57956 were gained from GEO Datasets. We analyzed the differentially methylated genes and differentially expressed genes online using GEO2R. Functional and enrichment analyses of MDEGs were conducted using the DAVID database. A protein-protein interaction (PPI) network was performed by STRING and then visualized in Cytoscape. Hub genes were ranked by cytoHubba, and a module analysis of the PPI network was conducted by MCODE in Cytoscape software.
RESULTS In total, we categorized 266 genes as hypermethylated, lowly expressed genes (Hyper-LGs) referring to endogenous and hormone stimulus, cell surface receptor linked signal transduction and behavior. In addition, 161 genes were labelled as hypomethylated, highly expressed genes (Hypo-HGs) referring to DNA replication and metabolic process, cell cycle and division. Pathway analysis illustrated that Hyper-LGs were enriched in cancer, Wnt, and chemokine signalling pathways, while Hypo-HGs were related to cell cycle and steroid hormone biosynthesis pathways. Based on PPI networks, PTGS2, PIK3CD, CXCL1, ESR1, and MMP2 were identified as hub genes for Hyper-LGs, and CDC45, DTL, AURKB, CDKN3, MCM2, and MCM10 were hub genes for Hypo-HGs by combining six ranked methods of cytoHubba.
CONCLUSION In the study, we disclose numerous novel genetic and epigenetic regulations and offer a vital molecular groundwork to understand the pathogenesis of HCC. Hub genes, including PTGS2, PIK3CD, CXCL1, ESR1, MMP2, CDC45, DTL, AURKB, CDKN3, MCM2, and MCM10, can be used as biomarkers based on aberrant methylation for the accurate diagnosis and treatment of HCC.
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Affiliation(s)
- Liang Sang
- Department of Ultrasound, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xue-Mei Wang
- Department of Ultrasound, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Dong-Yang Xu
- Department of Ultrasound, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Wen-Jing Zhao
- Department of Ultrasound, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Liu TL, Fan XC, Li YH, Yuan YJ, Yin YL, Wang XT, Zhang LX, Zhao GH. Expression Profiles of mRNA and lncRNA in HCT-8 Cells Infected With Cryptosporidium parvum IId Subtype. Front Microbiol 2018; 9:1409. [PMID: 30013528 PMCID: PMC6036261 DOI: 10.3389/fmicb.2018.01409] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/08/2018] [Indexed: 12/03/2022] Open
Abstract
Cryptosporidium parvum is one of the most important enteric protozoan pathogens, responsible for severe diarrhea in immunocompromised human and livestock. However, few effective agents were available for controlling this parasite. Accumulating evidences suggest that long non-coding RNA (lncRNA) played key roles in many diseases through regulating the gene expression. Here, the expression profiles of lncRNAs and mRNAs were analyzed in HCT-8 cells infected with C. parvum IId subtype using microarray assay. A total of 821 lncRNAs and 1,349 mRNAs were differentially expressed in infected cells at 24 h post infection (pi). Of them, all five types of lncRNAs were identified, including 22 sense, 280 antisense, 312 intergenic, 44 divergent, 33 intronic lncRNAs, and 130 lncRNAs that were not found the relationship with mRNAs’ location. Additionally, real-time polymerase chain reactions of 10 lncRNAs and 10 mRNAs randomly selected were successfully confirmed the microarray results. The co-expression and target prediction analysis indicated that 27 mRNAs were cis-regulated by 29 lncRNAs and 109 were trans-regulated by 114 lncRNAs. These predicted targets were enriched in several pathways involved in the interaction between host and C. parvum, e.g., hedgehog signaling pathway, Wnt signaling pathway, and tight junction, suggesting that these differentially expressed lncRNAs would play important regulating roles during the infection of C. parvum IId subtype.
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Affiliation(s)
- Ting-Li Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Xian-Chen Fan
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yun-Hui Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Ya-Jie Yuan
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yan-Ling Yin
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Xue-Ting Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Long-Xian Zhang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Guang-Hui Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
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Yang J, Li J, Liu B, Zhang R, Gu F, Zhao J, Cheng S. Long Noncoding RNAAK021443Promotes Cell Proliferation and Migration by Regulating Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma Cells. DNA Cell Biol 2018; 37:481-490. [PMID: 29638164 DOI: 10.1089/dna.2017.4030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Jihong Yang
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Jinghua Li
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Bo Liu
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Rui Zhang
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Feng Gu
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Jisen Zhao
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
| | - Shujie Cheng
- Department of General Surgery, The Affiliated Hospital of Hebei University, Baoding, China
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Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 2018; 15:137-151. [PMID: 29317776 DOI: 10.1038/nrgastro.2017.169] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
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El Khodiry A, Afify M, El Tayebi HM. Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis. World J Gastroenterol 2018; 24:549-572. [PMID: 29434445 PMCID: PMC5799857 DOI: 10.3748/wjg.v24.i5.549] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/17/2018] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future.
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Affiliation(s)
- Aya El Khodiry
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Menna Afify
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Hend M El Tayebi
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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Qiu M, Feng D, Zhang H, Xia W, Xu Y, Wang J, Dong G, Zhang Y, Yin R, Xu L. Comprehensive analysis of lncRNA expression profiles and identification of functional lncRNAs in lung adenocarcinoma. Oncotarget 2017; 7:16012-22. [PMID: 26918601 PMCID: PMC4941294 DOI: 10.18632/oncotarget.7559] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Accepted: 02/07/2016] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence has highlighted the critical roles of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets for cancer. Here, we characterized lncRNA expression profile in lung adenocarcinoma (LUAD). A training-validation method was applied to identify differentially expressed lncRNAs between LUAD samples and normal samples. 856 differentially expressed lncRNAs were identified. Bioinformatics analyses showed that these lncRNAs were located nearby transcription start sites and key regulators of cancer and these lncRNAs were involved in many critical biological processes. We found the lung cancer associated lncRNA 6 (LCAL6) was significantly unregulated and predicted survival in LUAD. Silence of LCAL6 inhibited LUAD tumor cell growth both in vitro and in vivo. To summary, we comprehensively analyze lncRNA expression profile in LUAD and provide resources for further search for clinical biomarkers and therapeutic targets of LUAD.
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Affiliation(s)
- Mantang Qiu
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.,The Fourth Clinical College of Nanjing Medical University, Nanjing, China
| | - Dongjie Feng
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Haitian Zhang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.,The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Wenjia Xia
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.,The Fourth Clinical College of Nanjing Medical University, Nanjing, China
| | - Youtao Xu
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Jie Wang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.,Department of Scientific Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Gaochao Dong
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.,Department of Scientific Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Yewei Zhang
- Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Rong Yin
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China
| | - Lin Xu
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China
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