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Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
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Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
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2
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Adugna A, Amare GA, Jemal M. Machine Learning Approach and Bioinformatics Analysis Discovered Key Genomic Signatures for Hepatitis B Virus-Associated Hepatocyte Remodeling and Hepatocellular Carcinoma. Cancer Inform 2025; 24:11769351251333847. [PMID: 40291818 PMCID: PMC12033511 DOI: 10.1177/11769351251333847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Hepatitis B virus (HBV) causes liver cancer, which is the third most common cause of cancer-related death worldwide. Chronic inflammation via HBV in the host hepatocytes causes hepatocyte remodeling (hepatocyte transformation and immortalization) and hepatocellular carcinoma (HCC). Recognizing cancer stages accurately to optimize early screening and diagnosis is a primary concern in the outlook of HBV-induced hepatocyte remodeling and liver cancer. Genomic signatures play important roles in addressing this issue. Recently, machine learning (ML) models and bioinformatics analysis have become very important in discovering novel genomic signatures for the early diagnosis, treatment, and prognosis of HBV-induced hepatic cell remodeling and HCC. We discuss the recent literature on the ML approach and bioinformatics analysis revealed novel genomic signatures for diagnosing and forecasting HBV-associated hepatocyte remodeling and HCC. Various genomic signatures, including various microRNAs and their associated genes, long noncoding RNAs (lncRNAs), and small nucleolar RNAs (snoRNAs), have been discovered to be involved in the upregulation and downregulation of HBV-HCC. Moreover, these genetic biomarkers also affect different biological processes, such as proliferation, migration, circulation, assault, dissemination, antiapoptosis, mitogenesis, transformation, and angiogenesis in HBV-infected hepatocytes.
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Affiliation(s)
- Adane Adugna
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Ethiopia
| | - Gashaw Azanaw Amare
- Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Ethiopia
| | - Mohammed Jemal
- Department of Biomedical Sciences, School of Medicine, Debre Markos University, Ethiopia
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3
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Priya S, Kma L. Identification of novel microRNAs: Biomarkers for pathogenesis of hepatocellular carcinoma in mice model. Biochem Biophys Rep 2025; 41:101896. [PMID: 39881957 PMCID: PMC11774814 DOI: 10.1016/j.bbrep.2024.101896] [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: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most fatal cancer that has affected both male and female populations globally. With poor diagnosis and patient survival rates, it has become a global need for scientists to come to the aid. The main objective of the study was to profile the miRNAs in the serum of Control and DEN-treated mice at different time intervals (4 Weeks, 8 Weeks, 12 Weeks, and 16 Weeks) and identify HCC-associated miRNA as putative early biomarkers along with the miRNA regulated candidate gene which may be involved in HCC. Our study group involves 4,8,12, & 16 weeks 16-week-old treated male mice. Each group was sacrificed and analyzed for the stages of HCC. We employed in silico techniques for the small RNA-Seq and bioinformatics pipeline for further analysis. Our analysis revealed over 400 differentially expressed miRNAs in each treated sample and 10 novel miRNAs. The downstream analysis of these differentially expressed miRNAs, and their target genes opened an arena of different biological processes and pathways that these miRNAs affect during the development of HCC. The work has a promising role as the miRNAs predicted through this study can be used as biomarkers for early detection of HCC.
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Affiliation(s)
- Shivani Priya
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Noida, UP, India
| | - Lakhon Kma
- Department of Biochemistry, North Eastern Hill University, Shillong, India
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4
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Yerukala Sathipati S, Jeong S, Sharma P, Mayer J, Sharma R, Ho SY, Hebbring S. Exploring prognostic implications of miRNA signatures and telomere maintenance genes in kidney cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200874. [PMID: 39399813 PMCID: PMC11467672 DOI: 10.1016/j.omton.2024.200874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/01/2024] [Accepted: 09/05/2024] [Indexed: 10/15/2024]
Abstract
Kidney cancer, particularly clear cell renal cell carcinoma (KIRC), presents significant challenges in disease-specific survival. This study investigates the prognostic potential of microRNAs (miRNAs) in kidney cancers, including KIRC and kidney papillary cell carcinoma (KIRP), focusing on their interplay with telomere maintenance genes. Utilizing data from The Cancer Genome Atlas, miRNA expression profiles of 166 KIRC and 168 KIRP patients were analyzed. An evolutionary learning-based kidney survival estimator identified robust miRNA signatures predictive of 5-year survival for both cancer types. For KIRC, a 37-miRNA signature showed a correlation coefficient (R) of 0.82 and mean absolute error (MAE) of 0.65 years. Similarly, for KIRP, a 23-miRNA signature exhibited an R of 0.82 and MAE of 0.64 years, demonstrating comparable predictive accuracy. These signatures also displayed diagnostic potential with receiver operating characteristic curve values between 0.70 and 0.94. Bioinformatics analysis revealed targeting of key telomere-associated genes such as TERT, DKC1, CTC1, and RTEL1 by these miRNAs, implicating crucial pathways such as cellular senescence and proteoglycans in cancer. This study highlights the significant link between miRNAs and telomere genes in kidney cancer survival, offering insights for therapeutic targets and improved prognostic markers.
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Affiliation(s)
| | - Sohyun Jeong
- Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
| | - Param Sharma
- Department of Cardiology, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - John Mayer
- Office of Research Computing and Analytics, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Rohit Sharma
- Department of Surgical Oncology, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Scott Hebbring
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
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5
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Dwianingsih EK, Hartanto RA, Safitri S, Krisnugraha YP, Sianipar CM, Basuki E, Dananjoyo K, Asmedi A, Sun B, Malueka RG. Analysis of Circulating Plasma MicroRNA Profile in Low-Grade and High-Grade Glioma - A Cross-Sectional Study. F1000Res 2024; 13:1361. [PMID: 39801574 PMCID: PMC11725040 DOI: 10.12688/f1000research.153731.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 01/16/2025] Open
Abstract
Background Glioma is the second most common type of brain tumor, accounting for 24% of all brain tumor cases. The current diagnostic procedure is through an invasive tissue sampling to obtain histopathological analysis, however, not all patients are able to undergo a high-risk procedure. Circulating microRNAs (miRNAs) are considered as promising biomarkers for glioma due to their sensitivity, specificity, and non-invasive properties. There is currently no defined miRNA profile that contributes to determining the grade of glioma. This study aims to find the answer for "Is there any significant miRNA that able to distinguish different grades of glioma?". Methods This study was conducted to compare the expression of miRNAs between low-grade glioma (LGG) and high-grade glioma (HGG). Eighteen blood plasma samples from glioma patients and 6 healthy controls were analyzed for 798 human miRNA profiles using NanoString nCounter Human v3 miRNA Expression Assay. The differential expressions of miRNAs were then analyzed to identify the differences in miRNA expression between LGG and HGG. Results Analyses showed significant expressions in 12 miRNAs between LGG and HGG, where all of them were downregulated. Out of these significant miRNAs, miR-518b, miR-1271-3p, and miR-598-3p showed the highest potential for distinguishing HGG from LGG, with area under curve (AUC) values of 0.912, 0.889, and 0.991, respectively. Conclusion miR-518b, miR-1271-3p, and miR-598-3p demonstrate significant potentials in distinguishing LGG and HGG.
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Affiliation(s)
- Ery Kus Dwianingsih
- Department of Anatomical Pathology, Faculty of Medicine, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Rachmat Andi Hartanto
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Sekar Safitri
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Yeshua Putra Krisnugraha
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Christina Megawimanti Sianipar
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Endro Basuki
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Kusumo Dananjoyo
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Ahmad Asmedi
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
| | - Bo Sun
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, England, OX3 7BN, UK
| | - Rusdy Ghazali Malueka
- Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito General Hospital, Special Region of Yogyakarta, 55281, Indonesia
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Garcia CJC, Grisetti L, Tiribelli C, Pascut D. The ncRNA-AURKA Interaction in Hepatocellular Carcinoma: Insights into Oncogenic Pathways, Therapeutic Opportunities, and Future Challenges. Life (Basel) 2024; 14:1430. [PMID: 39598228 PMCID: PMC11595987 DOI: 10.3390/life14111430] [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: 08/30/2024] [Revised: 10/15/2024] [Accepted: 11/03/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.
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Affiliation(s)
- Clarissa Joy C. Garcia
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
- Department of Life Sciences, Università degli Studi di Trieste, 34127 Trieste, Italy
| | - Luca Grisetti
- National Institute of Gastroenterology—IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
| | - Devis Pascut
- Liver Cancer Unit, Fondazione Italiana Fegato—ONLUS, 34149 Trieste, Italy
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7
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Zhang Y, Ma W, Huang Z, Liu K, Feng Z, Zhang L, Li D, Mo T, Liu Q. Research and application of omics and artificial intelligence in cancer. Phys Med Biol 2024; 69:21TR01. [PMID: 39079556 DOI: 10.1088/1361-6560/ad6951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/30/2024] [Indexed: 10/19/2024]
Abstract
Cancer has a high incidence and lethality rate, which is a significant threat to human health. With the development of high-throughput technologies, different types of cancer genomics data have been accumulated, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. A comprehensive analysis of various omics data is needed to understand the underlying mechanisms of tumor development. However, integrating such a massive amount of data is one of the main challenges today. Artificial intelligence (AI) techniques such as machine learning are now becoming practical tools for analyzing and understanding multi-omics data on diseases. Enabling great optimization of existing research paradigms for cancer screening, diagnosis, and treatment. In addition, intelligent healthcare has received widespread attention with the development of healthcare informatization. As an essential part of innovative healthcare, practical, intelligent prognosis analysis and personalized treatment for cancer patients are also necessary. This paper introduces the advanced multi-omics data analysis technology in recent years, presents the cases and advantages of the combination of both omics data and AI applied to cancer diseases, and finally briefly describes the challenges faced by multi-omics analysis and AI at the current stage, aiming to provide new perspectives for oncology research and the possibility of personalized cancer treatment.
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Affiliation(s)
- Ye Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Wenwen Ma
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Zhiqiang Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Kun Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Zhaoyi Feng
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Lei Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Dezhi Li
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Tianlu Mo
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
| | - Qing Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, People's Republic of China
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8
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Ho YL, Ho YJ, Ko FY, Ho SY. Evolutionary learning-derived lncRNA signature with biomarker discovery for predicting stage of colon adenocarcinoma. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2024; 2024:1-5. [PMID: 40039814 DOI: 10.1109/embc53108.2024.10781761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
In recent years, long non-coding RNAs (lncRNAs) have emerged as potential regulators of biological processes and genes, with the potential to serve as valuable biomarkers for cancer diagnosis and prognosis prediction. This work proposes an evolutionary learning-based method, EL-COAD, to identify a robust lncRNA signature with biomarker discovery for predicting stages of colon adenocarcinoma (COAD). The COAD patient cohorts were obtained from both the Cancer Genome Atlas and Gene Expression Omnibus (gse17536) databases. EL-COAD incorporates a bi-objective combinatorial genetic algorithm with a support vector machine for selecting a minimal number of lncRNAs while maximizing prediction accuracy. EL-COAD identified a 15-lncRNA signature and achieved a five-fold cross-validation and area under receiver operating characteristic curve of 79.4% and 0.792, respectively. Utilising the 10 lncRNAs from the signature for an independent dataset gse17536, the Sequential Minimal Optimization model achieved a test accuracy of 64.15%. Furthermore, the lncRNAs of the signature were prioritized, with the top five being TMEM105, DUXAP8, APCDD1L-DT, PCAT6, and a novel transcript, ENSG00000226308. Furthermore, both Kyoto Encyclopedia of Genes and Genomes pathway and Disease Ontology analyses provided strong support for the viability of this model-independent signature, emphasising ENSG00000226308 as a promising biomarker.
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Smith K, Beach D, Silva R, Balazs G, Salani F, Crea F. Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: Prognostic, predictive significance and pathway insights. PLoS One 2024; 19:e0296198. [PMID: 38635644 PMCID: PMC11025735 DOI: 10.1371/journal.pone.0296198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/19/2024] [Indexed: 04/20/2024] Open
Abstract
Robust prognostic and predictive factors for hepatocellular carcinoma, a leading cause of cancer-related deaths worldwide, have not yet been identified. Previous studies have identified potential HCC determinants such as genetic mutations, epigenetic alterations, and pathway dysregulation. However, the clinical significance of these molecular alterations remains elusive. MicroRNAs are major regulators of protein expression. MiRNA functions are frequently altered in cancer. In this study, we aimed to explore the prognostic value of differentially expressed miRNAs in HCC, to elucidate their associated pathways and their impact on treatment response. To this aim, bioinformatics techniques and clinical dataset analyses were employed to identify differentially expressed miRNAs in HCC compared to normal hepatic tissue. We validated known associations and identified a novel miRNA signature with potential prognostic significance. Our comprehensive analysis identified new miRNA-targeted pathways and showed that some of these protein coding genes predict HCC patients' response to the tyrosine kinase inhibitor sorafenib.
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Affiliation(s)
- Kayleigh Smith
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom
| | - Dan Beach
- School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Roger Silva
- Department of Medicine, Cancer Research Program Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Gyorffy Balazs
- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
- Research Centre for Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary
| | - Francesca Salani
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Institute of Interdisciplinary Research “Health Science”, Scuola Superiore Sant’Anna, Pisa, Italy
| | - Francesco Crea
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom
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10
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Sathipati SY, Tsai MJ, Aimalla N, Moat L, Shukla S, Allaire P, Hebbring S, Beheshti A, Sharma R, Ho SY. An evolutionary learning-based method for identifying a circulating miRNA signature for breast cancer diagnosis prediction. NAR Genom Bioinform 2024; 6:lqae022. [PMID: 38406797 PMCID: PMC10894035 DOI: 10.1093/nargab/lqae022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/11/2024] [Accepted: 02/13/2024] [Indexed: 02/27/2024] Open
Abstract
Breast cancer (BC) is one of the most commonly diagnosed cancers worldwide. As key regulatory molecules in several biological processes, microRNAs (miRNAs) are potential biomarkers for cancer. Understanding the miRNA markers that can detect BC may improve survival rates and develop new targeted therapeutic strategies. To identify a circulating miRNA signature for diagnostic prediction in patients with BC, we developed an evolutionary learning-based method called BSig. BSig established a compact set of miRNAs as potential markers from 1280 patients with BC and 2686 healthy controls retrieved from the serum miRNA expression profiles for the diagnostic prediction. BSig demonstrated outstanding prediction performance, with an independent test accuracy and area under the receiver operating characteristic curve were 99.90% and 0.99, respectively. We identified 12 miRNAs, including hsa-miR-3185, hsa-miR-3648, hsa-miR-4530, hsa-miR-4763-5p, hsa-miR-5100, hsa-miR-5698, hsa-miR-6124, hsa-miR-6768-5p, hsa-miR-6800-5p, hsa-miR-6807-5p, hsa-miR-642a-3p, and hsa-miR-6836-3p, which significantly contributed towards diagnostic prediction in BC. Moreover, through bioinformatics analysis, this study identified 65 miRNA-target genes specific to BC cell lines. A comprehensive gene-set enrichment analysis was also performed to understand the underlying mechanisms of these target genes. BSig, a tool capable of BC detection and facilitating therapeutic selection, is publicly available at https://github.com/mingjutsai/BSig.
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Affiliation(s)
| | - Ming-Ju Tsai
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA 02131, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA
| | - Nikhila Aimalla
- Department of Internal Medicine-Pediatrics, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Luke Moat
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Sanjay K Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Patrick Allaire
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Scott Hebbring
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Afshin Beheshti
- Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA94035, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Rohit Sharma
- Department of Surgical Oncology, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
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11
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Lv Y, Sun X. Role of miRNA in pathogenesis, diagnosis, and prognosis in hepatocellular carcinoma. Chem Biol Drug Des 2024; 103:e14352. [PMID: 37726253 DOI: 10.1111/cbdd.14352] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/27/2023] [Accepted: 09/04/2023] [Indexed: 09/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and is responsible for the second cancer-related death globally. Many treatment regimens have been developed to cure the disease; however, life expectancy is still low. Therefore, there is an urgent need to explore new selective, specific, and robust diagnosis markers for efficient early recognition of the ailment. Along with the diagnosis, the treatment's effectiveness can be determined by prognostic markers, and miRNAs are excellent tools for the diagnosis and prognosis of HCC. In addition, the altered expression profile of a few miRNAs promotes HCC cell migration and invasion, and selective up- or downregulation of these responsible genes may help mitigate the disorder. On one hand, few of the miRNAs have been found to enhance angiogenesis, a crucial step of tumor growth; on the other hand, upregulation of specific miRNAs is reported to suppress angiogenesis and resulting tumor growth of HCC cells. Exosomal miRNAs have significant implications in promoting angiogenesis, increased endothelial cell permeability, tube formation, and metastasis to hepatic and pulmonary tissues. miRNA also attributes to drug resistance toward chemotherapy and the prevention of autophagy also. Identifying novel miRNA and determining their differential expression in HCC tissue may serve as a potential tool for diagnosis, prognosis, and therapy to enhance the life expectancy and quality of life of HCC patients. In the present review, we have summarized the recent advances in HCC-related research.
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Affiliation(s)
- Yi Lv
- Hepatobiliary and Pancreatic Surgery, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xiujuan Sun
- Department of Pathology, Liuzhou People's Hospital, Liuzhou, Guangxi, China
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12
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Jiao R, Wu B, Han S, Cui D, Sun J, Zhao T, Zhan Y, Chang Y. miRn-3 inhibits cutaneous wound healing by targeting gelsolin in the sea cucumber Apostichopus japonicus. Int J Biol Macromol 2024; 254:127801. [PMID: 37918586 DOI: 10.1016/j.ijbiomac.2023.127801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/18/2023] [Accepted: 10/29/2023] [Indexed: 11/04/2023]
Abstract
The microRNA novel-3 (miRn-3) is a 23-nt small endogenous noncoding RNA of unknown function. To enrich our knowledge of the regulatory function of miRn-3 in the process of wound healing, the sea cucumber Apostichopus japonicus was used as a target model in this study. Gelsolin (AjGSN), a potential target gene of miRn-3, was cloned and characterized, and the interaction between miRn-3 and AjGSN was verified. The function of the miRn-3/AjGSN axis in regulating cutaneous wound healing was explored in the sea cucumber A. japonicus. The results showed that 1) the full-length cDNA of AjGSN was 2935 bp, with a high level of sequence conservation across the echinoderms; 2) miRn-3 could bind to the 3'UTR of AjGSN and negatively regulate the expression of AjGSN; 3) overexpression of miRn-3 and inhibition of the expression of AjGSN suppressed cutaneous wound healing in A. japonicus. In general, all observations of this study suggest that miRn-3 plays an important role in the early process of cutaneous wound healing by negatively targeting AjGSN, and that it may be a potential biomarker in wound healing.
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Affiliation(s)
- Renhe Jiao
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China
| | - Boqiong Wu
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China
| | - Senrong Han
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China
| | - Dongyao Cui
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China; College of Biological Science and Technology, Shenyang Agricultural University, Shenyang, Liaoning 110866, PR China
| | - Jingxian Sun
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China; College of Life Science, Liaoning Normal University, Dalian, Liaoning 116029, PR China
| | - Tanjun Zhao
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China; College of Life Science, Liaoning Normal University, Dalian, Liaoning 116029, PR China
| | - Yaoyao Zhan
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China.
| | - Yaqing Chang
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture and Rural Affairs, Dalian Ocean University, Dalian, Liaoning 116023, PR China; College of Biological Science and Technology, Shenyang Agricultural University, Shenyang, Liaoning 110866, PR China; College of Life Science, Liaoning Normal University, Dalian, Liaoning 116029, PR China.
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13
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Lin T, Guo X, Du Q, Liu W, Zhong X, Wang S, Cao L. MicroRNA let-7c-5p Alleviates in Hepatocellular Carcinoma by Targeting Enhancer of Zeste Homolog 2: A Study Intersecting Bioinformatic Analysis and Validated Experiments. Crit Rev Immunol 2024; 44:23-39. [PMID: 38505919 DOI: 10.1615/critrevimmunol.2024051519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
Enhancer of zeste homolog 2 (EZH2)gene has a prognostic role in hepatocellular carcinoma (HCC). This study aimed to identify the role of microRNAs (miRNAs) let-7c-5p by targeting EZH2 in HCC. We downloaded gene and miRNA RNA-seq data from The Cancer Genome Atlas (TCGA) database. Differences in EZH2 expression between different groups were analyzed and the association of EZH2 expression with HCC prognosis was detected using Cox regression analysis. The miRNA-EZH2-pathway network was constructed. Dual-luciferase reporter assay was performed to detect the hsa-let-7c-5p-EZH2. Cell proliferation, migration, invasion, and apoptosis were detected by CCK-8, Wound healing, Transwell, and Flow cytometry, respectively. RT-qPCR and Western blot were used to detect the expression of let-7c-5p and EZH2. EZH2 was upregulated in HCC tumors (P < 0.0001). Cox regression analysis showed that TCGA HCC patients with high EZH2 expression levels showed a short survival time [hazard ratio (HR) = 1.677, 95% confidence interval (CI) 1.316-2.137; P < 0.0001]. Seven miRNAs were negatively correlated with EZH2 expression and were significantly downregulated in HCC tumor samples (P < 0.0001), in which hsa-let-7c-5p was associated with prognosis in HCC (HR = 0.849 95% CI 0.739-0.975; P = 0.021). We identified 14 immune cells that showed significant differences in EZH2 high- and low-expression groups. Additionally, let-7c-5p inhibited HCC cell proliferation, migration, and invasion and reversed the promoted effects of EZH2 on HCC cell malignant characteristics. hsa-let-7c-5p-EZH2 significantly suppressed HCC malignant characteristics, which can be used for HCC prognosis.
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Affiliation(s)
- Tianyu Lin
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University
| | - Xinli Guo
- Department of Operating Room, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Qian Du
- Department of General Surgery, The 903rd Hospital of PLA, Hangzhou 310000, China
| | - Wei Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Xin Zhong
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Suihan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Liping Cao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
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Yerukala Sathipati S, Aimalla N, Tsai MJ, Carter T, Jeong S, Wen Z, Shukla SK, Sharma R, Ho SY. Prognostic microRNA signature for estimating survival in patients with hepatocellular carcinoma. Carcinogenesis 2023; 44:650-661. [PMID: 37701974 DOI: 10.1093/carcin/bgad062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/01/2023] [Accepted: 09/08/2023] [Indexed: 09/14/2023] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is one of the leading cancer types with increasing annual incidence and high mortality in the USA. MicroRNAs (miRNAs) have emerged as valuable prognostic indicators in cancer patients. To identify a miRNA signature predictive of survival in patients with HCC, we developed a machine learning-based HCC survival estimation method, HCCse, using the miRNA expression profiles of 122 patients with HCC. METHODS The HCCse method was designed using an optimal feature selection algorithm incorporated with support vector regression. RESULTS HCCse identified a robust miRNA signature consisting of 32 miRNAs and obtained a mean correlation coefficient (R) and mean absolute error (MAE) of 0.87 ± 0.02 and 0.73 years between the actual and estimated survival times of patients with HCC; and the jackknife test achieved an R and MAE of 0.73 and 0.97 years between actual and estimated survival times, respectively. The identified signature has seven prognostic miRNAs (hsa-miR-146a-3p, hsa-miR-200a-3p, hsa-miR-652-3p, hsa-miR-34a-3p, hsa-miR-132-5p, hsa-miR-1301-3p and hsa-miR-374b-3p) and four diagnostic miRNAs (hsa-miR-1301-3p, hsa-miR-17-5p, hsa-miR-34a-3p and hsa-miR-200a-3p). Notably, three of these miRNAs, hsa-miR-200a-3p, hsa-miR-1301-3p and hsa-miR-17-5p, also displayed association with tumor stage, further emphasizing their clinical relevance. Furthermore, we performed pathway enrichment analysis and found that the target genes of the identified miRNA signature were significantly enriched in the hepatitis B pathway, suggesting its potential involvement in HCC pathogenesis. CONCLUSIONS Our study developed HCCse, a machine learning-based method, to predict survival in HCC patients using miRNA expression profiles. We identified a robust miRNA signature of 32 miRNAs with prognostic and diagnostic value, highlighting their clinical relevance in HCC management and potential involvement in HCC pathogenesis.
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Affiliation(s)
| | - Nikhila Aimalla
- Department of Internal Medicine-Pediatrics, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Ming-Ju Tsai
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Tonia Carter
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Sohyun Jeong
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Zhi Wen
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Sanjay K Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Rohit Sharma
- Department of Surgical Oncology, Marshfield Clinic Health System, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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15
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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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16
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Zhou J, Xiang H, Cao Z. Dual mechanism of Let-7i in tumor progression. Front Oncol 2023; 13:1253191. [PMID: 37829341 PMCID: PMC10565035 DOI: 10.3389/fonc.2023.1253191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/06/2023] [Indexed: 10/14/2023] Open
Abstract
Let-7i regulates tumors primarily by binding to the 3' untranslated region (3' UTR) of mRNA, which indirectly regulates post-transcriptional gene expression. Let-7i also has an epigenetic function via modulating DNA methylation to directly regulate gene expression. Let-7i performs a dual role by inducing both the promotion and inhibition of various malignancies, depending on its target. The mechanism of Let-7i action involves cancer cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition, EV transmission, angiogenesis, autophagy, and drug resistance sensitization. Let-7i is closely related to cancer, and hence, is a potential biomarker for the diagnosis and prognosis of various cancers. Therapeutically, it can be used to promote an anti-cancer immune response by modifying exosomes, thus exerting a tumor-suppressive effect.
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Affiliation(s)
- Jiapei Zhou
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hongjie Xiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Zhiqun Cao
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
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17
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Yang Z, Qi Y, Wang Y, Chen X, Wang Y, Zhang X. Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA-Gene Interaction Network Analysis. Curr Issues Mol Biol 2023; 45:7374-7387. [PMID: 37754250 PMCID: PMC10529263 DOI: 10.3390/cimb45090466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/26/2023] [Accepted: 09/07/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. METHODS We performed a miRNA-gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM-DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. RESULTS By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term "Liver" with a statistical p-value of 1.71 × 10-26. Function enrichment analysis indicated that these genes were significantly overrepresented in the term "monocarboxylic acid metabolic process" with a p-value = 2.94 × 10-18. Two sets (fourteen genes and five miRNAs) were screened by a miRNA-gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. CONCLUSION We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC.
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Affiliation(s)
- Zhiyuan Yang
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
| | - Yuanyuan Qi
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
| | - Yijing Wang
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
| | - Xiangyun Chen
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
| | - Yuerong Wang
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
| | - Xiaoli Zhang
- School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou 310018, China (X.Z.)
- School of Physics and Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
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18
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Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
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19
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Yerukala Sathipati S, Tsai MJ, Shukla SK, Ho SY. Artificial intelligence-driven pan-cancer analysis reveals miRNA signatures for cancer stage prediction. HGG ADVANCES 2023; 4:100190. [PMID: 37124139 PMCID: PMC10130501 DOI: 10.1016/j.xhgg.2023.100190] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
The ability to detect cancer at an early stage in patients who would benefit from effective therapy is a key factor in increasing survivability. This work proposes an evolutionary supervised learning method called CancerSig to identify cancer stage-specific microRNA (miRNA) signatures for early cancer predictions. CancerSig established a compact panel of miRNA signatures as potential markers from 4,667 patients with 15 different types of cancers for the cancer stage prediction, and achieved a mean performance: 10-fold cross-validation accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of 84.27% ± 6.31%, 0.81 ± 0.12, 0.80 ± 0.10, and 0.80 ± 0.06, respectively. The pan-cancer analysis of miRNA signatures suggested that three miRNAs, hsa-let-7i-3p, hsa-miR-362-3p, and hsa-miR-3651, contributed significantly toward stage prediction across 8 cancers, and each of the 67 miRNAs of the panel was a biomarker of stage prediction in more than one cancer. CancerSig may serve as the basis for cancer screening and therapeutic selection..
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Affiliation(s)
- Srinivasulu Yerukala Sathipati
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
- Corresponding author
| | - Ming-Ju Tsai
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Sanjay K. Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Corresponding author
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20
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Yerukala Sathipati S, Ho SY. Survival associated miRNA signature in patients with head and neck carcinomas. Heliyon 2023; 9:e17218. [PMID: 37360084 PMCID: PMC10285236 DOI: 10.1016/j.heliyon.2023.e17218] [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: 03/09/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/28/2023] Open
Abstract
Head and neck carcinoma (HNSC) is often diagnosed at advanced stage, incurring poor patient outcome. Despite of advances in chemoradiation and surgery approaches, limited improvements in survival rates of HNSC have been observed over the last decade. Accumulating evidences have demonstrated the importance of microRNAs (miRNAs) in carcinogenesis. In this context, we sought to identify a miRNA signature associated with the survival time in patients with HNSC. This study proposed a survival estimation method called HNSC-Sig that identified a miRNA signature consists of 25 miRNAs associated with the survival in 133 patients with HNSC. HNSC-Sig achieved 10-fold cross validation a mean correlation coefficient and a mean absolute error of 0.85 ± 0.01 and 0.46 ± 0.02 years, respectively, between actual and estimated survival times. The survival analysis revealed that five miRNAs, hsa-miR-3605-3p, hsa-miR-629-3p, hsa-miR-3127-5p, hsa-miR-497-5p, and hsa-miR-374a-5p, were significantly associated with prognosis in patients with HNSC. Comparing the relative expression difference of top 10 prioritized miRNAs, eight miRNAs, hsa-miR-629-3p, hsa-miR-3127-5p, hsa-miR-221-3p, hsa-miR-501-5p, hsa-miR-491-5p, hsa-miR-149-3p, hsa-miR-3934-5p, and hsa-miR-3170, were significantly expressed between cancer and normal groups. In addition, biological relevance, disease association, and target interactions of the miRNA signature were discussed. Our results suggest that identified miRNA signature have potential to serve as biomarker for diagnosis and clinical practice in HNSC.
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Affiliation(s)
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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21
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EL-shqnqery HE, Mohamed RH, Samir O, Ayoub I, El-Sayed WM, Sayed AA. miRNome of Child A hepatocellular carcinoma in Egyptian patients. Front Oncol 2023; 13:1137585. [PMID: 37168369 PMCID: PMC10164962 DOI: 10.3389/fonc.2023.1137585] [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: 01/04/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) has different etiologies that contribute to its heterogeneity. In regards to the number of HCC patients, Egypt ranks third in Africa and fifteenth worldwide. Despite significant advancements in HCC diagnosis and treatment, the precise biology of the tumor is still not fully understood, which has a negative impact on patient outcomes. METHODS Advances in next-generation sequencing (NGS) have increased our knowledge of the molecular complexity of HCC. RESULTS & DISCUSSION In this research, 16 HCC and 6 tumor adjacent tissues (control) of Child A Egyptian patients were successfully profiled for the expression profile of miRNAs by NGS. Forty-one differentially expressed miRNAs (DEMs) were found by differential expression analysis, with 31 being upregulated and 10 being downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was then conducted on these differentially expressed miRNAs revealing that Sensitivity and specificity analysis showed that hsa-miR-4488, hsa-miR-3178, and hsa-miR-3182 were unique miRNAs as they are expressed in HCC tissues only. These miRNAs were all highly involved in AMPK signaling pathways. However, hsa-miR-214-3p was expressed in control tissues about eight times higher than in cancer tissues and was most abundant in "pathways in cancer and PI3K-Akt signaling pathway" KEGG terms. As promising HCC diagnostic markers, we here suggest hsa-miR-4488, hsa-miR-3178, hsa-miR-3182, and hsa-miR-214-3p. We further urge future research to confirm these markers' diagnostic and prognostic potential as well as their roles in the pathophysiology of HCC.
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Affiliation(s)
- Hend E. EL-shqnqery
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Cairo, Egypt
- Genomics and Epigenomics Program, Department of Basic Research, Children’s Cancer Hospital Egypt, Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Omar Samir
- Genomics and Epigenomics Program, Department of Basic Research, Children’s Cancer Hospital Egypt, Cairo, Egypt
| | - Islam Ayoub
- Department of Hepatopancreato Biliary Surgery, National Liver Institute, Menoufia University, Cairo, Egypt
| | - Wael M. El-Sayed
- Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Ahmed A. Sayed
- Genomics and Epigenomics Program, Department of Basic Research, Children’s Cancer Hospital Egypt, Cairo, Egypt
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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22
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Hosseiniyan Khatibi SM, Najjarian F, Homaei Rad H, Ardalan M, Teshnehlab M, Zununi Vahed S, Pirmoradi S. Key therapeutic targets implicated at the early stage of hepatocellular carcinoma identified through machine-learning approaches. Sci Rep 2023; 13:3840. [PMID: 36882466 PMCID: PMC9992672 DOI: 10.1038/s41598-023-30720-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Early-stage detection plays an essential role in making treatment decisions and identifying dominant molecular mechanisms. We utilized machine learning algorithms to find significant mRNAs and microRNAs (miRNAs) at the early and late stages of HCC. First, pre-processing approaches, including organization, nested cross-validation, cleaning, and normalization were applied. Next, the t-test/ANOVA methods and binary particle swarm optimization were used as a filter and wrapper method in the feature selection step, respectively. Then, classifiers, based on machine learning and deep learning algorithms were utilized to evaluate the discrimination power of selected features (mRNAs and miRNAs) in the classification step. Finally, the association rule mining algorithm was applied to selected features for identifying key mRNAs and miRNAs that can help decode dominant molecular mechanisms in HCC stages. The applied methods could identify key genes associated with the early (e.g., Vitronectin, thrombin-activatable fibrinolysis inhibitor, lactate dehydrogenase D (LDHD), miR-590) and late-stage (e.g., SPRY domain containing 4, regucalcin, miR-3199-1, miR-194-2, miR-4999) of HCC. This research could establish a clear picture of putative candidate genes, which could be the main actors at the early and late stages of HCC.
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Affiliation(s)
- Seyed Mahdi Hosseiniyan Khatibi
- Kidney Research Center, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz, 51665118, Iran.,Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Niyayesh Blvd., Tabriz, Iran.,Rahat Breath and Sleep Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Farima Najjarian
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Homaei Rad
- Rahat Breath and Sleep Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammadreza Ardalan
- Kidney Research Center, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz, 51665118, Iran
| | - Mohammad Teshnehlab
- Department of Electric and Computer Engineering, K.N. Toosi University of Technology, Tehran, Iran
| | - Sepideh Zununi Vahed
- Kidney Research Center, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz, 51665118, Iran.
| | - Saeed Pirmoradi
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Niyayesh Blvd., Tabriz, Iran.
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23
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LncRNA CASC2 Regulate Cell Proliferation and Invasion by Targeting miR-155/SOCS1 Axis in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2023; 2023:8457112. [PMID: 36816357 PMCID: PMC9937765 DOI: 10.1155/2023/8457112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/08/2022] [Accepted: 10/12/2022] [Indexed: 02/12/2023]
Abstract
Long noncoding RNAs (lncRNAs) have been reported to be involved in the development and progression of various human malignancies. However, the role of lncRNA CASC2 in hepatocellular carcinoma (HCC) remains mostly unknown. The aim of this study was to investigate the potential roles and underlying mechanisms of CASC2 in HCC progression. We found that CASC2 expressions were downregulated in HCC tissue samples and cell lines. The clinical assays revealed that lower levels of CASC2 were associated with the TNM stage, lymph node metastasis, and a poorer prognosis specific to HCC patients. Overexpression of CASC2 inhibited the proliferating, migratory, and invasion capacity of HCC cells. Bioinformatics analysis and the luciferase reporter assay revealed that CASC2 worked as a molecular sponge for miR-155. And CASC2 could upregulate SOCS1 expression by inhibiting miR-155 expression in HCC cells. Furthermore, SOCS1 inhibition partially inverses the suppression effect of cell proliferation, migration, and invasion regulated by CASC2 in Huh7 and HepG2 cells. Taken together, our findings identified CASC2 as a tumor suppressor to inhibit HCC development by regulating the miR-155/SOCS1 axis, and CASC2 might be a potential therapeutic target of HCC for future clinical treatment.
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24
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Singh AK, Singh SV, Kumar R, Kumar S, Senapati S, Pandey AK. Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise. World J Hepatol 2023; 15:1-18. [PMID: 36744169 PMCID: PMC9896505 DOI: 10.4254/wjh.v15.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/02/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year, with an estimated 5-year survival rate of 30%-35% after diagnosis. Hepatocellular carcinoma (HCC) constitutes a significant subtype of liver cancer (approximate75%) and is considered primary liver cancer. Treatment for liver cancer mainly depends on the stage of its progression, where surgery including, hepatectomy and liver transplantation, and ablation and radiotherapy are the prime choice. For advanced liver cancer, various drugs and immunotherapy are used as first-line treatment, whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins. Sorafenib and lenvatinib are first-line therapies, while regorafenib and ramucirumab are second-line therapy. Various metabolic and signaling pathways such as Notch, JAK/ STAT, Hippo, TGF-β, and Wnt have played a critical role during HCC progression. Dysbiosis has also been implicated in liver cancer. Drug-induced toxicity is a key obstacle in the treatment of liver cancer, necessitating the development of effective and safe medications, with natural compounds such as resveratrol, curcumin, diallyl sulfide, and others emerging as promising anticancer agents. This review highlights the current status of liver cancer research, signaling pathways, therapeutic targets, current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.
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Affiliation(s)
- Amit Kumar Singh
- Department of Botany, Government Naveen Girls College, Balod (Hemchand Yadav University), Durg, Chattisgarh, India
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Shashank Kumar
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sabyasachi Senapati
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India.
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25
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Goswami B, Ahuja D, Pastré D, Ray PS. p53 and HuR combinatorially control the biphasic dynamics of microRNA-125b in response to genotoxic stress. Commun Biol 2023; 6:110. [PMID: 36707647 PMCID: PMC9883498 DOI: 10.1038/s42003-023-04507-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 01/19/2023] [Indexed: 01/29/2023] Open
Abstract
Post-transcriptional regulation of p53, by the microRNA miR-125b and the RNA-binding protein HuR, controls p53 expression under genotoxic stress. p53 mRNA translation is repressed by miR-125b, tightly regulating its basal level of expression. The repression is relieved upon DNA damage by a decrease in miR-125b level, contributing to pulsatile expression of p53. The pulse of p53, as also of HuR, in response to UV irradiation coincides with a time-dependent biphasic change in miR-125b level. We show that the cause for the decrease in miR-125b level immediately post DNA-damage is enhanced exosomal export mediated by HuR. The subsequent increase in miR-125b level is due to p53-mediated transcriptional upregulation and enhanced processing, demonstrating miR-125b as a transcriptional and processing target of p53. p53 activates the transcription of primary miR-125b RNA from a cryptic promoter in response to UV irradiation. Together, these regulatory processes constitute reciprocal feedback loops that determine the biphasic change in miR-125b level, ultimately contributing to the fine-tuned temporal regulation of p53 expression in response to genotoxic stress.
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Affiliation(s)
- Binita Goswami
- grid.417960.d0000 0004 0614 7855Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, Nadia, 741246 West Bengal India
| | - Deepika Ahuja
- grid.417960.d0000 0004 0614 7855Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, Nadia, 741246 West Bengal India
| | - David Pastré
- grid.460789.40000 0004 4910 6535SABNP, Univ Evry, INSERM U1204, Université Paris-Saclay, 91025 Evry, France
| | - Partho Sarothi Ray
- grid.417960.d0000 0004 0614 7855Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, Nadia, 741246 West Bengal India
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26
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Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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27
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Mokhtari F, Kaboosi H, Mohebbi SR, Asadzadeh Aghdaei H, Zali MRZ, Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran, Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Evaluation of Circulating MicroRNA-222 in Patients with Chronic Hepatitis B virus Infection as a Potential Noninvasive Diagnostic Biomarker. IRANIAN JOURNAL OF MEDICAL MICROBIOLOGY 2022. [DOI: 10.30699/ijmm.16.6.543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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28
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Pane K, Zanfardino M, Grimaldi AM, Baldassarre G, Salvatore M, Incoronato M, Franzese M. Discovering Common miRNA Signatures Underlying Female-Specific Cancers via a Machine Learning Approach Driven by the Cancer Hallmark ERBB. Biomedicines 2022; 10:biomedicines10061306. [PMID: 35740327 PMCID: PMC9219956 DOI: 10.3390/biomedicines10061306] [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: 04/14/2022] [Revised: 05/25/2022] [Accepted: 05/29/2022] [Indexed: 11/29/2022] Open
Abstract
Big data processing, using omics data integration and machine learning (ML) methods, drive efforts to discover diagnostic and prognostic biomarkers for clinical decision making. Previously, we used the TCGA database for gene expression profiling of breast, ovary, and endometrial cancers, and identified a top-scoring network centered on the ERBB2 gene, which plays a crucial role in carcinogenesis in the three estrogen-dependent tumors. Here, we focused on microRNA expression signature similarity, asking whether they could target the ERBB family. We applied an ML approach on integrated TCGA miRNA profiling of breast, endometrium, and ovarian cancer to identify common miRNA signatures differentiating tumor and normal conditions. Using the ML-based algorithm and the miRTarBase database, we found 205 features and 158 miRNAs targeting ERBB isoforms, respectively. By merging the results of both databases and ranking each feature according to the weighted Support Vector Machine model, we prioritized 42 features, with accuracy (0.98), AUC (0.93–95% CI 0.917–0.94), sensitivity (0.85), and specificity (0.99), indicating their diagnostic capability to discriminate between the two conditions. In vitro validations by qRT-PCR experiments, using model and parental cell lines for each tumor type showed that five miRNAs (hsa-mir-323a-3p, hsa-mir-323b-3p, hsa-mir-331-3p, hsa-mir-381-3p, and hsa-mir-1301-3p) had expressed trend concordance between breast, ovarian, and endometrium cancer cell lines compared with normal lines, confirming our in silico predictions. This shows that an integrated computational approach combined with biological knowledge, could identify expression signatures as potential diagnostic biomarkers common to multiple tumors.
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Affiliation(s)
- Katia Pane
- IRCCS Synlab SDN, 80143 Naples, Italy; (K.P.); (A.M.G.); (M.S.); (M.I.); (M.F.)
| | - Mario Zanfardino
- IRCCS Synlab SDN, 80143 Naples, Italy; (K.P.); (A.M.G.); (M.S.); (M.I.); (M.F.)
- Correspondence:
| | - Anna Maria Grimaldi
- IRCCS Synlab SDN, 80143 Naples, Italy; (K.P.); (A.M.G.); (M.S.); (M.I.); (M.F.)
| | - Gustavo Baldassarre
- Molecular Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, 33081 Aviano, Italy;
| | - Marco Salvatore
- IRCCS Synlab SDN, 80143 Naples, Italy; (K.P.); (A.M.G.); (M.S.); (M.I.); (M.F.)
| | | | - Monica Franzese
- IRCCS Synlab SDN, 80143 Naples, Italy; (K.P.); (A.M.G.); (M.S.); (M.I.); (M.F.)
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29
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Yerukala Sathipati S, Tsai MJ, Shukla SK, Ho SY, Liu Y, Beheshti A. MicroRNA signature for estimating the survival time in patients with bladder urothelial carcinoma. Sci Rep 2022; 12:4141. [PMID: 35264666 PMCID: PMC8907292 DOI: 10.1038/s41598-022-08082-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 03/02/2022] [Indexed: 11/13/2022] Open
Abstract
Bladder urothelial carcinoma (BLC) is one of the most common cancers in men, and its heterogeneity challenges the treatment to cure this disease. Recently, microRNAs (miRNAs) gained promising attention as biomarkers due to their potential roles in cancer biology. Identifying survival-associated miRNAs may help identify targets for therapeutic interventions in BLC. This work aims to identify a miRNA signature that could estimate the survival in patients with BLC. We developed a survival estimation method called BLC-SVR based on support vector regression incorporated with an optimal feature selection algorithm to select a robust set of miRNAs as a signature to estimate the survival in patients with BLC. BLC-SVR identified a miRNA signature consisting of 29 miRNAs and obtained a mean squared correlation coefficient and mean absolute error of 0.79 ± 0.02 and 0.52 ± 0.32 year between actual and estimated survival times, respectively. The prediction performance of BLC-SVR had a better estimation capability than other standard regression methods. In the identified miRNA signature, 14 miRNAs, hsa-miR-432-5p, hsa-let-7e-3p, hsa-miR-652-3p, hsa-miR-629-5p, and hsa-miR-203a-3p, hsa-miR-129-5p, hsa-miR-769-3p, hsa-miR-570-3p, hsa-miR-320c, hsa-miR-642a-5p, hsa-miR-496, hsa-miR-5480-3p, hsa-miR-221-5p, and hsa-miR-7-1-3p, were found to be good biomarkers for BLC diagnosis; and the six miRNAs, hsa-miR-652-5p, hsa-miR-193b-5p, hsa-miR-129-5p, hsa-miR-143-5p, hsa-miR-496, and hsa-miR-7-1-3p, were found to be good biomarkers of prognosis. Further bioinformatics analysis of this miRNA signature demonstrated its importance in various biological pathways and gene ontology annotation. The identified miRNA signature would further help in understanding of BLC diagnosis and prognosis in the development of novel miRNA-target based therapeutics in BLC.
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Affiliation(s)
| | - Ming-Ju Tsai
- Hinda and Arthur Marcus Institute for Aging Research at Hebrew Senior Life, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Sanjay K Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi Liu
- Biomedical Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Afshin Beheshti
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, 94035, USA.,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
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30
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El-Nakeep S. Molecular and genetic markers in hepatocellular carcinoma: In silico analysis to clinical validation (current limitations and future promises). World J Gastrointest Pathophysiol 2022; 13:1-14. [PMID: 35116176 PMCID: PMC8788164 DOI: 10.4291/wjgp.v13.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second cause of cancer-related mortality. The diagnosis of HCC depends mainly on -fetoprotein, which is limited in its diagnostic and screening capabilities. There is an urgent need for a biomarker that detects early HCC to give the patients a chance for curative treatment. New targets of therapy could enhance survival and create future alternative curative methods. In silico analysis provides both; discovery of biomarkers, and understanding of the molecular pathways, to pave the way for treatment development. This review discusses the role of in silico analysis in the discovery of biomarkers, molecular pathways, and the role the author has contributed to this area of research. It also discusses future aspirations and current limitations. A literature review was conducted on the topic using various databases (PubMed, Science Direct, and Wiley Online Library), searching in various reviews, and editorials on the topic, with overviewing the author's own published and unpublished work. This review discussed the steps of the validation process from in silico analysis to in vivo validation, to incorporation into clinical practice guidelines. In addition, reviewing the recent lines of research of bioinformatic studies related to HCC. In conclusion, the genetic, molecular and epigenetic markers discoveries are hot areas for HCC research. Bioinformatics will enhance our ability to accomplish this understanding in the near future. We face certain limitations that we need to overcome.
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Affiliation(s)
- Sarah El-Nakeep
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt
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31
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Yerukala Sathipati S, Shukla SK, Ho SY. Tracking the amino acid changes of spike proteins across diverse host species of severe acute respiratory syndrome coronavirus 2. iScience 2022; 25:103560. [PMID: 34877480 PMCID: PMC8638202 DOI: 10.1016/j.isci.2021.103560] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 11/02/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022] Open
Abstract
Knowledge of the host-specific properties of the spike protein is of crucial importance to understand the adaptability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect multiple species and alter transmissibility, particularly in humans. Here, we propose a spike protein predictor SPIKES incorporating with an inheritable bi-objective combinatorial genetic algorithm to identify the biochemical properties of spike proteins and determine their specificity to human hosts. SPIKES identified 20 informative physicochemical properties of the spike protein, including information measures for alpha helix and relative mutability, and amino acid and dipeptide compositions, which have shown compositional difference at the amino acid sequence level between human and diverse animal coronaviruses. We suggest that alterations of these amino acids between human and animal coronaviruses may provide insights into the development and transmission of SARS-CoV-2 in human and other species and support the discovery of targeted antiviral therapies.
Differences exist in the amino acids within the S protein of diverse host species CoVs We developed SPIKES to identify informative properties of S protein SARS-CoV-2 variants have amino acid changes that alter infection and transmission The SPIKES identified changes in S protein properties from animal to human host CoVs
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Affiliation(s)
- Srinivasulu Yerukala Sathipati
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
- Corresponding author
| | - Sanjay K. Shukla
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Center for intelligent Drug Systems and Smart Bio-Devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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32
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Li X, Ren Y, Liu D, Yu X, Chen K. Role of miR-100-5p and CDC25A in breast carcinoma cells. PeerJ 2022; 9:e12263. [PMID: 35036112 PMCID: PMC8734459 DOI: 10.7717/peerj.12263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 09/16/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To inquiry about mechanism of miR-100-5p/CDC25A axis in breast carcinoma (BC), thus offering a new direction for BC targeted treatment. METHODS qRT-PCR was employed to explore miR-100-5p and CDC25A mRNA levels. Western blot was employed for detecting protein expression of CDC25A. Targeting relationship of miR-100-5p and CDC25A was verified by dual-luciferase assay. In vitro experiments were used for assessment of cell functions. RESULTS In BC tissue and cells, miR-100-5p was significantly lowly expressed (P < 0.05) while CDC25A was highly expressed. Besides, miR-100-5p downregulated CDC25A level. miR-100-5p had a marked influence on the prognosis of patients. The forced miR-100-5p expression hindered BC cell proliferation, migration and invasion, and facilitated cell apoptosis. Upregulated miR-100-5p weakened promotion of CDC25A on BC cell growth. CONCLUSION Together, these findings unveiled that CDC25A may be a key target of miR-100-5p that mediated progression of BC cells. Hence, miR-100-5p overexpression or CDC25A suppression may contribute to BC diagnosis.
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Affiliation(s)
- Xiaoping Li
- Faculty of Medicine, Macau University of Science and Technology, Macau, China.,Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang province, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China
| | - Donghong Liu
- Department of Laboratory Medicine, Hangyan hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang, China
| | - Xi Yu
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Keda Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang province, China
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33
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Bai H, Cheng Y, Che J. Pharmacokinetics and Disposition of Heparin-Binding Growth Factor Midkine Antisense Oligonucleotide Nanoliposomes in Experimental Animal Species and Prediction of Human Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model. Front Pharmacol 2021; 12:769538. [PMID: 34803711 PMCID: PMC8595129 DOI: 10.3389/fphar.2021.769538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/11/2021] [Indexed: 12/02/2022] Open
Abstract
Encapsulating the antisense oligonucleotide drug MK-ASODN with nanoliposomes greatly improved its potency and targeting to the heparin-binding growth factor midkine. The disposition and pharmacokinetic (PK) parameters of MK-ASODN nanoliposomes were studied in monkeys and rats, and the human PK parameters were predicted based on preclinical data using a physiologically based pharmacokinetic (PBPK) model. Following intravenous injection, the drug plasma concentration rapidly declined in a multiexponential manner, and the drug was rapidly transferred to tissues from the circulation. The terminal t1/2 in plasma was clearly longer than that of the unmodified antisense nucleic acid drug. According to the AUC,MK-ASODN nanoliposomes were mainly distributed in the kidney, spleen, and liver. . MK-ASODN nanoliposomes were highly plasma protein bound, limiting their urinary excretion. Very little MK-ASODN nanoliposomes were detected in urine or feces. The plasma disposition of MK-ASODN nanoliposomes appeared nonlinear over the studied dose range of 11.5–46 mg kg−1. The monkey PBPK model of MK-ASODN nanoliposomes was well established and successfully extrapolated to predict MK-ASODN nanoliposome PK in humans. These disposition and PK data support further development in phase I clinical studies.
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Affiliation(s)
- Haihong Bai
- Beijing Institute of Microbiology and Epidemiology, Beijing, China.,Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yuanguo Cheng
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Jinjing Che
- Beijing Institute of Microbiology and Epidemiology, Beijing, China.,Beijing Institution of Pharmacology and Toxicology, Beijing, China
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34
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Lee IC, Huang JY, Chen TC, Yen CH, Chiu NC, Hwang HE, Huang JG, Liu CA, Chau GY, Lee RC, Hung YP, Chao Y, Ho SY, Huang YH. Evolutionary Learning-Derived Clinical-Radiomic Models for Predicting Early Recurrence of Hepatocellular Carcinoma after Resection. Liver Cancer 2021; 10:572-582. [PMID: 34950180 PMCID: PMC8647074 DOI: 10.1159/000518728] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/24/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Current prediction models for early recurrence of hepatocellular carcinoma (HCC) after surgical resection remain unsatisfactory. The aim of this study was to develop evolutionary learning-derived prediction models with interpretability using both clinical and radiomic features to predict early recurrence of HCC after surgical resection. METHODS Consecutive 517 HCC patients receiving surgical resection with available contrast-enhanced computed tomography (CECT) images before resection were retrospectively enrolled. Patients were randomly assigned to a training set (n = 362) and a test set (n = 155) in a ratio of 7:3. Tumor segmentation of all CECT images including noncontrast phase, arterial phase, and portal venous phase was manually performed for radiomic feature extraction. A novel evolutionary learning-derived method called genetic algorithm for predicting recurrence after surgery of liver cancer (GARSL) was proposed to design prediction models for early recurrence of HCC within 2 years after surgery. RESULTS A total of 143 features, including 26 preoperative clinical features, 5 postoperative pathological features, and 112 radiomic features were used to develop GARSL preoperative and postoperative models. The area under the receiver operating characteristic curves (AUCs) for early recurrence of HCC within 2 years were 0.781 and 0.767, respectively, in the training set, and 0.739 and 0.741, respectively, in the test set. The accuracy of GARSL models derived from the evolutionary learning method was significantly better than models derived from other well-known machine learning methods or the early recurrence after surgery for liver tumor (ERASL) preoperative (AUC = 0.687, p < 0.001 vs. GARSL preoperative) and ERASL postoperative (AUC = 0.688, p < 0.001 vs. GARSL postoperative) models using clinical features only. CONCLUSION The GARSL models using both clinical and radiomic features significantly improved the accuracy to predict early recurrence of HCC after surgical resection, which was significantly better than other well-known machine learning-derived models and currently available clinical models.
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Affiliation(s)
- I-Cheng Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
| | - Jo-Yu Huang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Ting-Chun Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Chia-Heng Yen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan,Institute of Computer Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Nai-Chi Chiu
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsuen-En Hwang
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jia-Guan Huang
- National Taiwan University School of Medicine, Taipei, Taiwan
| | - Chien-An Liu
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Gar-Yang Chau
- Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Rheun-Chuan Lee
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ping Hung
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan,Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan,Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan,College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan,*Shinn-Ying Ho,
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,**Yi-Hsiang Huang,
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Lin Y, Yerukala Sathipati S, Ho SY. Predicting the Risk Genes of Autism Spectrum Disorders. Front Genet 2021; 12:665469. [PMID: 34194469 PMCID: PMC8236850 DOI: 10.3389/fgene.2021.665469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/29/2021] [Indexed: 11/16/2022] Open
Abstract
Autism spectrum disorder (ASD) refers to a wide spectrum of neurodevelopmental disorders that emerge during infancy and continue throughout a lifespan. Although substantial efforts have been made to develop therapeutic approaches, core symptoms persist lifelong in ASD patients. Identifying the brain temporospatial regions where the risk genes are expressed in ASD patients may help to improve the therapeutic strategies. Accordingly, this work aims to predict the risk genes of ASD and identify the temporospatial regions of the brain structures at different developmental time points for exploring the specificity of ASD gene expression in the brain that would help in possible ASD detection in the future. A dataset consisting of 13 developmental stages ranging from 8 weeks post-conception to 8 years from 26 brain structures was retrieved from the BrainSpan atlas. This work proposes a support vector machine–based risk gene prediction method ASD-Risk to distinguish the risk genes of ASD and non-ASD genes. ASD-Risk used an optimal feature selection algorithm called inheritable bi-objective combinatorial genetic algorithm to identify the brain temporospatial regions for prediction of the risk genes of ASD. ASD-Risk achieved a 10-fold cross-validation accuracy, sensitivity, specificity, area under a receiver operating characteristic curve, and a test accuracy of 81.83%, 0.84, 0.79, 0.84, and 72.27%, respectively. We prioritized the temporospatial features according to their contribution to the prediction accuracy. The top identified temporospatial regions of the brain for risk gene prediction included the posteroventral parietal cortex at 13 post-conception weeks feature. The identified temporospatial features would help to explore the risk genes that are specifically expressed in different brain regions of ASD patients.
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Affiliation(s)
- Yenching Lin
- Interdisciplinary Neuroscience Ph.D. Program, National Chiao Tung University, Hsinchu, Taiwan
| | - Srinivasulu Yerukala Sathipati
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States.,Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.,Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Shinn-Ying Ho
- Interdisciplinary Neuroscience Ph.D. Program, National Chiao Tung University, Hsinchu, Taiwan.,Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.,Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Center For Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Chiao Tung University, Hsinchu, Taiwan
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Dessie EY, Tsai JJP, Chang JG, Ng KL. A novel miRNA-based classification model of risks and stages for clear cell renal cell carcinoma patients. BMC Bioinformatics 2021; 22:270. [PMID: 34058987 PMCID: PMC8323484 DOI: 10.1186/s12859-021-04189-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 05/12/2021] [Indexed: 12/17/2022] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma and patients at advanced stage showed poor survival rate. Despite microRNAs (miRNAs) are used as potential biomarkers in many cancers, miRNA biomarkers for predicting the tumor stage of ccRCC are still limitedly identified. Therefore, we proposed a new integrated machine learning (ML) strategy to identify a novel miRNA signature related to tumor stage and prognosis of ccRCC patients using miRNA expression profiles. A multivariate Cox regression model with three hybrid penalties including Least absolute shrinkage and selection operator (Lasso), Adaptive lasso and Elastic net algorithms was used to screen relevant prognostic related miRNAs. The best subset regression (BSR) model was used to identify optimal prognostic model. Five ML algorithms were used to develop stage classification models. The biological significance of the miRNA signature was analyzed by utilizing DIANA-mirPath. Results A four-miRNA signature associated with survival was identified and the expression of this signature was strongly correlated with high risk patients. The high risk patients had unfavorable overall survival compared with the low risk group (HR = 4.523, P-value = 2.86e−08). Univariate and multivariate analyses confirmed independent and translational value of this predictive model. A combined ML algorithm identified six miRNA signatures for cancer staging prediction. After using the data balancing algorithm SMOTE, the Support Vector Machine (SVM) algorithm achieved the best classification performance (accuracy = 0.923, sensitivity = 0.927, specificity = 0.919, MCC = 0.843) when compared with other classifiers. Furthermore, enrichment analysis indicated that the identified miRNA signature involved in cancer-associated pathways. Conclusions A novel miRNA classification model using the identified prognostic and tumor stage associated miRNA signature will be useful for risk and stage stratification for clinical practice, and the identified miRNA signature can provide promising insight to understand the progression mechanism of ccRCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12859-021-04189-2.
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Affiliation(s)
- Eskezeia Y Dessie
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.,Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, Taiwan
| | - Jeffrey J P Tsai
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Jan-Gowth Chang
- Department of Laboratory Medicine, China Medical University, Taichung, Taiwan.
| | - Ka-Lok Ng
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, Taiwan.
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Yerukala Sathipati S, Ho SY. Identification and Characterization of Species-Specific Severe Acute Respiratory Syndrome Coronavirus 2 Physicochemical Properties. J Proteome Res 2021; 20:2942-2952. [PMID: 33856796 PMCID: PMC8056951 DOI: 10.1021/acs.jproteome.1c00156] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Indexed: 12/28/2022]
Abstract
There is an urgent need to elucidate the underlying mechanisms of coronavirus disease (COVID-19) so that vaccines and treatments can be devised. Severe acute respiratory syndrome coronavirus 2 has genetic similarity with bats and pangolin viruses, but a comprehensive understanding of the functions of its proteins at the amino acid sequence level is lacking. A total of 4320 sequences of human and nonhuman coronaviruses was retrieved from the Global Initiative on Sharing All Influenza Data and the National Center for Biotechnology Information. This work proposes an optimization method COVID-Pred with an efficient feature selection algorithm to classify the species-specific coronaviruses based on physicochemical properties (PCPs) of their sequences. COVID-Pred identified a set of 11 PCPs using a support vector machine and achieved 10-fold cross-validation and test accuracies of 99.53% and 97.80%, respectively. These findings could provide key insights into understanding the driving forces during the course of infection and assist in developing effective therapies.
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Affiliation(s)
- Srinivasulu Yerukala Sathipati
- Center for Precision Medicine Research,
Marshfield Clinic Research Institute, Marshfield, Wisconsin
54449, United States
- Institute of Bioinformatics and Systems Biology,
National Chiao Tung University, Hsinchu 300,
Taiwan
- Institute of Population Health Sciences,
National Health Research Institutes, Miaoli 350,
Taiwan
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology,
National Chiao Tung University, Hsinchu 300,
Taiwan
- Institute of Bioinformatics and Systems Biology,
National Yang Ming Chiao Tung University, Hsinchu 300,
Taiwan
- Department of Biological Science and Technology,
National Yang Ming Chiao Tung University, Hsinchu 300,
Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices
(IDSB), National Yang Ming Chiao Tung University,
Hsinchu 300, Taiwan
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Sathipati SY, Ho SY. Identification of the miRNA signature associated with survival in patients with ovarian cancer. Aging (Albany NY) 2021; 13:12660-12690. [PMID: 33910165 PMCID: PMC8148489 DOI: 10.18632/aging.202940] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/23/2021] [Indexed: 12/22/2022]
Abstract
Ovarian cancer is a major gynaecological malignant tumor associated with a high mortality rate. Identifying survival-related variants may improve treatment and survival in patients with ovarian cancer. In this work, we proposed a support vector regression (SVR)-based method called OV-SURV, which is incorporated with an inheritable bi-objective combinatorial genetic algorithm for feature selection to identify a miRNA signature associated with survival in patients with ovarian cancer. There were 209 patients with miRNA expression profiles and survival information of ovarian cancer retrieved from The Cancer Genome Atlas database. OV-SURV achieved a mean correlation coefficient of 0.77±0.01and a mean absolute error of 0.69±0.02 years using 10-fold cross-validation. Analysis of the top ranked miRNAs revealed that the miRNAs, hsa-let-7f, hsa-miR-1237, hsa-miR-98, hsa-miR-933, and hsa-miR-889, were significantly associated with the survival in patients with ovarian cancer. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that four of these miRNAs, hsa-miR-182, hsa-miR-34a, hsa-miR-342, and hsa-miR-1304, were highly enriched in fatty acid biosynthesis, and the five miRNAs, hsa-let-7f, hsa-miR-34a, hsa-miR-342, hsa-miR-1304, and hsa-miR-24, were highly enriched in fatty acid metabolism. The prediction model with the identified miRNA signature consisting of prognostic biomarkers can benefit therapeutic decision making of ovarian cancer.
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Affiliation(s)
- Srinivasulu Yerukala Sathipati
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA.,Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.,Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.,Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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Females and Males Show Differences in Early-Stage Transcriptomic Biomarkers of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma. Diagnostics (Basel) 2021; 11:diagnostics11020347. [PMID: 33669819 PMCID: PMC7922551 DOI: 10.3390/diagnostics11020347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/25/2022] Open
Abstract
The incidence and mortality rates of lung cancers are different between females and males. Therefore, sex information should be an important part of how to train and optimize a diagnostic model. However, most of the existing studies do not fully utilize this information. This study carried out a comparative investigation between sex-specific models and sex-independent models. Three feature selection algorithms and five classifiers were utilized to evaluate the contribution of the sex information to the detection of early-stage lung cancers. Both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) showed that the sex-specific models outperformed the sex-independent detection of early-stage lung cancers. The Venn plots suggested that females and males shared only a few transcriptomic biomarkers of early-stage lung cancers. Our experimental data suggested that sex information should be included in optimizing disease diagnosis models.
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