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1
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Glaser K, Schepers EJ, Zwolshen HM, Lake CM, Timchenko NA, Karns RA, Cairo S, Geller JI, Tiao GM, Bondoc AJ. EZH2 is a key component of hepatoblastoma tumor cell growth. Pediatr Blood Cancer 2024; 71:e30774. [PMID: 37990130 PMCID: PMC10842061 DOI: 10.1002/pbc.30774] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/17/2023] [Accepted: 11/06/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND Enhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time-specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2-independent mechanism via proto-oncogenic, direct protein interaction, including β-catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2-independent manner. METHODS AND RESULTS We demonstrate that EZH2 promotes proliferation in HB tumor-derived cell lines through interaction with β-catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene-expression patterns and interaction with SUZ12, a PRC2 component, and β-catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation. CONCLUSIONS EZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β-catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.
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Affiliation(s)
- Kathryn Glaser
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Emily J Schepers
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Harrison M Zwolshen
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Charissa M Lake
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Nikolai A Timchenko
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Rebekah A Karns
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Stefano Cairo
- Champions Oncology, US Research Headquarters, Rockville, Maryland, USA
| | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Gregory M Tiao
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alexander J Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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2
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Sartorius K, Sartorius B, Winkler C, Chuturgoon A, Shen TW, Zhao Y, An P. Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study. Int J Mol Sci 2024; 25:975. [PMID: 38256049 PMCID: PMC10815595 DOI: 10.3390/ijms25020975] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2001, South Africa
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, QLD 4102, Australia
| | - Cheryl Winkler
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
| | - Tsai-Wei Shen
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Yongmei Zhao
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Ping An
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
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3
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Liu F, Liao Z, Zhang Z. MYC in liver cancer: mechanisms and targeted therapy opportunities. Oncogene 2023; 42:3303-3318. [PMID: 37833558 DOI: 10.1038/s41388-023-02861-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023]
Abstract
MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.
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Affiliation(s)
- Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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4
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Sak R, Ozbalci D, Alanoglu EG, Ozturk KH. Malignancy-related mir-210, mir-373 and let-7 levels are affected in iron deficiency anemia. Afr Health Sci 2023; 23:245-253. [PMID: 38357103 PMCID: PMC10862612 DOI: 10.4314/ahs.v23i3.30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Background Hypoxia is the hallmark of iron deficiency anemia (IDA) and in hypoxic environment, significant changes are observed in malignancy-related microRNAs (miRNA). Our aim is to examine whether there is any difference in the levels of miR-210, miR-373 and let-7, which are directly related to malignancies in patients with IDA. Methods Thirty-five female patients with IDA between the ages of 18-65 and 10 healthy controls were included in the study. Patients who received oral iron therapy, who had inflammatory disease, and who were pregnant were excluded from the study. Student t Test was used for comparing variables with normal distribution in two independent groups, and Mann-Whitney U Test was used for variables without normal distribution. Comparison of categorical data was made using the chi-square test. Results The mean hemoglobin and ferritin level were 10,78±0,93 and 6.28±5,76 respectively. Plasma miR-210 expression were found as -7.27±2.23 and -6.15±0,88 in IDA and control group respectively (p = 0.022). Plasma miRNA-373 were -7.36±2,58 and -6,96±1,93 and let-7 expression were 2.14±2,15 and 3,57±2,21 in IDA and control group. (p = 0.65 and p = 0.20, respectively). Conclusions Plasma miR-210 expression was significantly up-regulated and miR-373 and let-7 expression was down-regulated, though insignificantly, in IDA group.
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Affiliation(s)
- Ruveyda Sak
- City Hospital of Etlik, Department of Rheumatology
| | - Demircan Ozbalci
- Suleyman Demirel University School of Medicine, Department of Hematology
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5
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O'Neill AF, Meyers RL, Katzenstein HM, Geller JI, Tiao GM, López-Terrada D, Malogolowkin M. Children's Oncology Group's 2023 blueprint for research: Liver tumors. Pediatr Blood Cancer 2023; 70 Suppl 6:e30576. [PMID: 37495540 PMCID: PMC10529117 DOI: 10.1002/pbc.30576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/28/2023]
Abstract
Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.
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Affiliation(s)
- Allison F O'Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Rebecka L Meyers
- Division of Pediatric Surgery, University of Utah, Salt Lake City, Utah, USA
| | | | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Greg M Tiao
- Division of Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Dolores López-Terrada
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, Texas, USA
| | - Marcio Malogolowkin
- Pediatric Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California, USA
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6
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Fang J, Singh S, Cheng C, Natarajan S, Sheppard H, Abu-Zaid A, Durbin AD, Lee HW, Wu Q, Steele J, Connelly JP, Jin H, Chen W, Fan Y, Pruett-Miller SM, Rehg JE, Koo SC, Santiago T, Emmons J, Cairo S, Wang R, Glazer ES, Murphy AJ, Chen T, Davidoff AM, Armengol C, Easton J, Chen X, Yang J. Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma. Nat Commun 2023; 14:4003. [PMID: 37414763 PMCID: PMC10326052 DOI: 10.1038/s41467-023-39717-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2023] [Indexed: 07/08/2023] Open
Abstract
A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma.
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Affiliation(s)
- Jie Fang
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Shivendra Singh
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Changde Cheng
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Sivaraman Natarajan
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Heather Sheppard
- Comparative Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ahmed Abu-Zaid
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Adam D Durbin
- Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Ha Won Lee
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Qiong Wu
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jacob Steele
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jon P Connelly
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hongjian Jin
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Wenan Chen
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Shondra M Pruett-Miller
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jerold E Rehg
- Comparative Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Selene C Koo
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Teresa Santiago
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Joseph Emmons
- VPC Diagnostic Laboratory, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Stefano Cairo
- Champions Oncology, 1330 Piccard dr, Rockville, MD, USA
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Disease, Hematology/Oncology & BMT, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Evan S Glazer
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Andrew M Davidoff
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, 910 Madison Ave., Suite 325, Memphis, TN, USA
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA
- Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Carolina Armengol
- Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Translational Program in Cancer Research (CARE), Badalona, Spain
- CIBER, Hepatic and Digestive Diseases, Barcelona, Spain
- CIBERehd, Madrid, Spain
| | - John Easton
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Xiang Chen
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
| | - Jun Yang
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
- St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
- Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
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7
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PRDM16, Negatively Regulated by miR-372-3p, Suppresses Cell Proliferation and Invasion in Prostate Cancer. Andrologia 2023. [DOI: 10.1155/2023/9821829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023] Open
Abstract
Prostate cancer (PCa) is one of the most prevalent malignant tumors. The alternation of microRNA (miRNA) expression is associated with prostate cancer progression, whereas its way to influence progression of prostate cancer remains elusive. The expression levels of PRDM16 mRNA and miR-372-3p in PCa cell lines were analyzed using qRT-PCR. The protein expression of PRDM16 in PCa cell lines was also analyzed using western blot. CCK-8, wound healing, and Transwell assays were applied to examine cell proliferation, migration, and invasion in prostate cancer cells, respectively. Dual-luciferase reporter assay was utilized to validate the interaction between miR-372-3p and PRDM16. In the present study, markedly decreased PRDM16 mRNA and protein expression levels were observed in prostate cancer cells. PRDM16 overexpression hampered cellular proliferation, migration, and invasion, while silencing PRDM16 had the opposite effect. Moreover, miR-372-3p could target the regulation expression of PRDM16. Rescue experiments demonstrated that upregulating miR-372-3p conspicuously restored the inhibitory effect of increased PRDM16 on cell proliferation, migration, and invasion in PCa. Overall, our study clarifies the biological role of miR-372-3p/PRDM16 axis in prostate cancer progression, which may be effective biomarkers for clinical treatment of prostate cancer.
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8
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Prochownik EV. Regulation of Normal and Neoplastic Proliferation and Metabolism by the Extended Myc Network. Cells 2022; 11:3974. [PMID: 36552737 PMCID: PMC9777120 DOI: 10.3390/cells11243974] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/30/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
The Myc Network, comprising a small assemblage of bHLH-ZIP transcription factors, regulates many hundreds to thousands of genes involved in proliferation, energy metabolism, translation and other activities. A structurally and functionally related set of factors known as the Mlx Network also supervises some of these same functions via the regulation of a more limited but overlapping transcriptional repertoire. Target gene co-regulation by these two Networks is the result of their sharing of three members that suppress target gene expression as well as by the ability of both Network's members to cross-bind one another's consensus DNA sites. The two Networks also differ in that the Mlx Network's control over transcription is positively regulated by several glycolytic pathway intermediates and other metabolites. These distinctive properties, functions and tissue expression patterns potentially allow for sensitive control of gene regulation in ways that are differentially responsive to environmental and metabolic cues while allowing for them to be both rapid and of limited duration. This review explores how such control might occur. It further discusses how the actual functional dependencies of the Myc and Mlx Networks rely upon cellular context and how they may differ between normal and neoplastic cells. Finally, consideration is given to how future studies may permit a more refined understanding of the functional interrelationships between the two Networks.
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Affiliation(s)
- Edward V. Prochownik
- Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
- The Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- The UPMC Hillman Comprehensive Cancer Center, Pittsburgh, PA 15232, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15224, USA
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9
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Vishnubalaji R, Shaath H, Al-Alwan M, Abdelalim EM, Alajez NM. Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers. Semin Cancer Biol 2022; 87:1-16. [PMID: 36354097 DOI: 10.1016/j.semcancer.2022.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis. We provide our view on the potential to interfere with key miRNA-TF networks through the use of RNA-based therapeutics as single agents or in combination with other therapeutic strategies, to abrogate the CSC state and render tumor cells more responsive to standard and targeted therapies.
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Affiliation(s)
- Radhakrishnan Vishnubalaji
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Hibah Shaath
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Monther Al-Alwan
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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10
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Yin G, Yan C, Hao J, Zhang C, Wang P, Zhao C, Cai S, Meng B, Zhang A, Li L. PRDM16, negatively regulated by miR-372-3p, suppresses cell proliferation and invasion in prostate cancer. Andrologia 2022:e14529. [PMID: 35858224 DOI: 10.1111/and.14529] [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: 03/03/2022] [Revised: 05/27/2022] [Accepted: 06/26/2022] [Indexed: 11/26/2022] Open
Abstract
Prostate cancer (PCa) is one of the most prevalent malignant tumours. The alternation of microRNAs (miRNAs) expression is associated with prostate cancer progression, whereas its way to influence progression of prostate cancer remains elusive. The expression levels of PRDM16 mRNA and miR-372-3p in PCa cell lines were analysed using qRT-PCR. The protein expression of PRDM16 in PCa cell lines was also analysed using Western blot. CCK-8, wound healing and Transwell assays were applied to examine cell proliferation, migration, and invasion in prostate cancer cells, respectively. Dual-luciferase reporter assay was utilised to validate the interaction between miR-372-3p and PRDM16. In the present study, markedly decreased PRDM16 mRNA and protein expression levels were observed in prostate cancer cells. PRDM16 overexpression hampered cellular proliferation, migration, and invasion, while silencing PRDM16 had the opposite effect. Moreover, miR-372-3p could target the regulation expression of PRDM16. Rescue experiments demonstrated that upregulating miR-372-3p conspicuously restored the inhibitory effect of increased PRDM16 on cell proliferation, migration, and invasion in PCa. Overall, our study clarifies the biological role of miR-372-3p/PRDM16 axis in prostate cancer progression, which may be effective biomarkers for clinical treatment of prostate cancer.
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Affiliation(s)
- Guangwei Yin
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Chengquan Yan
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Jing Hao
- Office of Academic Affairs, North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Chunying Zhang
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Pengfei Wang
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Chaofei Zhao
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Shengyong Cai
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Bin Meng
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Aili Zhang
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
| | - Lin Li
- The Third Department of Urology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China
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11
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Baranovsky A, Ivanov T, Granovskaya M, Papatsenko D, Pervouchine DD. Transcriptome analysis reveals high tumor heterogeneity with respect to re-activation of stemness and proliferation programs. PLoS One 2022; 17:e0268626. [PMID: 35587924 PMCID: PMC9119523 DOI: 10.1371/journal.pone.0268626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 05/03/2022] [Indexed: 12/01/2022] Open
Abstract
Significant alterations in signaling pathways and transcriptional regulatory programs together represent major hallmarks of many cancers. These, among all, include the reactivation of stemness, which is registered by the expression of pathways that are active in the embryonic stem cells (ESCs). Here, we assembled gene sets that reflect the stemness and proliferation signatures and used them to analyze a large panel of RNA-seq data from The Cancer Genome Atlas (TCGA) Consortium in order to specifically assess the expression of stemness-related and proliferation-related genes across a collection of different tumor types. We introduced a metric that captures the collective similarity of the expression profile of a tumor to that of ESCs, which showed that stemness and proliferation signatures vary greatly between different tumor types. We also observed a high degree of intertumoral heterogeneity in the expression of stemness- and proliferation-related genes, which was associated with increased hazard ratios in a fraction of tumors and mirrored by high intratumoral heterogeneity and a remarkable stemness capacity in metastatic lesions across cancer cells in single cell RNA-seq datasets. Taken together, these results indicate that the expression of stemness signatures is highly heterogeneous and cannot be used as a universal determinant of cancer. This calls into question the universal validity of diagnostic tests that are based on stem cell markers.
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Affiliation(s)
- Artem Baranovsky
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Timofei Ivanov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | | | - Dmitri Papatsenko
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Dmitri D. Pervouchine
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
- * E-mail:
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12
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Wang D, Tian J, Yan Z, Yuan Q, Wu D, Liu X, Yang S, Guo S, Wang J, Yang Y, Xing J, An J, Huang Q. Mitochondrial fragmentation is crucial for c-Myc-driven hepatoblastoma-like liver tumor. Mol Ther 2022; 30:1645-1660. [PMID: 35085814 PMCID: PMC9077476 DOI: 10.1016/j.ymthe.2022.01.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/19/2021] [Accepted: 01/20/2022] [Indexed: 11/26/2022] Open
Abstract
Hepatoblastoma is the most common liver cancer in children, and the aggressive subtype often has a poor prognosis and lacks effective targeted therapy. Although aggressive hepatoblastoma (HB) is often accompanied by abnormally high expression of the transcription factor c-Myc, the underlying mechanism remains unclear. In this study, we found that mitochondrial fragmentation was enhanced by c-Myc overexpression in human aggressive HB tissues and was associated with poor prognosis. Then, a mouse model resembling human HB was established via hydrodynamic injection of c-Myc plasmids. We observed that liver-specific knockout of the mitochondrial fusion molecule MFN1 or overexpression of mitochondrial fission molecule DRP1 promoted the occurrence of c-Myc-driven liver cancer. In contrast, when MFN1 was overexpressed in the liver, tumor formation was delayed. In vitro experiments showed that c-Myc transcriptionally upregulated the expression of DRP1 and decreased MFN1 expression through upregulation of miR-373-3p. Moreover, enhanced mitochondrial fragmentation significantly promoted aerobic glycolysis and the proliferation of HB cells by significantly increasing reactive oxygen species (ROS) production and activating the RAC-alpha serine/threonine-protein kinase (AKT)/mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathways. Taken together, our results indicate that c-Myc-mediated mitochondrial fragmentation promotes the malignant transformation and progression of HB by activating ROS-mediated multi-oncogenic signaling.
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13
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Johnston ME, Rivas MP, Nicolle D, Gorse A, Gulati R, Kumbaji M, Weirauch MT, Bondoc A, Cairo S, Geller J, Tiao G, Timchenko N. Olaparib Inhibits Tumor Growth of Hepatoblastoma in Patient-Derived Xenograft Models. Hepatology 2021; 74:2201-2215. [PMID: 34037269 PMCID: PMC8463483 DOI: 10.1002/hep.31919] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Hepatoblastoma (HBL) is a devastating pediatric liver cancer with multiple treatment options, but it ultimately requires surgery for a cure. The most malicious form of HBL is a chemo-resistant aggressive tumor that is characterized by rapid growth, metastases, and poor response to treatment. Very little is known of the mechanisms of aggressive HBL, and recent focuses have been on developing alternative treatment strategies. In this study, we examined the role of human chromosomal regions, called aggressive liver cancer domains (ALCDs), in liver cancer and evaluated the mechanisms that activate ALCDs in aggressive HBL. RESULTS We found that ALCDs are critical regions of the human genome that are located on all human chromosomes, preferentially in intronic regions of the oncogenes and other cancer-associated genes. In aggressive HBL and in patients with Hepatocellular (HCC), JNK1/2 phosphorylates p53 at Ser6, which leads to the ph-S6-p53 interacting with and delivering the poly(adenosine diphosphate ribose) polymerase 1 (PARP1)/Ku70 complexes on the oncogenes containing ALCDs. The ph-S6-p53-PARP1 complexes open chromatin around ALCDs and activate multiple oncogenic pathways. We found that the inhibition of PARP1 in patient-derived xenografts (PDXs) from aggressive HBL by the Food and Drug Administration (FDA)-approved inhibitor olaparib (Ola) significantly inhibits tumor growth. Additionally, this is associated with the reduction of the ph-S6-p53/PARP1 complexes and subsequent inhibition of ALCD-dependent oncogenes. Studies in cultured cancer cells confirmed that the Ola-mediated inhibition of the ph-S6-p53-PARP1-ALCD axis inhibits proliferation of cancer cells. CONCLUSIONS In this study, we showed that aggressive HBL is moderated by ALCDs, which are activated by the ph-S6-p53/PARP1 pathway. By using the PARP1 inhibitor Ola, we suppressed tumor growth in HBL-PDX models, which demonstrated its utility in future clinical models.
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Affiliation(s)
- Michael Edward Johnston
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH,Department of SurgeryUniversity of CincinnatiCincinnatiOH
| | - Maria Prates Rivas
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | | | | | - Ruhi Gulati
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Meenasri Kumbaji
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Matthew T. Weirauch
- Center for Autoimmune Genomics and EtiologyCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Alexander Bondoc
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Stefano Cairo
- XenTech 4Évry‐CourcouronnesFrance,Istituto di Ricerca PediatricaPaduaItaly
| | - James Geller
- Department of OncologyCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Gregory Tiao
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Nikolai Timchenko
- Division of General and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH,Department of SurgeryUniversity of CincinnatiCincinnatiOH
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Shah JA, Khattak S, Rauf MA, Cai Y, Jin J. Potential Biomarkers of miR-371-373 Gene Cluster in Tumorigenesis. Life (Basel) 2021; 11:life11090984. [PMID: 34575133 PMCID: PMC8465240 DOI: 10.3390/life11090984] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
microRNAs (miRNAs) are small non-coding RNA transcripts (20–24 nucleotides) that bind to their complementary sequences in the 3′-untranslated regions (3′-UTR) of targeted genes to negatively or positively regulate their expression. miRNAs affect the expression of genes in cells, thereby contributing to several important biological processes, including tumorigenesis. Identifying the miRNA cluster as a human embryonic stem cell (hESC)-specific miRNAs initially led to the identification of miR-371, miR-372, miR-373, and miR-373*, which can ultimately be translated into mature miRNAs. Recent evidence suggests that miR-371–373 genes are abnormally expressed in various cancers and act either as oncogenes or tumor suppressors, indicating they may be suitable as molecular biomarkers for cancer diagnosis and prevention. In this article, we summarize recent studies linking miR-371–373 functions to tumorigenesis and speculate on the potential applications of miR-371–373 as biomarkers for cancer diagnosis and treatment.
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Affiliation(s)
- Junaid Ali Shah
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.A.S.); (Y.C.)
| | - Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China;
| | - Mohd Ahmar Rauf
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; or
| | - Yong Cai
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.A.S.); (Y.C.)
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jingji Jin
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.A.S.); (Y.C.)
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
- Correspondence:
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15
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Delivery of LNA-antimiR-142-3p by Mesenchymal Stem Cells-Derived Exosomes to Breast Cancer Stem Cells Reduces Tumorigenicity. Stem Cell Rev Rep 2021; 16:541-556. [PMID: 31898802 DOI: 10.1007/s12015-019-09944-w] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Exosomes, nano-sized cell-derived vesicles, have been employed as non-synthetic carriers of various pharmaceutics in numerous studies. As higher expression levels of miR-142-3p and miR-150 in breast cancer stem cells (BCSCs) are associated with their clonogenic and tumorigenic capabilities, the present study aims to exploit the mesenchymal stem cells-derived exosomes (MSCs-Exo) to deliver LNA-antimiR-142-3p into MCF7-derived cancer stem-like cells to suppress expression levels of miR-142-3p and miR-150 in order to reduce clonogenicity and tumorigenicity. Our results indicated that the MSCs-Exo can efficiently deliver the LNA-antimiR-142-3p to breast cancer stem-like cells to reduce the miR-142-3p and miR-150 expression levels. Furthermore, the inhibition of the oncomiRs with the delivery of LNA-antimiR-142-3p resulted in a significant reduction of clone-formation and tumor-initiating abilities of the MCF7-derived cancer stem-like cells. In conclusion, we showed that MSCs-derived exosomes could be used as a feasible nanovehicles to deliver RNA-based therapeutics into BCSCs to improve the cancer treatment. HIGHLIGHTS: Exosomes secreted by bone marrow-derived mesenchymal stem cells efficiently transfer the LNA-antimiR-142-3p to breast cancer stem cells. Exosomes-mediated delivery of LNA-antimiR-142-3p to the breast cancer stem cells leads to downregulation of miR-142-3p and miR-150 and the overexpression of target genes. Delivery of LNA-antimiR-142-3p by the exosomes reduces the colony formation capability of breast cancer stem cells in vitro. Inhibition of miR-142-3p and miR-150 by the LNA-antimiR-142-3p loaded exosomes reduces the tumorigenicity of breast cancer stem cells in vivo.
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16
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Fatma H, Siddique HR. Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer. Expert Rev Anticancer Ther 2021; 21:853-864. [PMID: 33832395 DOI: 10.1080/14737140.2021.1915137] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel-like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.Area covered: We cover recent discoveries and investigate the role of OSKM in inducing pluripotency and stem cell-like properties in various cancers with special emphasis on liver cancer. We review Yamanaka factors' role in stemness and chemoresistance of liver cancer.Expert opinion: In CSCs, including liver CSCs, the deregulation of various signaling pathways is one of the major reasons for stemness and drug resistance and is primarily due to OSKM. OSKM are responsible for tumor heterogeneity which renders targeting drug useless after a certain period. These factors can be exploited to understand the underlying mechanism of cancer stemness and resistance to chemotherapeutic drugs.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
| | - Hifzur Rahman Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
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17
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miRNAs and Biomarkers in Testicular Germ Cell Tumors: An Update. Int J Mol Sci 2021; 22:ijms22031380. [PMID: 33573132 PMCID: PMC7866514 DOI: 10.3390/ijms22031380] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
Testicular germ cell tumors (TGCTs) are the leading form of solid cancer and death affecting males between the ages of 20 and 40. Today, their surgical resection and chemotherapy are the treatments of first choice, even if sometimes this is not enough to save the lives of patients with TGCT. As seen for several tumors, the deregulation of microRNAs (miRNAs) is also a key feature in TGCTs. miRNAs are small molecules of RNA with biological activity that are released into biological fluids by testicular cancer cells. Their presence, therefore, can be detected and monitored by considering miRNAs as diagnostic and prognostic markers for TGCTs. The purpose of this review is to collect all the studies executed on miRNAs that have a potential role as biomarkers for testicular tumors.
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18
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Weiss JBW, Wagner AE, Eberherr C, Häberle B, Vokuhl C, von Schweinitz D, Kappler R. High expression of IGF2-derived intronic miR-483 predicts outcome in hepatoblastoma. Cancer Biomark 2021; 28:321-328. [PMID: 32390604 DOI: 10.3233/cbm-191390] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The role of microRNAs (miRs) as biomarkers to predict outcome in hepatoblastoma (HB), the most common malignant liver tumor in childhood, has still to be determined. Recently, the so-called four-miR signature has been described to efficiently stratify HB patients according to their prognosis. OBJECTIVE We examined the recently described four-miR signature for its clinical relevance in an independent validation cohort of HB patients and tried to optimize its predictive value by analyzing four additional miRs involved in HB biology. METHODS Expression of eight miR was determined in 29 tumor and 10 normal liver samples by TaqMan assays and association studies and Kaplan-Meier estimators determined their clinical relevance. RESULTS Stratifying HB patients by the four-miR signature showed no difference in patients' outcome, which was also reflected by the lack of association with any clinical risk parameter. Adding miR-23b-5p and miR-23b-3p did also not increase its discriminating power. However, the integration of miR-483-5p and miR-483-3p into the four-miR signature could predict patients with poor outcome that were associated with large tumors and vessel invasive growth with high accuracy. CONCLUSIONS The expansion of the four-miR signature by miR-483 serves as a useful biomarker to predict outcome of HB patients.
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Affiliation(s)
- Jakob Benjamin Wilhelm Weiss
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.,Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Alexandra Elisabeth Wagner
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.,Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Corinna Eberherr
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Beate Häberle
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | | | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
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19
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Abstract
Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.
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Affiliation(s)
- Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Stefano Cairo
- XenTech, Evry, France,Istituto di Ricerca Pediatrica, Padova, Italy
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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20
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Honda S, Chatterjee A, Leichter AL, Miyagi H, Minato M, Fujiyoshi S, Ara M, Kitagawa N, Tanaka M, Tanaka Y, Shinkai M, Hatanaka KC, Taketomi A, Eccles MR. A MicroRNA Cluster in the DLK1-DIO3 Imprinted Region on Chromosome 14q32.2 Is Dysregulated in Metastatic Hepatoblastomas. Front Oncol 2020; 10:513601. [PMID: 33282720 PMCID: PMC7689214 DOI: 10.3389/fonc.2020.513601] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 10/15/2020] [Indexed: 01/08/2023] Open
Abstract
Hepatoblastoma (HB) is the most common malignant liver neoplasm in children. Despite progress in HB therapy, outcomes for patients with metastatic disease remain poor. Dysregulation of miRNA expression is one of the potential epigenetic mechanisms associated with pathogenesis of HB. However, miRNA profiles related to the different stages of HB tissues and cells, in particular of lung metastatic tumor cells, are unknown. In the present study, using array-based miRNA expression and DNA methylation analysis on formalin-fixed paraffin-embedded tissues, we aimed to identify miRNA changes that can discriminate between lung metastatic tumors, primary tumors (fetal and embryonal subtypes), and nontumorous surrounding livers. Our analysis demonstrated that a large cluster of microRNAs and snoRNAs located within the 14q32.2 DLK1-DIO3 region showed a strikingly upregulated expression pattern in HB tumors, especially metastatic tumors, compared to normal liver tissues. This revealed dysregulation of miRNAs similar to that seen in a malignant stem-like subtype of hepatocellular carcinoma associated with poor prognosis. These findings in HB mirror similar findings made in multiple other cancer types. With further analysis this may in future allow stratification of different stages and types of HB tumors based on their miRNA profiles, which could lead to new approaches to diagnosis and treatment in progressive HB patients.
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Affiliation(s)
- Shohei Honda
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Anna L Leichter
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Hisayuki Miyagi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masashi Minato
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Sunao Fujiyoshi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Momoko Ara
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Norihiko Kitagawa
- Department of Surgery, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Mio Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Masato Shinkai
- Department of Surgery, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Kanako C Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Michael R Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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21
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Hsu WY, Chang HH, Lu MY, Yang YL, Jou ST, Chen HL, Ni YH, Hsu HY, Chang MH, Wu JF. Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan. Pediatr Neonatol 2020; 61:393-398. [PMID: 32291200 DOI: 10.1016/j.pedneo.2020.03.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/16/2019] [Accepted: 03/18/2020] [Indexed: 10/24/2022] Open
Abstract
BACKGORUND Hepatoblastoma is the most common primary liver malignancy in young children. METHODS To identify predictors of the clinical outcomes of hepatoblastoma, we retrospectively reviewed the medical records of 45 children with hepatoblastoma in the National Taiwan University Hospital from 1998 to 2018. All of the children were classified as high risk according to the pretreatment extent of disease (PRETEXT) staging system. The patients' clinical data (sex, age at diagnosis, PRETEXT status, presence of metastasis or tumor rupture, tumor pathologic type, and clinical outcomes) were analyzed. RESULTS A total of 45 children with high-risk hepatoblastoma were diagnosed at an average age of 3.2 years. The survival analysis showed that the event-free survival duration was significantly longer in patients aged ≤1.25 years at diagnosis than those >1.25 years (hazard ratio = 2.86, p = 0.036). The absence of initial tumor rupture was associated with longer event-free survival (hazard ratio = 2.74, p = 0.039). Diagnosis at age >1.25 years was correlated with the presence of multifocal liver tumors (p = 0.0002) and tumor rupture at diagnosis (p = 0.02). There was no significant difference in event-free survival between the groups classified as intermediate versus high risk according to the Children's Hepatic tumors International Collaboration hepatoblastoma stratification system (p = 0.13). CONCLUSIONS Diagnosis at ≤ 1.25 years of age and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma.
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Affiliation(s)
- Wei-Yun Hsu
- Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Meng-Yao Lu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yung-Li Yang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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22
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Zhang Q, Lou Y, Bai XL, Liang TB. Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies. World J Gastroenterol 2020; 26:3720-3736. [PMID: 32774053 PMCID: PMC7383842 DOI: 10.3748/wjg.v26.i26.3720] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by high heterogeneity in both intratumoral and interpatient manners. While interpatient heterogeneity is related to personalized therapy, intratumoral heterogeneity (ITH) largely influences the efficacy of therapies in individuals. ITH contributes to tumor growth, metastasis, recurrence, and drug resistance and consequently limits the prognosis of patients with HCC. There is an urgent need to understand the causes, characteristics, and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival. Here, we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity. In parallel, evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem. We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions, combined with population-based clinical trials, will help to clarify the clinical implications of ITH, develop novel intervention strategies, and improve patient prognosis.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Xue-Li Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Ting-Bo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, Zhejiang Province, China
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Kurbegovic A, Trudel M. The master regulators Myc and p53 cellular signaling and functions in polycystic kidney disease. Cell Signal 2020; 71:109594. [PMID: 32145315 DOI: 10.1016/j.cellsig.2020.109594] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 01/08/2023]
Abstract
The transcription factors Myc and p53 associated with oncogenesis play determinant roles in a human genetic disorder, autosomal dominant polycystic kidney disease (ADPKD), that was coined early in ADPKD etiology a «neoplasia in disguise ». These factors are interdependent master cell regulators of major biological processes including proliferation, apoptosis, cell growth, metabolism, inflammation, fibrosis and differentiation that are all modulated in ADPKD. Myc and p53 proteins evolved to respond and carry out overlapping functions via opposing mechanisms of action. Studies in human ADPKD kidneys, caused by mutations in the PKD1 or PKD2 genes, reveal reduced p53 expression and high expression of Myc in the cystic tubular epithelium. Myc and p53 via direct interaction act respectively, as transcriptional activator and repressor of PKD1 gene expression, consistent with increased renal PKD1 levels in ADPKD. Mouse models generated by Pkd1 and Pkd2 gene dosage dysregulation reproduce renal cystogenesis with activation of Myc expression and numerous signaling pathways, strikingly similar to those determined in human ADPKD. In fact, upregulation of renal Myc expression is also detected in virtually all non-orthologous animal models of PKD. A definitive causal connection of Myc with cystogenesis was established by renal overexpression of Myc in transgenic mice that phenocopies human ADPKD. The network of activated signaling pathways in human and mouse cystogenesis individually or in combination can target Myc as a central node of PKD pathogenesis. One or many of the multiple functions of Myc upon activation can play a role in every phases of ADPKD development and lend credence to the notion of "Myc addiction" for cystogenesis. We propose that the residual p53 levels are conducive to an ADPKD biological program without cancerogenesis while a "p53 dependent annihilation" mechanism would be permissive to oncogenesis. Of major importance, Myc ablation in orthologous mouse models or direct inhibition in non-orthologous mouse model significantly delays cystogenesis consistent with pharmacologic or genetic inhibition of Myc upstream regulator or downstream targets in the mouse. Together, these studies on PKD proteins upon dysregulation not only converged on Myc as a focal point but also attribute to Myc upregulation a causal and « driver » role in pathogenesis. This review will present and discuss our current knowledge on Myc and p53, focused on PKD mouse models and ADPKD.
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Affiliation(s)
- Almira Kurbegovic
- Institut de Recherches Cliniques de Montréal, Molecular Genetics and Development, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Marie Trudel
- Institut de Recherches Cliniques de Montréal, Molecular Genetics and Development, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
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Abstract
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
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Wang H, Zhao Y, Chen T, Liu G, He N, Hu H. MiR-371 promotes proliferation and metastasis in hepatocellular carcinoma by targeting PTEN. BMB Rep 2019. [PMID: 30940319 PMCID: PMC6549920 DOI: 10.5483/bmbrep.2019.52.5.155] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide. MiR-371 has recently emerged as an important regulator in tumorigenesis, and may serve as a biomarker for malignant tumors. We transfected miR-371 or its inhibitor in two human HCC cell lines, then used 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, soft agar colony formation, and transwell migration assays to evaluate the effects on cell proliferation, migration, and invasion. We found that miR-371 was positively correlated with HCC metastasis and poor prognosis in the inflicted patients, and the high expression of miR-371 was promoted, whereas a low level of miR-371 depressed cell proliferation and invasion. We found PTEN to be a direct target of miR-371. The overexpression or knockdown of PTEN exhibited the opposite effects from those of miR-371 on cell proliferation and migration. Our study demonstrates that miR-371 promotes proliferation and metastasis in HCC by targeting PTEN.
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Affiliation(s)
- Hao Wang
- Eastern Hepatobiliary Surgery Hospital (EHBH), Second Military Medical University, Shanghai City 200438, China
| | - Yi Zhao
- Eastern Hepatobiliary Surgery Hospital (EHBH), Second Military Medical University, Shanghai City 200438, China
| | - Tingsong Chen
- The Seventh People's Hospital of Shanghai, Shanghai City 200137, China
| | - Guofang Liu
- Eastern Hepatobiliary Surgery Hospital (EHBH), Second Military Medical University, Shanghai City 200438, China
| | - Nan He
- Guangdong Ascendas Genomics Technology Co., Ltd., Zhongshan 519000, China
| | - Heping Hu
- Eastern Hepatobiliary Surgery Hospital (EHBH), Second Military Medical University, Shanghai City 200438, China
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Dysregulation of liver developmental microRNA contribute to hepatic carcinogenesis. J Formos Med Assoc 2019; 119:1041-1051. [PMID: 31627983 DOI: 10.1016/j.jfma.2019.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/31/2019] [Accepted: 09/27/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND/PURPOSE To investigate the role of microRNA (miRNA) dysregulation in liver cancer by assessing the miRNA profiles of human hepatic stem cells (HpSCs), marker-carrying human hepatoblastoma (HB) cells, and hepatocellular carcinoma (HCC) cells vs. those of fetal hepatocytes. METHODS We subjected human HCC and HB tumor specimens to immunohistochemical (IHC) staining for markers of HpSCs. We analyzed the miRNA patterns of HpSCs, HCC cells, HB cells, and fetal hepatocytes using microarray analysis, with confirmation via quantitative real-time polymerase chain reaction. The roles of the miRNAs in liver cancer stem cells (CSCs) were also elucidated. RESULTS The epithelial cell adhesion molecule (EpCAM) was the most prevalent HpSCs marker in human HB and HCC tumor cells and hepatoma cells. EpCAM-positive HB and HCC cells exhibited greater self-renewal and tumorigenicity than their EpCAM-negative counterparts or EpCAM-positive fetal hepatocytes. In EpCAM-positive fetal hepatocytes, miR-126 expression level increased with gestational age. The EpCAM-positive HB cells exhibited downregulation of miR-126 in comparison to EpCAM-positive fetal hepatocytes. An miR-126 mimic reduced sphere and colony formation in, and induced apoptosis of, HB cells. In comparison to EpCAM-positive fetal hepatocytes, EpCAM-positive HCC cells exhibited downregulation of miR-126, miR-144, and miR-451. Transfection of miR-126, miR-144, and miR-451 induced apoptosis of, and reduced sphere and colony formation in, HCC cells. CONCLUSION Dysregulation of liver developmental miRNAs, which exert a tumor suppressant effect, in EpCAM-positive HpSCs may contribute to liver carcinogenesis by promoting the transformation of HpSCs to CSCs of HB and HCC.
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El-Ahwany EGE, Mourad L, Zoheiry MMK, Abu-Taleb H, Hassan M, Atta R, Hassanien M, Zada S. MicroRNA-122a as a non-invasive biomarker for HCV genotype 4-related hepatocellular carcinoma in Egyptian patients. Arch Med Sci 2019; 15:1454-1461. [PMID: 31749873 PMCID: PMC6855160 DOI: 10.5114/aoms.2019.86621] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/22/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection persists in most infected individuals and can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have a crucial role in various liver diseases, especially HCC. The expression profiles of circulating microRNAs have been studied aiming at the identification of novel non-invasive biomarkers. This study aims to develop a non-invasive diagnostic tool based on measuring the serum levels of different miRNAs in order to detect HCV-induced HCC at the early stages of the disease. MATERIAL AND METHODS Five main miRNAs (miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a) were selected according to the literature that demonstrated their unique expression pattern during HCC development. Serum samples were collected from 42 cases of chronic hepatitis C (CHC) without cirrhosis, 45 cases of CHC with cirrhosis (LC), 38 cases of HCC with HCV, and 40 healthy individuals serving as a control. The five miRNAs were measured using real-time reverse transcription PCR. The conventional HCC markers α-fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) were measured with commercial kits. RESULTS Serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a were significantly lower (p < 0.01) in HCC than in CHC and LC groups. As a single marker, miRNA-122a had the highest sensitivity for HCC, followed by miRNA-199a, miRNA-145, miRNA-139, and miRNA-125a. CONCLUSIONS These findings indicate that measurement of serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a can differentiate HCC from CHC and LC. Our results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for HCV-induced HCC.
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Affiliation(s)
| | - Lobna Mourad
- Department of Biology, The American University, Cairo, Egypt
| | - Mona M. K. Zoheiry
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Hoda Abu-Taleb
- Department of Environmental Research, Theodor Bilharz Research Institute, Giza, Egypt
| | - Marwa Hassan
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Raafat Atta
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Moataz Hassanien
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Suher Zada
- Department of Biology, The American University, Cairo, Egypt
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Luo Z, Cao P. Long noncoding RNA PVT1 promotes hepatoblastoma cell proliferation through activating STAT3. Cancer Manag Res 2019; 11:8517-8527. [PMID: 31572006 PMCID: PMC6759231 DOI: 10.2147/cmar.s213707] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/15/2019] [Indexed: 12/29/2022] Open
Abstract
Background Hepatoblastoma is the most common liver malignancy in children. The long noncoding RNA (IncRNA) PVT1 plays oncogenic roles in human cancers; however, its regulation and function in hepatoblastoma remain poorly understood. Purpose This study was designed to investigate the regulation and function of PVT1 in hepatoblastoma. Methods PVT1 expression was compared between human hepatoblastoma tissues and adjacent non-tumor tissues, and then analyzed using Kaplan-Meier method. The proliferation of hepatoblastoma cells was determined by BrdU incorporation assay. The tumor xenograft model was used to assess tumor proliferation in vivo. The gene expression level was measured by qRT-pCR, Western blot and immunohistochemistry analyses. Results Compared with normal counterparts, PVT1 is upregulated in human hepatoblastoma tissues as well as in hepatoblastoma cell lines. Additionally, PVT1 promotes the proliferation of hepatoblastoma cells in vitro and accelerates tumor growth in xenograft model in vivo. Mechanistically, PVT1 promotes the activation of the signal transducer and activator of transcription 3 (STAT3), which leads to the transcriptional activation of downstream targets involved in cell cycle progression, and moreover,STAT3 inhibition with the selective inhibitor stattic abolishes PVT1 pro-proliferative role in hepatoblastoma cells. Conclusion PVT1 promotes hepatoblastoma cell proliferation through activating STAT3-induced cell cycle progression, which may implicate PVT1 as a potential therapeutic target for hepatoblastoma treatment.
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Affiliation(s)
- Zhenqin Luo
- Oncology Department, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
| | - Peiguo Cao
- Oncology Department, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People's Republic of China
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The Emerging Roles of Cancer Stem Cells and Wnt/Beta-Catenin Signaling in Hepatoblastoma. Cancers (Basel) 2019; 11:cancers11101406. [PMID: 31547062 PMCID: PMC6826653 DOI: 10.3390/cancers11101406] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/11/2019] [Accepted: 09/11/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatoblastoma (HB) is the most common form of primary liver malignancy found in pediatric populations. HB is considered to be clonal and arises from hepatoblasts, or embryonic liver progenitor cells. These less differentiated tumor-initiating progenitor cells, or cancer stem cells (CSCs), may contribute to tumor recurrence and resistance to therapies, and have high metastatic abilities. Phenotypic heterogeneity, undesired genetic and epigenetic alterations, and dysregulated signaling pathways provide CSCs with a survival advantage over current therapies. The molecular and cellular basis of HB and the mechanism of CSC induction are not fully understood. The Wnt/beta-catenin pathway is one of the major developmental pathways and is believed to play an important role in the pathogenesis of HB and CSC formation. This review summarizes the cellular and molecular characteristics of HB with a specific emphasis on CSCs and Wnt/beta-catenin signaling.
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30
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Ye Y, Zhang L, Song Y, Zhuang J, Wang G, Ni J, Zhang S, Xia W. MicroRNA‑373 exerts anti‑tumor functions in human liver cancer by targeting Rab22a. Mol Med Rep 2019; 20:3874-3882. [PMID: 31485646 DOI: 10.3892/mmr.2019.10600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/12/2018] [Indexed: 11/06/2022] Open
Abstract
Liver cancer is a one of the most frequent types of tumor worldwide. It has long been recognized that microRNAs are important participants in the progression of various types of cancer. The present study explored the role of microRNA‑373 (miR‑373) in liver cancer development. Reverse transcription‑quantitative polymerase chain reaction was performed to evaluate the transcription level of miR‑373 in 96 liver cancer tissues and adjacent normal liver tissues. The association of miR‑373 with clinicopathological characteristics was analyzed using the χ2 test. Kaplan‑Meier univariate analysis and multivariate hazard analysis were performed to identify the clinical potential of miR‑373 in the prognosis of liver cancer patients. Transfection of miR‑373 mimics into Hep3B and HepG2 liver cancer cell lines was conducted to reveal the underlying mechanism in regulating liver cancer progression. The functional assays included proliferation, migration, invasion and luciferase assays. The findings of the present study demonstrated that miR‑373 transcription level was markedly downregulated in liver cancer tissues compared with the adjacent normal tissues and was associated with the clinical prognosis of liver cancer patients. Overexpressing miR‑373 mimics in liver cancer cell lines decreased cell proliferation and invasion, suggesting that miR‑373 exerts anti‑tumor effects in liver cancer. In addition, data from the present study demonstrated the direct effect of miR373 on inhibiting the expression and signaling of Ras‑related protein Rab22a, a well‑known oncoprotein. Taken together, the results from the present study suggested that miR‑373 suppresses liver cancer progression and may serve as a promising prognosis prediction biomarker.
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Affiliation(s)
- Ying Ye
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Lijun Zhang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Yanan Song
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Juhua Zhuang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Jing Ni
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Suiliang Zhang
- Department of Oncology, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China
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31
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The Role of MicroRNAs in Hepatoblastoma Tumors. Cancers (Basel) 2019; 11:cancers11030409. [PMID: 30909459 PMCID: PMC6468899 DOI: 10.3390/cancers11030409] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 12/19/2022] Open
Abstract
Hepatoblastoma is the most common hepatic malignancy during childhood. However, little is still known about the molecular mechanisms that govern the development of this disease. This review is focused on the recent advances regarding the study of microRNAs in hepatoblastoma and their substantial contribution to improv our knowledge of the pathogenesis of this disease. We show here that miRNAs represent valuable tools to identify signaling pathways involved in hepatoblastoma progression as well as useful biomarkers and novel molecular targets to develop alternative therapeutic strategies in this disease.
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32
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Guo H, Ji F, Zhao X, Yang X, He J, Huang L, Zhang Y. MicroRNA-371a-3p promotes progression of gastric cancer by targeting TOB1. Cancer Lett 2019; 443:179-188. [DOI: 10.1016/j.canlet.2018.11.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 11/19/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
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A microRNA signature for the differential diagnosis of salivary gland tumors. PLoS One 2019; 14:e0210968. [PMID: 30682201 PMCID: PMC6347363 DOI: 10.1371/journal.pone.0210968] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 01/04/2019] [Indexed: 12/15/2022] Open
Abstract
Salivary gland tumors (SGTs) are rare tumors of the head and neck with different clinical behavior. Preoperative diagnosis, based on instrumental and cytologic examinations, is crucial for their correct management. The identification of molecular markers might improve the accuracy of pre-surgical diagnosis helping to plan the proper treatment especially when a definitive diagnosis based only on cytomorphology cannot be achieved. miRNAs appear to be new promising biomarkers in the diagnosis and prognosis of cancer. Studies concerning the useful of miRNA expression in clinical decision-making regarding SGTs remain limited and controversial.The expression of a panel of 798 miRNAs was investigated using Nanostring technology in 14 patients with malignant SGTs (6 mucoepidermoid carcinomas, 4 adenoid cystic carcinomas, 1 acinic cell carcinoma, 1 ductal carcinoma, 1 cystadenocarcinoma and 1 adenocarcinoma) and in 10 patients with benign SGTs (pleomorphic adenomas). The DNA Intelligent Analysis (DIANA)-miRPath v3.0 software was used to determinate the miRNA regulatory roles and to identify the controlled significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways. Forty six miRNAs were differentially expressed (False Discovery Rate—FDR<0.05) between malignant and benign SGTs. DIANA miRPath software revealed enriched pathways involved in cancer processes as well as tumorigenesis, cell proliferation, cell growth and survival, tumor suppressor expression, angiogenesis and tumor progression. Interestingly, clustering analysis showed that this signature of 46 miRNAs is able to differentiate the two analyzed groups. We found a correlation between histological diagnosis (benign or malignant) and miRNA expression profile.The molecular signature identified in this study might become an important preoperative diagnostic tool.
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Kogan AA, Lapidus RG, Baer MR, Rassool FV. Exploiting epigenetically mediated changes: Acute myeloid leukemia, leukemia stem cells and the bone marrow microenvironment. Adv Cancer Res 2019; 141:213-253. [PMID: 30691684 DOI: 10.1016/bs.acr.2018.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute myeloid leukemia (AML) derives from the clonal expansion of immature myeloid cells in the bone marrow, and results in the disruption of normal hematopoiesis and subsequent bone marrow failure. The bone marrow microenvironment (BME) and its immune and other supporting cells are regarded to facilitate the survival, differentiation and proliferation of leukemia stem cells (LSCs), which enables AML cells to persist and expand despite treatment. Recent studies have identified epigenetic modifications among AML cells and BME constituents in AML, and have shown that epigenetic therapy can potentially reprogram these alterations. In this review, we summarize the interactions between the BME and LSCs, and discuss changes in how the BME and immune cells interact with AML cells. After describing the epigenetic modifications seen across chromatin, DNA, the BME, and the immune microenvironment, we explore how demethylating agents may reprogram these pathological interactions, and potentially re-sensitize AML cells to treatment.
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Affiliation(s)
- Aksinija A Kogan
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
| | - Rena G Lapidus
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Maria R Baer
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Feyruz V Rassool
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
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Krejcik Z, Belickova M, Hrustincova A, Votavova H, Jonasova A, Cermak J, Dyr JE, Merkerova MD. MicroRNA profiles as predictive markers of response to azacitidine therapy in myelodysplastic syndromes and acute myeloid leukemia. Cancer Biomark 2018; 22:101-110. [PMID: 29630523 DOI: 10.3233/cbm-171029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Azacitidine (AZA) is a nucleoside analog used for treatment of myelodysplasia and the prediction of AZA responsiveness is important for the therapy management. METHODS Using microarrays and reverse-transcription quantitative-PCR, we analyzed microRNA (miRNA) expression in bone marrow CD34+ cells of 27 patients with higher-risk myelodysplastic syndromes or acute myeloid leukemia with myelodysplasia-related changes before and during AZA treatment. RESULTS At baseline, we found that future overall response rate was significantly higher in patients with upregulated miR-17-3p and downregulated miR-100-5p and miR-133b. Importantly, the high level of miR-100-5p at baseline was associated with shorter overall survival (HR = 4.066, P= 0.008). After AZA treatment, we observed deregulation of 30 miRNAs in responders (including downregulation of miR-10b-5p, miR-15a-5p/b-5p, miR-24-3p, and miR-148b-3p), while their levels remained unchanged in non-responders. CONCLUSIONS Our study demonstrates that responders and non-responders have distinct miRNA patterns and that the level of specific miRNAs before therapy may predict the efficacy of AZA treatment.
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Affiliation(s)
- Zdenek Krejcik
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Monika Belickova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | | | - Hana Votavova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | | | - Jaroslav Cermak
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Jan E Dyr
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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Wen DY, Huang JC, Wang JY, Pan WY, Zeng JH, Pang YY, Yang H. Potential clinical value and putative biological function of miR-122-5p in hepatocellular carcinoma: A comprehensive study using microarray and RNA sequencing data. Oncol Lett 2018; 16:6918-6929. [PMID: 30546424 PMCID: PMC6256359 DOI: 10.3892/ol.2018.9523] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023] Open
Abstract
In order to determine the diagnostic efficacy of microRNA (miR)-122-5p and to identify the potential molecular signaling pathways underlying the function of miR-122-5p in hepatocellular carcinoma (HCC), the expression profiles of data collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and literature databases were analyzed, along with any associations between clinicopathological characteristics and the diagnostic value of miR-122-5p in HCC. The intersection of 12 online prediction databases and differentially expressed genes from TCGA and GEO were utilized in order to select the prospective target genes of miR-122-5p in HCC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction network (PPI) analyses were subsequently performed based on the selected target genes. The average expression level of miR-122-5p was decreased in HCC patients compared with controls from TCGA database (P<0.001), and the downregulation of miR-122-5p was significantly associated with HCC tissues (P<0.001), tumor vascular invasion (P<0.001), metastasis (P=0.001), sex (P=0.006), virus infection status (P=0.001) and tissue (compared with serum; P<0.001) in cases from the GEO database. The pooled sensitivity and specificity for miR-122-5p to diagnose HCC were 0.60 [95% confidence interval (CI), 0.48–0.71] and 0.81 (95% CI, 0.70–0.89), respectively. The area under the curve (AUC) value was 0.76 (95% CI, 0.72–0.80), while in Meta-DiSc 1.4, the AUC was 0.76 (Q*=0.70). The pooled sensitivity and specificity were 0.60 (95% CI, 0.57–0.62) and 0.79 (95% CI, 0.76–0.81), respectively. A total of 198 overlapping genes were selected as the potential target genes of miR-122-5p, and 7 genes were defined as the hub genes from the PPI network. Cell division cycle 6 (CDC6), minichromosome maintenance complex component 4 (MCM4) and MCM8, which serve pivotal functions in the occurrence and development of HCC, were the most significant hub genes. The regulation of cell proliferation for cellular adhesion and the biosynthesis of amino acids was highlighted in the GO and KEGG pathway analyses. The downregulation of miR-122-5p in HCC demonstrated diagnostic value, worthy of further attention. Therefore, miR-122-5p may function as a tumor suppressor by modulating genome replication.
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Affiliation(s)
- Dong-Yue Wen
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jia-Cheng Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie-Yu Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Wen-Ya Pan
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiang-Hui Zeng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yu-Yan Pang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong Yang
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Hepatitis B virus promotes proliferation and metastasis in male Chinese hepatocellular carcinoma patients through the LEF-1/miR-371a-5p/SRCIN1/pleiotrophin/Slug pathway. Exp Cell Res 2018; 370:174-188. [DOI: 10.1016/j.yexcr.2018.06.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 06/14/2018] [Accepted: 06/16/2018] [Indexed: 12/13/2022]
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Malpeli G, Barbi S, Tosadori G, Greco C, Zupo S, Pedron S, Brunelli M, Bertolaso A, Scupoli MT, Krampera M, Kamga PT, Croce CM, Calin GA, Scarpa A, Zamò A. MYC-related microRNAs signatures in non-Hodgkin B-cell lymphomas and their relationships with core cellular pathways. Oncotarget 2018; 9:29753-29771. [PMID: 30038718 PMCID: PMC6049865 DOI: 10.18632/oncotarget.25707] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 04/28/2018] [Indexed: 12/19/2022] Open
Abstract
In order to investigate the role of microRNAs in the pathogenesis of different B-cell lymhoma subtypes, we have applied an array-based assay to a series of 76 mixed non-Hodgkin B-cell lymphomas, including Burkitt's lymphoma (BL), diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma. Lymphomas clustered according to histological subtypes, driven by two miRNA clusters (the miR-29 family and the miR-17-92 cluster). Since the two miRNA clusters are known to be MYC-regulated, we investigated whether this would be supported in MYC-driven experimental models, and found that this signature separated BL cell lines and a MYC-translocated MCL cell lines from normal germinal center B-cells and other B-cell populations. Similar results were also reproduced in tissue samples comparing BL and reactive lymph node samples. The same series was then quantitatively analyzed for MYC expression by immunohistochemistry and MYC protein levels were compared with corresponding miRNA signatures. A specific metric was developed to summarize the levels of MYC-related microRNAs and the corresponding protein levels. We found that MYC-related signatures are directly related to MYC protein expression across the whole spectrum of B-cells and B-cell lymphoma, suggesting that the MYC-responsive machinery shows predominantly quantitative, rather than qualitative, modifications in B-cell lymphoma. Novel MYC-related miRNAs were also discovered by this approach. Finally, network analysis found that in BL MYC-related differentially expressed miRNAs could control, either positively or negatively, a limited number of hub proteins, including BCL2, CDK6, MYB, ZEB1, CTNNB1, BAX and XBP1.
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Affiliation(s)
- Giorgio Malpeli
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Stefano Barbi
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Gabriele Tosadori
- Center for BioMedical Computing, University of Verona, Verona, Italy
| | - Corinna Greco
- Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Verona, Italy
| | - Simonetta Zupo
- Laboratory of Molecular Diagnostics, IRCCS-AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Serena Pedron
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Anna Bertolaso
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Maria Teresa Scupoli
- Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
| | - Mauro Krampera
- Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Verona, Italy
| | - Paul Takam Kamga
- Center for BioMedical Computing, University of Verona, Verona, Italy
| | - Carlo Maria Croce
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - George Adrian Calin
- Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
- Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy
| | - Alberto Zamò
- Department of Oncology, University of Turin, Torino, Italy
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Armengol C, Cairo S. Identification of theranostic biomarkers to improve the stratification of patients with pediatric liver cancer: Opportunities and challenges. Hepatology 2018; 68:10-12. [PMID: 29328497 DOI: 10.1002/hep.29779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 01/04/2018] [Indexed: 12/07/2022]
Affiliation(s)
- Carolina Armengol
- Childhood Liver Oncology Group (c-LOG)-CIBEREHD, Program for Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP) I Campus Can Ruti, Badalona, Spain
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von Frowein J, Hauck SM, Kappler R, Pagel P, Fleischmann KK, Magg T, Cairo S, Roscher A, von Schweinitz D, Schmid I. MiR-492 regulates metastatic properties of hepatoblastoma via CD44. Liver Int 2018; 38:1280-1291. [PMID: 29314711 DOI: 10.1111/liv.13687] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 12/18/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential. METHODS Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples. RESULTS We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival. CONCLUSIONS We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.
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Affiliation(s)
- Julia von Frowein
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum Munich (GmbH), German Research Center for Environmental Health, Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Philipp Pagel
- Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Freising, Germany.,numares AG, Regensburg, Germany
| | - Katrin K Fleischmann
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Thomas Magg
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefano Cairo
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.,XenTech, Evry, France
| | - Adelbert Roscher
- Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Irene Schmid
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
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Zhang Y, Zhao Y, Wu J, Liangpunsakul S, Niu J, Wang L. MicroRNA-26-5p functions as a new inhibitor of hepatoblastoma by repressing lin-28 homolog B and aurora kinase a expression. Hepatol Commun 2018; 2:861-871. [PMID: 30027143 PMCID: PMC6049067 DOI: 10.1002/hep4.1185] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/10/2018] [Accepted: 03/15/2018] [Indexed: 12/16/2022] Open
Abstract
Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA‐26a‐5p (miR‐26a‐5p), lin‐28 homolog B (LIN28B), Ras‐related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up‐regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR‐26a‐5p‐mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR‐26a‐5p markedly decreased LIN28B and AURKA 3′‐untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re‐expression of LIN28B and AURKA rescued miR‐26a‐5p‐mediated suppression of HB cell growth and clonality. Importantly, a decreased miR‐26a‐5p expression correlated with the poor outcome of patients with HB. Conclusion: miR‐26a‐5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B–RAN–AURKA pathway. (Hepatology Communications 2018;2:481‐491)
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Affiliation(s)
- Yutong Zhang
- Department of Physiology and Neurobiology and Institute for Systems Genomics University of Connecticut Storrs CT.,Department of Pediatric Oncology The First Hospital of Jilin University Changchun China
| | - Yulan Zhao
- Department of Physiology and Neurobiology and Institute for Systems Genomics University of Connecticut Storrs CT
| | - Jianguo Wu
- Department of Physiology and Neurobiology and Institute for Systems Genomics University of Connecticut Storrs CT
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine Indiana University School of Medicine Indianapolis IN.,Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis IN.,Roudebush Veterans Administration Medical Center Indianapolis IN
| | - Junqi Niu
- Department of Hepatology The First Hospital of Jilin University Changchun China
| | - Li Wang
- Department of Physiology and Neurobiology and Institute for Systems Genomics University of Connecticut Storrs CT.,Department of Internal Medicine Section of Digestive Diseases, Yale University New Haven CT.,Veterans Affairs Connecticut Healthcare System West Haven CT
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Cast A, Valanejad L, Wright M, Nguyen P, Gupta A, Zhu L, Shin S, Timchenko N. C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer. Hepatology 2018; 67:1857-1871. [PMID: 29159818 PMCID: PMC8221081 DOI: 10.1002/hep.29677] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 10/20/2017] [Accepted: 11/16/2017] [Indexed: 12/19/2022]
Abstract
UNLABELLED Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. CONCLUSION The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871).
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Affiliation(s)
- Ashley Cast
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Leila Valanejad
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Mary Wright
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Phuong Nguyen
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Anita Gupta
- Department of Pathology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Liqin Zhu
- Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN
| | - Soona Shin
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Nikolai Timchenko
- Department of Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229.,Correspondent author, Nikolai Timchenko, PhD, Professor of Pediatric General, and Thoracic Surgery, Director of Liver Tumor Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, Phone: 513-636-0129,
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Li H, Jin Y, Hu Y, Jiang L, Liu F, Zhang Y, Hao Y, Chen S, Wu X, Liu Y. The PLGF/c-MYC/miR-19a axis promotes metastasis and stemness in gallbladder cancer. Cancer Sci 2018; 109:1532-1544. [PMID: 29575299 PMCID: PMC5980328 DOI: 10.1111/cas.13585] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/14/2018] [Accepted: 03/17/2018] [Indexed: 12/13/2022] Open
Abstract
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract system. Epithelial-mesenchymal transition (EMT) plays a vital role in the process of tumor metastasis. Mesenchymal-like cells can serve as a source of cancer stem cells, which can confer the EMT phenotype. Placental growth factor (PLGF) belongs to the vascular endothelial growth factor family and plays a vital role in cancer. However, the underlying molecular mechanisms about the influence of PLGF on EMT in GBC remain unknown. Here we show that PLGF expression levels were higher in GBC tissues than in normal adjacent tissues and were associated with poor prognosis in GBC patients. Exogenous PLGF enhanced the migration, invasion, and tumorsphere formation of GBC cells. Conversely, knockdown of PLGF decreased the aggressive phenotype of GBC cells. Mechanistically, exogenous PLGF upregulated microRNA-19a (miR-19a) expression through the activation of c-MYC. Moreover, Spearman's correlation analysis showed a positive pairwise correlation among PLGF, c-MYC, and miR-19a expression in GBC tissues. Taken together, these results suggest that PLGF promotes EMT and tumorsphere formation through inducing miR-19a expression by upregulating c-MYC. Thus, PLGF could be a promising molecular therapeutic target for GBC.
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Affiliation(s)
- Huaifeng Li
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunpeng Jin
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yunping Hu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lin Jiang
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fatao Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yijian Zhang
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yajuan Hao
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shili Chen
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiangsong Wu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yingbin Liu
- Department of General Surgery and Laboratory of General SurgeryXinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Institute of Biliary Tract DiseaseShanghai Jiao Tong University School of MedicineShanghaiChina
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Ji F, Zhang ZH, Zhang Y, Shen SL, Cao QH, Zhang LJ, Li SQ, Peng BG, Liang LJ, Hua YP. Low expression of c-Myc protein predicts poor outcomes in patients with hepatocellular carcinoma after resection. BMC Cancer 2018; 18:460. [PMID: 29690860 PMCID: PMC5926532 DOI: 10.1186/s12885-018-4379-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 04/16/2018] [Indexed: 01/22/2023] Open
Abstract
Background Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-β) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-β signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-β signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood Methods The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-β1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined. Results The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-β1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-β1 or/and low ELF expression was associated with the worst DFS and OS. Conclusions Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-β1, and ELF can be used to accurately predict outcomes of patients with HCC.
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Affiliation(s)
- Fei Ji
- Pediatric Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Zhi-Heng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Yi Zhang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Shun-Li Shen
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Qing-Hua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Long-Juan Zhang
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Shao-Qiang Li
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Bao-Gang Peng
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Li-Jian Liang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Yun-Peng Hua
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
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Buendia MA, Armengol C, Cairo S. Molecular classification of hepatoblastoma and prognostic value of the HB 16-gene signature. Hepatology 2017; 66:1351-1352. [PMID: 28510309 DOI: 10.1002/hep.29262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 04/02/2017] [Indexed: 12/12/2022]
Affiliation(s)
| | - Carolina Armengol
- Childhood Liver Oncology Group (c-LOG), Program of Predictive and Personalized Medicine of Cancer (PMPCC), Health Sciences Institute Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona, Barcelona, Spain.,Centro de Investigación Biomédica en Red, CIBERehd, Madrid, Spain
| | - Stefano Cairo
- Research and Development Department, XenTech, Évry, France
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Yamamoto M, Xin B, Watanabe K, Ooshio T, Fujii K, Chen X, Okada Y, Abe H, Taguchi Y, Miyokawa N, Furukawa H, Nishikawa Y. Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:2711-2725. [PMID: 28964793 DOI: 10.1016/j.ajpath.2017.07.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/27/2017] [Accepted: 07/28/2017] [Indexed: 12/11/2022]
Abstract
Activation of the phosphoinositide 3-kinase-AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA for Afp, Dlk1, Nanog, and Sox2 and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase-AKT pathway is a key determinant of differentiation.
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Affiliation(s)
- Masahiro Yamamoto
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Bing Xin
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Kenji Watanabe
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Takako Ooshio
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Kiyonaga Fujii
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Xi Chen
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroaki Abe
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoshimitsu Taguchi
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Naoyuki Miyokawa
- Department of Surgical Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
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Wu JF, Chang HH, Lu MY, Jou ST, Chang KC, Ni YH, Chang MH. Prognostic roles of pathology markers immunoexpression and clinical parameters in Hepatoblastoma. J Biomed Sci 2017; 24:62. [PMID: 28851352 PMCID: PMC5574230 DOI: 10.1186/s12929-017-0369-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/21/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Hepatoblastoma, a leading primary hepatic malignant tumor in children, is originated from primitive hepatic stem cells. We aimed to elucidate the relationships between the histological distribution of β-catenin and hepatic stem cell markers with the clinical outcomes of hepatoblastoma. METHODS Immunohistochemistry was applied to detect β-catenin and hepatic stem cell markers expression in 31 hepatoblastoma tumors. We analyzed the relationship between the stem cell markers and the clinical course of hepatoblastoma. RESULTS Thirty-one hepatoblastoma patients were diagnosed at a mean age of 2.58 ± 3.78 years, and 7 (22.58%) died. A lack of anticipated decrease in alpha-fetal protein levels after neoadjuvant chemotherapy indicated a higher mortality rate. Nuclear β-catenin expression was significantly associated with membranous epithelial cell adhesion molecule (EpCAM) expression in hepatoblastoma tumor specimens. The co-expression of nuclear β-catenin and membranous EpCAM together with an age at diagnosis ≤1.25 years were predictive of an alpha-fetoprotein level < 1200 ng/mL after neoadjuvant chemotherapy (P < 0.05). An alpha-fetoprotein level < 1200 ng/mL after neoadjuvant chemotherapy and age at hepatoblastoma diagnosis ≤1.25 years are both predictors of better overall and native liver survival in hepatoblastoma patients. CONCLUSIONS Presence of membranous EpCAM with nuclear β-catenin and younger diagnostic age of hepatoblastoma are predictive of serum alpha-fetoprotein levels drop after chemotherapy. Younger diagnostic age and lower alpha-fetoprotein levels after neoadjuvant chemotherapy and are predictive of better overall and native liver survival in hepatoblastoma patients.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan
| | - Meng-Yao Lu
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Emergency, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd, Taipei, Taiwan.
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Liu Y, Cheng Z, Pan F, Yan W. MicroRNA-373 Promotes Growth and Cellular Invasion in Osteosarcoma Cells by Activation of the PI3K/AKT-Rac1-JNK Pathway: The Potential Role in Spinal Osteosarcoma. Oncol Res 2017; 25:989-999. [PMID: 28244849 PMCID: PMC7841136 DOI: 10.3727/096504016x14813867762123] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Spinal osteosarcoma (OS) has been proven to be more difficult to treat owing to potently malignant metastasis. The present study aimed to explore the functional role of microRNA (miR)-373 in cell growth and invasion of OS cells, as well as its underlying mechanism. The expression of miR-373 was analyzed in spinal OS tissues and cell lines. MG-63 cells were transfected with the miR-373 mimic or inhibitor and/or treated with the phosphoinositide 3-kinase (PI3K) (LY294002) inhibitor or Ras-related C3 botulinum toxin substrate 1 (Rac) guanosine triphosphate (GTPase) (NSC23766) inhibitor, and then the impact of miR-373 aberrant expression on cell growth and invasion was measured, along with the impact of overexpressing miR-373 on the expression of p53 and PI3K/AKT pathway-related proteins. We found that miR-373 was specifically upregulated in spinal OS tissues (p < 0.01) and OS cell lines (p < 0.01 or p < 0.001). Moreover, miR-373 expression was significantly associated with TNM stage (p = 0.035) and tumor size (p = 0.002). Overexpression of miR-373 promoted MG-63 cell viability, migration, invasion, and colony formation (all p < 0.05), while silencing of miR-373 and LY294002 exerted the opposite effects. Additionally, miR-373 overexpression downregulated p53 as well as its downstream targeted genes and orderly activated the PI3K/AKT-Rac1-JNK signaling pathway. In conclusion, miR-373 promotes growth and cellular invasion in OS cells by activating the PI3K/AKT-Rac1-JNK pathway. Therefore, miR-373 might be a candidate for molecular targeted therapy of spinal OS.
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Affiliation(s)
- Yufeng Liu
- *Spinal Surgery Dept1, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Zhengzhou, P.R. China
| | - Zhengliang Cheng
- †The First Department of Orthopedics, Ankang Hospital of Traditional Chinese Medicine, Ankang, P.R. China
| | - Feng Pan
- ‡Department of Acupuncture and Physiotherapy, Maternal and Child Health Care of Zaozhuang, Zaozhuang, P.R. China
| | - Weigang Yan
- §Spinal Surgery Dept4, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, P.R. China
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Valanejad L, Lewis K, Wright M, Jiang Y, D'Souza A, Karns R, Sheridan R, Gupta A, Bove K, Witte D, Geller J, Tiao G, Nelson DL, Timchenko L, Timchenko N. FXR-Gankyrin axis is involved in development of pediatric liver cancer. Carcinogenesis 2017; 38:738-747. [PMID: 28535186 PMCID: PMC5862323 DOI: 10.1093/carcin/bgx050] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 04/12/2017] [Accepted: 05/16/2017] [Indexed: 12/22/2022] Open
Abstract
The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.
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Affiliation(s)
| | | | | | - Yanjun Jiang
- Huffington Center on Aging, One Baylor Plaza, Houston, Texas, 77030, USA
| | | | | | | | | | | | | | | | | | | | - Lubov Timchenko
- Neurology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA; Baylor College of Medicine
| | - Nikolai Timchenko
- Departments of Surgery
- Huffington Center on Aging, One Baylor Plaza, Houston, Texas, 77030, USA
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