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1
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Lee SW, Kim J. Locking the Fate: How PROX1 Represses Plasticity and Liver Cancer. Cell Reprogram 2025. [PMID: 40135273 DOI: 10.1089/cell.2025.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
A Transcriptional Ridge in the Waddington Landscape. The Waddington landscape model, proposed in 1957, provides a powerful framework for understanding cell fate determination (Waddington, 1957). As development progresses, cells become restricted to distinct fates, separated by high "ridges" that prevent identity switching. A recent study in Nature Genetics uncovers such a ridge in hepatocyte lineage specification (Lim et al., 2025). Lim et al. report that prospero homeobox protein 1 (PROX1) acts as a hepatocyte-specific safeguard repressor, ensuring lineage stability by actively suppressing alternative cell fates and preventing cholangiocarcinoma development.
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Affiliation(s)
- Seung-Won Lee
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University (OHSU), School of Medicine, Portland, Oregon, USA
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University (OHSU), School of Medicine, Portland, Oregon, USA
- Department of Molecular and Medical Genetics, OHSU School of Medicine, Portland, Oregon USA
- Cancer Biology Program, Knight Cancer Institute, OHSU School of Medicine, Portland, Oregon, USA
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2
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Cui B, Tu S, Li H, Zeng Z, Xiao R, Guo J, Liang X, Liu C, Pan L, Chen W, Ge M, Zhong X, Ye L, Chen H, Zhang Q, Xu Y. METTL3 knockout accelerates hepatocarcinogenesis via inhibiting endoplasmic reticulum stress response. FEBS Open Bio 2025. [PMID: 40103332 DOI: 10.1002/2211-5463.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 02/24/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common causes of cancer-related deaths worldwide. Previous studies showed that N6-methyladenosine (m6A), the most abundant chemical modification in eukaryotic RNAs, is implicated in HCC progression. Using liver-specific conditional knockout mice, we found that the loss of METTL3, the core catalytic subunit of m6A methyltransferase, significantly promoted hepatic tumor initiation under various oncogenic challenges, contrary to the previously reported oncogenic role of METTL3 in liver cancer cell lines or xenograft models. Mechanistically, we hypothesized that METTL3 deficiency accelerated HCC initiation by inhibiting m6A deposition on MANF transcripts, impairing nuclear export and thus MANF protein levels, which led to insufficient endoplasmic reticulum (ER) stress response pathway activation. Our findings suggest a tumor-suppressive role for METTL3 in the early stages of HCC, emphasizing the importance of understanding the dynamic role of epigenetic regulation in tumorigenesis and targeted therapy.
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Affiliation(s)
- Bo Cui
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Silin Tu
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haibo Li
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhancheng Zeng
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ruiqi Xiao
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Guo
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqi Liang
- Cell-Gene Therapy Translational Medicine Research Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chang Liu
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lijie Pan
- Laboratory Animal Center, Sun Yat-sen University, Guangzhou, China
| | - Wenjie Chen
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Cell-Gene Therapy Translational Medicine Research Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mian Ge
- Department of Anesthesiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaofen Zhong
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linsen Ye
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huaxin Chen
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Cell-Gene Therapy Translational Medicine Research Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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3
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Liang Z, Ye Y, Deng Z, Lan H, Liu C, Xu Y, Fan M, Liu Z, Wu P, An L, Wang C. CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent in hepatocellular carcinoma. Pharmacol Res 2025; 215:107698. [PMID: 40107635 DOI: 10.1016/j.phrs.2025.107698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
Hepatocellular carcinoma (HCC) was associated with high morbidity and mortality, representing a significant health challenge. Chondroitin sulfate (CS), a glycosaminoglycan composed of glucuronic acid and N-acetylgalactosamine, is implicated in HCC progression through its role in cancer cell migration and proliferation as well as interactions with cell surface receptors integrin β-1 and CD44. Chondroitin polymerization factor 2 (CHPF2), the key to CS synthesis, has an undefined role in HCC. Our study aims to demonstrate that decreasing CHPF2 enzyme activity can inhibit the migration and proliferation of HCC cells. Bioinformatics analysis and in vitro experiments on clinical HCC samples confirmed the knockdown of CHPF2 inhibited HCC cell proliferation and migration. We further explored Rabdosia rubescens, a plant used in cancer therapy, for its potential to modulate CHPF2. Structural biology and ligand fishing identified ponicidin, a compound that significantly suppresses HCC cell growth and migration in both in vitro and in vivo models. These findings propose CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent for HCC management.
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Affiliation(s)
- Zuhui Liang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Yingyi Ye
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Zhihong Deng
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Huan Lan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Caihong Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Yuanhang Xu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Minqi Fan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Zhongqiu Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China
| | - Peng Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China.
| | - Lin An
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China.
| | - Caiyan Wang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China.
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4
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Molina-Pelayo FA, Zarate-Lopez D, García-Carrillo R, Rodríguez-Beas C, Íñiguez-Palomares R, Rodríguez-Mejía JL, Soto-Guzmán A, Velasco-Loyden G, Sierra-Martínez M, Virgen-Ortiz A, Sánchez-Pastor E, Magaña-Vergara NE, Baltiérrez-Hoyos R, Alamilla J, Chagoya de Sánchez V, Dagnino-Acosta A, Chávez E, Castro-Sánchez L. miRNAs-Set of Plasmatic Extracellular Vesicles as Novel Biomarkers for Hepatocellular Carcinoma Diagnosis Across Tumor Stage and Etiologies. Int J Mol Sci 2025; 26:2563. [PMID: 40141205 PMCID: PMC11942138 DOI: 10.3390/ijms26062563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of miRNAs in Extracellular Vesicles (EVs) from HCC. miRNA expression in EVs was analyzed using HCC cell lines, circulating EVs from a Diethylnitrosamine (DEN)-induced liver tumor rat model, and plasma samples from HCC patients. Receiver Operating Characteristics (ROCs) were applied to evaluate the diagnostic accuracy of circulating EV miRNAs in patients. Five miRNAs (miR-183-5p, miR-19a-3p, miR-148b-3p, miR-34a-5p, and miR-215-5p) were consistently up-regulated in EVs across in vitro and in vivo HCC models. These miRNAs showed statistically significant differences in HCC patients stratified by TNM staging and Edmondson-Steiner grading compared to healthy controls. They also differentiated HCC patients with various etiologies from the control group and distinguished HCC patients, with or without liver cirrhosis, from cirrhotic and healthy individuals. Individually and as a panel, they demonstrated high sensitivity, specificity, and accuracy in identifying HCC patients. Their consistent upregulation across models and clinical samples highlights their robustness as biomarkers for HCC diagnosis, offering the potential for early disease management and prognosis.
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Affiliation(s)
- Francisco A. Molina-Pelayo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - David Zarate-Lopez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Rosendo García-Carrillo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - César Rodríguez-Beas
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - Ramón Íñiguez-Palomares
- Departamento de Física, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico; (C.R.-B.); (R.Í.-P.)
| | - José L. Rodríguez-Mejía
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Adriana Soto-Guzmán
- Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo 83000, Sonora, Mexico;
| | - Gabriela Velasco-Loyden
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Mónica Sierra-Martínez
- Unidad de investigación en Salud, Hospital Regional de Alta Especialidad de Ixtapaluca, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS-BIENESTAR), Ciudad de México 01020, Mexico;
| | - Adolfo Virgen-Ortiz
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Enrique Sánchez-Pastor
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
| | - Nancy E. Magaña-Vergara
- Facultad de Ciencias Químicas, Universidad de Colima, Coquimatlán 28400, Colima, Mexico;
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | | | - Javier Alamilla
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Victoria Chagoya de Sánchez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Adán Dagnino-Acosta
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
| | - Enrique Chávez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (G.V.-L.); (V.C.d.S.)
| | - Luis Castro-Sánchez
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Colima, Mexico; (F.A.M.-P.); (D.Z.-L.); (R.G.-C.); (J.L.R.-M.); (A.V.-O.); (E.S.-P.); (J.A.); (A.D.-A.)
- SECIHTI—Universidad de Colima, Colima 28045, Colima, Mexico
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5
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Lim B, Kamal A, Gomez Ramos B, Adrian Segarra JM, Ibarra IL, Dignas L, Kindinger T, Volz K, Rahbari M, Rahbari N, Poisel E, Kafetzopoulou K, Böse L, Breinig M, Heide D, Gallage S, Barragan Avila JE, Wiethoff H, Berest I, Schnabellehner S, Schneider M, Becker J, Helm D, Grimm D, Mäkinen T, Tschaharganeh DF, Heikenwalder M, Zaugg JB, Mall M. Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis. Nat Genet 2025; 57:668-679. [PMID: 39948437 PMCID: PMC11906372 DOI: 10.1038/s41588-025-02081-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 01/08/2025] [Indexed: 02/20/2025]
Abstract
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
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Affiliation(s)
- Bryce Lim
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Aryan Kamal
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Borja Gomez Ramos
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Juan M Adrian Segarra
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ignacio L Ibarra
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Lennart Dignas
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tim Kindinger
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Volz
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nuh Rahbari
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
| | - Eric Poisel
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kanela Kafetzopoulou
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lio Böse
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Marco Breinig
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
| | - Suchira Gallage
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | | | - Hendrik Wiethoff
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Ivan Berest
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Sarah Schnabellehner
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Jonas Becker
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
| | - Dominic Helm
- Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
- German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, Heidelberg, Germany
| | - Taija Mäkinen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Translational Cancer Medicine Program and Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Darjus F Tschaharganeh
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | - Judith B Zaugg
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany.
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
| | - Moritz Mall
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany.
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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6
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Kulkarni AM, Kruse D, Harper K, Lam E, Osman H, Ansari DH, Sivanesan U, Bashir MR, Costa AF, McInnes M, van der Pol CB. Current State of Evidence for Use of MRI in LI-RADS. J Magn Reson Imaging 2025. [PMID: 39981949 DOI: 10.1002/jmri.29748] [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: 12/21/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/22/2025] Open
Abstract
The American College of Radiology Liver Imaging Reporting and Data System (LI-RADS) is the preeminent framework for classification and risk stratification of liver observations on imaging in patients at high risk for hepatocellular carcinoma. In this review, the pathogenesis of hepatocellular carcinoma and the use of MRI in LI-RADS is discussed, including specifically the LI-RADS diagnostic algorithm, its components, and its reproducibility with reference to the latest supporting evidence. The LI-RADS treatment response algorithms are reviewed, including the more recent radiation treatment response algorithm. The application of artificial intelligence, points of controversy, LI-RADS relative to other liver imaging systems, and possible future directions are explored. After reading this article, the reader will have an understanding of the foundation and application of LI-RADS as well as possible future directions.
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Affiliation(s)
- Ameya Madhav Kulkarni
- Department of Medical Imaging, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
- Department of Diagnostic Imaging, Juravinski Hospital and Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Danielle Kruse
- Departments of Radiology and Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Kelly Harper
- Department of Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
| | - Eric Lam
- Ottawa Hospital Research Institute Clinical Epidemiology Program, Ottawa, Ontario, Canada
| | - Hoda Osman
- Ottawa Hospital Research Institute Clinical Epidemiology Program, Ottawa, Ontario, Canada
| | - Danyaal H Ansari
- Ottawa Hospital Research Institute Clinical Epidemiology Program, Ottawa, Ontario, Canada
| | - Umaseh Sivanesan
- Department of Diagnostic Radiology, Kingston Health Sciences Centre, Kingston General Hospital, Kingston, Ontario, Canada
| | - Mustafa R Bashir
- Departments of Radiology and Medicine, Duke University Medical Center, Durham, North Carolina, USA
- Center for Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, North Carolina, USA
| | - Andreu F Costa
- Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Matthew McInnes
- Department of Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute Clinical Epidemiology Program, Ottawa, Ontario, Canada
| | - Christian B van der Pol
- Department of Medical Imaging, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
- Department of Diagnostic Imaging, Juravinski Hospital and Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada
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7
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Watling CZ, Hua X, Petrick JL, Zhang X, Do WL, Wang L, Maestri E, Yu K, Wang XW, McGlynn KA. Pan-serological antibodies and liver cancer risk: a nested case-control analysis. Sci Rep 2025; 15:5450. [PMID: 39953193 PMCID: PMC11828989 DOI: 10.1038/s41598-025-89629-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
Recently, studies have reported that pan-viral serology signatures may be predictive for liver cancer development. However, whether these same findings are observed for prospective studies has not been previously investigated. The nested case-control analysis included 191 persons who developed liver cancer and 382 controls from the PLCO prospective cohort. The presence of circulating antibodies, measured by VirScan, was determined in serum samples obtained at study recruitment. The presence of antibodies was compared between cases and controls using multivariable conditional logistic regressions, and prediction models were used to estimate whether exposures predicted liver cancer development. No significant associations were found between antibodies to viruses, bacteria or allergens and liver cancer risk after adjustment for multiple testing. The agent most significantly associated with risk was hepatitis C virus (HCV), but it was only detected among 23 participants (odds ratio (OR): 3.98; 95% confidence intervals (CI):1.59-9.99; p = 0.0032, False Discovery Rate (FDR) = 0.35). In prediction models based on 109 antibody features, no associations with liver cancer risk were observed (area under the curve [AUC]: 0.52-0.54). In analyses restricted to the most common type of liver cancer, hepatocellular carcinoma, the association with HCV was stronger (OR: 23.16, 95% CI: 4.55-117.68; FDR p-value = 0.0016), although prediction models based on all detected antibodies were similar (AUC = 0.55; 95% CI:0.43-0.68). Antibodies to no infectious agents, other than HCV, were found to be prospectively associated with liver cancer risk. The utility of using an antibody exposure signature prospectively for liver cancer development needs to be further explored.
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Affiliation(s)
- Cody Z Watling
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Xing Hua
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | | | - Xuehong Zhang
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Whitney L Do
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Limin Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Evan Maestri
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
- National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, 20850, USA.
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8
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Zhang B, Yang S, Chao X, Qi L, Qin W, Bai H, Wang X. Nitrogen-modified reduced graphene oxide for serum enrichment of N-glycans and MALDI-TOF MS-based identification of HCC biomarkers. Analyst 2025; 150:650-660. [PMID: 39831414 DOI: 10.1039/d4an01324g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Protein N-glycosylation, as one of the most crucial post-translational modifications, plays a significant role in various biological processes. The structural alterations of N-glycans are closely associated with the onset and progression of numerous diseases. Therefore, the precise and specific identification of disease-related N-glycans in complex biological samples is invaluable for understanding their involvement in physiological and pathological processes, as well as for discovering clinical diagnostic biomarkers. However, protein N-glycosylation suffers from microscopic heterogeneity and low abundance in biological systems, leading to N-glycopeptide signals being overshadowed by those of their non-glycosylated counterparts during mass spectrometry (MS) analysis. Consequently, there is an urgent demand for the development of novel methods for highly efficient N-glycan enrichment. In this study, we introduced a novel hydrophilic nanomaterial, nitrogen-modified reduced graphene oxide (N-rGO), tailored for this purpose, which was formed by a condensation reaction between the amino groups of rGO and the carboxyl groups of Fmoc-Photo-Linker. Compared to other enrichment materials, N-rGO not only supports efficient N-glycans enrichment via hydrophilic interaction (HILIC), but also serves as an effective matrix for direct MALDI-TOF MS analysis combined with DHB, thereby avoiding sample loss during N-glycans release. 76 and 81 serum N-glycans were obtained from 3 healthy individuals and 3 hepatocellular carcinoma (HCC) patients. Notably, relative quantification of serum N-glycans between 20 patients and 20 healthy controls showed significant expression differences, such as H5N4F1S1, H6N5F1, H5N4S2, H5N4F2S1 and H5N5F1S1, indicating the potential of N-rGO for biomarker discovery.
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Affiliation(s)
- Baoying Zhang
- Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China.
- National Center for Protein Sciences Beijing, State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Shengjie Yang
- Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China.
- Phase I Clinical Trial Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, PR China
| | - Xuyuan Chao
- Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China.
| | - Lu Qi
- Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China.
| | - Weijie Qin
- National Center for Protein Sciences Beijing, State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China
| | - Haihong Bai
- Department of Pharmacy, Beijing Youan Hospital of Capital Medical University, Beijing 100069, PR China.
| | - Xinghe Wang
- Phase I Clinical Trial Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China.
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9
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Nishitani M, Okada H, Nio K, Hayashi T, Terashima T, Iida N, Shimakami T, Takatori H, Honda M, Kaneko S, Sakamoto T, Yamashita T. Mint3 as a Molecular Target Activated in the Early Stage of Hepatocarcinogenesis. Int J Mol Sci 2025; 26:1430. [PMID: 40003897 PMCID: PMC11855386 DOI: 10.3390/ijms26041430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 01/30/2025] [Accepted: 02/02/2025] [Indexed: 02/27/2025] Open
Abstract
Mint3 enhances aerobic ATP production with subsequent nuclear translocation of hypoxia-inducible factor-1 (HIF-1) and activation of angiogenesis-related genes. It remains unclear if and when Mint3 is activated and whether it is involved in hepatocarcinogenesis. We explored the expression of Mint3 in surgically resected hepatocellular carcinoma (HCC) tissues. We evaluated the effects of Mint3 knockdown on spheroid formation capacity and subcutaneous tumor growth in immune-deficient mice. We used Mint3 knockout mice to evaluate the effects of chemically induced HCC development. Mint3 was overexpressed in well-differentiated HCC with the activation of HIF-1 target genes irrespective of the absence of hypervascularization. Mint3 knockdown ameliorated the expression of HIF-1 target genes in patient-derived HCC cell lines and suppressed spheroid formation. Mint3 knockdown further inhibited subcutaneous tumor formation in vivo in immune-deficient mice. Chemical HCC development induced by N-nitrosodiethylamine (DEN) or DEN/CCl4 was dramatically suppressed in Mint3 knockout mice compared to control mice. Mint3 plays a crucial role in early-stage HCC development before hypervascularization by activating HIF-1 target genes before the tumor becomes hypoxic. Mint3 is a molecular target that prevents HCC development in the early stages.
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MESH Headings
- Animals
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/chemically induced
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/chemically induced
- Humans
- Mice
- Mice, Knockout
- Male
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
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Affiliation(s)
- Masaki Nishitani
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Hikari Okada
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Tomoyuki Hayashi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
| | - Takeharu Sakamoto
- Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Osaka, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan; (M.N.); (H.O.); (K.N.); (T.H.); (T.T.); (N.I.); (T.S.); (H.T.); (M.H.); (S.K.)
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10
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Yu KL, Shen S. Could intratumoural microbiota be key to unlocking treatment responses in hepatocellular carcinoma? Eur J Cancer 2025; 216:115195. [PMID: 39729679 DOI: 10.1016/j.ejca.2024.115195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/12/2024] [Accepted: 12/18/2024] [Indexed: 12/29/2024]
Abstract
Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide. Current treatments include surgery and immunotherapy with variable response. Despite aggressive treatment, disease progression remains the biggest contributor to mortality. Thus, there is an urgent unmet need to improve current treatments through a better understanding of HCC tumourigenesis. The gut microbiota has been intensively examined in the context of HCC, with evidence showing gut modulation has the potential to modulate tumourigenesis and prognosis. In addition, recent literature suggests the presence of an intratumoural microbiota that may exert significant impacts on the development of solid tumours including HCC. By drawing parallels between the gut and hepatic/tumoural microbiota, we explore in the present review how the hepatic microbiota is established, its impact on tumourigenesis, and how modulation of the gut and hepatic microbiota may be key to improving current treatments of HCC. In particular, we highlight key bacteria that have been discovered in HCC tumours, and how they may affect the tumour immune microenvironment and HCC tumourigenesis. We then explore current therapies that target the intratumoural microbiota. With a deeper understanding of how the intratumoural microbiota is established, how different bacteria may be involved in HCC tumourigenesis, and how they can be targeted, we hope to spark future research in validating intratumoural microbiota as an avenue for improving treatment responses in HCC.
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Affiliation(s)
- Kin Lam Yu
- School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Kensington, NSW, Australia
| | - Sj Shen
- Microbiome Research Centre, St George and Sutherland Clinical Campuses, UNSW Sydney, Kogarah, NSW, Australia.
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11
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Ramakrishnan K, Sanjeev D, Rehman N, Raju R. A Network Map of Intracellular Alpha-Fetoprotein Signalling in Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e14035. [PMID: 39668590 DOI: 10.1111/jvh.14035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/03/2024] [Accepted: 10/18/2024] [Indexed: 12/14/2024]
Abstract
Alpha fetoprotein (AFP) is a glycoprotein of foetal origin belonging to the albumin protein family. Serum AFP is a long-conceived early-diagnostic biomarker for HCC with its elevated expression in different liver pathologies ranging from hepatitis viral infections to fibrosis, cirrhosis, and HCC. Beyond their utility as biomarkers, in support of its contribution to these clinical outcomes, the function of AFP as an immune suppressor and inducer of malignant transformation in HCC patients is well reported. Multiple reports show that AFP is secreted by hepatocytes, binds to its cognate receptor, AFP-receptor (AFPR), and exerts its actions. However, there is only limited information available in this context. There is an urgent need to gather more insight into the AFP signalling pathway and consider it a classical intracellular signalling pathway, among others. AFP is a highly potent intracellular molecule that has the potential to bind to many interactors like PTEN, Caspase, RAR, and so on. It has been shown that cellular AFP and secreted AFP have different roles in HCC pathophysiology, and a comprehensive map of the AFP signalling pathway is warranted for further theranostic applications.
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Affiliation(s)
| | - Diya Sanjeev
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
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12
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Sahu C, Sahu RK, Roy A. A Review on Nanotechnologically Derived Phytomedicines for the Treatment of Hepatocellular Carcinoma: Recent Advances in Molecular Mechanism and Drug Targeting. Curr Drug Targets 2025; 26:167-187. [PMID: 39385414 DOI: 10.2174/0113894501312571240920070441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/17/2024] [Accepted: 08/30/2024] [Indexed: 10/12/2024]
Abstract
The second largest cause of cancer-related death worldwide, Hepatocellular Carcinoma (HCC) is also the most common primary liver cancer. HCC typically arises in patients with liver cirrhosis. Existing synthetic medicines for treating chronic liver disease are ineffective and come with undesirable side effects. Although herbal remedies have widespread popularity, there is still a long road ahead before they are fully accepted by the scientific community. Secondary metabolites and phytochemicals found in plants are abundant in both the human diet and the non-human environment. Natural plant chemicals have been shown to be beneficial as therapeutic and chemopreventive treatments for a wide variety of chronic disorders. Many diseases, including HCC, can be effectively treated with the help of phytochemicals found in food. Resveratrol, curcumin, urolithin A, silibinin, quercetin, N-trans-feruloyl octopamine, emodin, lycopene, caffeine, and phloretin are all examples. Approximately, 60% of all anticancer medications are determined to be derived from natural substances, according to recent studies. Plant derivatives have played an important role in cancer due to their capacity to scavenge free radicals, limit cell proliferation, and set off apoptosis. The progression of HCC is linked to inflammatory signaling pathways, and this study sought to look at how novel approaches, such as phytomedicines, are being used to fight cancer. Recent advancements in molecular mechanisms and drug targeting for HCC have been discussed in this review.
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Affiliation(s)
| | - Ram Kumar Sahu
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Chauras Campus, Tehri Garhwal-249161, Uttarakhand, India
| | - Amit Roy
- Chhatrapati Shivaji Institute of Pharmacy, Bhilai, Chhattisgarh-491001, India
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13
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Alkafaas SS, Khedr SA, ElKafas SS, Hafez W, Loutfy SA, Sakran M, Janković N. Targeting JNK kinase inhibitors via molecular docking: A promising strategy to address tumorigenesis and drug resistance. Bioorg Chem 2024; 153:107776. [PMID: 39276490 DOI: 10.1016/j.bioorg.2024.107776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/13/2024] [Accepted: 08/28/2024] [Indexed: 09/17/2024]
Abstract
Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun N-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.
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Affiliation(s)
- Samar Sami Alkafaas
- Molecular Cell Biology Unit, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, 31527, Egypt.
| | - Sohila A Khedr
- Industrial Biotechnology Department, Faculty of Science, Tanta University, Tanta 31733, Egypt
| | - Sara Samy ElKafas
- Production Engineering and Mechanical Design Department, Faculty of Engineering, Menofia University, Menofia, Egypt; Faculty of Control System and Robotics, ITMO University, Saint-Petersburg, Russia
| | - Wael Hafez
- NMC Royal Hospital, 16th St - Khalifa City - SE-4 - Abu Dhabi, United Arab Emirates; Department of Internal Medicine, Medical Research and Clinical Studies Institute, The National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, Cairo Governorate 12622, Egypt
| | - Samah A Loutfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Sakran
- Biochemistry Department, Faculty of Science, University of Tabuk, Tabuk 47512, Saudi Arabia
| | - Nenad Janković
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
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14
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Song M, Tao Y, Zhang H, Du M, Guo L, Hu C, Zhang W. Gd-EOB-DTPA-enhanced MR imaging features of hepatocellular carcinoma in non-cirrhotic liver. Magn Reson Imaging 2024; 114:110241. [PMID: 39362318 DOI: 10.1016/j.mri.2024.110241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 09/17/2024] [Accepted: 09/29/2024] [Indexed: 10/05/2024]
Abstract
OBJECTIVE To evaluate clinical, pathological and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) findings of hepatocellular carcinoma (HCC) in non-cirrhotic livers and compare with HCC in cirrhotic livers. METHODS This retrospective study included patients with pathologically confirmed HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI between January 2015 and October 2021. Propensity scores were utilized to match non-cirrhotic HCCs (NCHCCs) patients with cirrhotic HCCs (CHCCs) patients. The clinical, pathological and MR imaging features of NCHCCs were compared with CHCCs. Correlation between these features and the presence of NCHCCs were analyzed by logistic regression analysis. The predictive efficacy was evaluated using receiver operating characteristic (ROC) analysis. The area under the receiver operating characteristic curve (AUC) was used to compare performance, and the Delong test was used to compare AUCs. RESULTS After propensity score matching (1:3), a total of 144 patients with HCCs (36 NCHCCs and 108 CHCCs) were included. NCHCCs were larger in tumor size than CHCCs (P < 0.001, Cohen's d = 0.737). NCHCCs were more common in patients who have hepatitis C (5.6 % vs 1.9 %, P > 0.05) or have no known liver disease (11.1 % vs 0.9 %, P = 0.004), while hepatitis B was more common in CHCC patients (83.3 % vs 97.2 %, P = 0.003). Compared with CHCCs, NCHCCs more frequently demonstrated non-smooth tumor margin (P = 0.001, Cramer's V = 0.273), peri-tumoral hyperintensity (P < 0.05, Cramer's V = 0.185), hyperintense and heterogeneous signals in hepatobiliary phase (HBP) (P < 0.05). CHCCs were more likely to have satellite nodules compared to NCHCCs (33.3 % vs 57.4 %, P < 0.05, Cramer's V = 0.209). Based on the univariate and multivariate logistic regression analysis, the tumor size, non-smooth tumor margin, heterogeneous intensity in HBP and satellite nodule were significantly correlated to NCHCCs (P all <0.05). ROC curve analysis demonstrated that tumor size and non-smooth tumor margin were potential imaging predictors for the diagnosis of NCHCC, with AUC values of 0.715 and 0.639, respectively. The combination of the two imaging features for identifying NCHCC achieved an AUC value of 0.761, with a sensitivity of 0.889 and a specificity of 0.630. CONCLUSION NCHCCs were more likely to show larger tumor size, non-smooth tumor margin, peri-tumoral hyperintensity, as well as hyperintense and heterogeneous signals in HBP at Gd-EOB-DTPA-enhanced MR imaging compared with NCHCCs. Tumor size and non-smooth tumor margin in HBP may help to discriminate NCHCCs.
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Affiliation(s)
- Mingyue Song
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yuhao Tao
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Hanjun Zhang
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Mingzhan Du
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Chunhong Hu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Weiguo Zhang
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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15
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Zhao Y, Wang F, Lei X, Li Z, Cao Q, Jiang R, Xu C, Li K. High throughput sequencing reveals alterations in B cell receptor repertoires associated with the progression of hepatic cirrhosis to hepatocellular carcinoma. TUMORI JOURNAL 2024; 110:462-469. [PMID: 39482814 DOI: 10.1177/03008916241290638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is developed as a consequence of chronic liver cirrhosis, and both diseases are difficult to diagnose and differentiate. Accurate noninvasive biomarkers for HCC and liver cirrhosis are urgently needed. METHODS Here we used high-throughput sequencing to characterize the B cell receptor (BCR) repertoires from 36 HCC tumor samples and 10 liver cirrhosis (LC) tissue biopsies to understand the immune alterations during hepatic carcinogenesis. RESULTS The principal components analysis (PCA) showed that the pattern of BCR in HCC was distinct from that in LC. As measured by Clonality and Shannon indexes, the diversity of BCR repertoire was significantly lower in HCC than in LC (P < 0.01). CONCLUSION Our results corroborated that the BCR diversity and composition could be closely correlated with hepatic carcinogenesis. And BCR repertoire may be used to predict the progression of HCC and design targeting immunotherapy in the near future.
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Affiliation(s)
- Yingying Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Fengyan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
- Shandong Provincial Key Laboratory of Neuroprotective Drugs, Zibo 255400, China
| | - Xiaofei Lei
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Ziqiang Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Qiwei Cao
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, 250013, China
| | - Runze Jiang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250013, China
| | - Changqing Xu
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
| | - Kun Li
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University&Shandong provincial Qianfoshan Hospital, Jinan, 250013, China
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16
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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17
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Yeh CH, Chen RY, Wu TH, Chang SY, Hsieh TY, Shih YL, Lin YW. Promoter hypermethylation-mediated downregulation of PAX6 promotes tumor growth and metastasis during the progression of liver cancer. Clin Epigenetics 2024; 16:174. [PMID: 39614377 DOI: 10.1186/s13148-024-01789-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/19/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND The progression of liver cancer is a complicated process that involves genetic and epigenetic changes. Paired box 6 (PAX6) is a critical transcription factor for embryonic development. PAX6 is abnormally methylated in human cancer. The role of the PAX6 gene in the pathogenesis of hepatocellular carcinoma (HCC) is still unclear. METHODS Transcriptional silencing of PAX6 mediated by promoter methylation was confirmed using quantitative methylation-specific polymerase chain reaction (PCR) and reverse-transcription (RT)-PCR. Then we conducted gain-and-loss of function approaches to evaluate the function of PAX6 in HCC progression in vitro. Moreover, we designed xenograft mouse models to assess the effect of PAX6 on tumor growth and metastasis. Finally, we used RNA sequencing (RNA-seq) strategy and phenotypic rescue experiments to identify potential targets of PAX6 performing tumor-suppressive function. RESULTS Constitutive expression of PAX6 suppressed anchorage-independent growth and cell invasion in vitro as well as tumor growth and metastasis in xenograft mouse models. In contrast, the inhibition of PAX6 using knockout and knockdown strategies increased tumor growth both in vitro and in vivo. Downregulation of PAX6 by doxycycline depletion partially reversed the malignant phenotypes of HCC cells induced by PAX6. Moreover, we identified E-cadherin (CDH1) and thrombospondin-1 (THBS1) as targets of PAX6. Ultimately, we demonstrated that the knockdown of CDH1 and overexpression of THBS1 in PAX6-expressing HCC cells partly reversed the tumor-suppressive effect. CONCLUSION PAX6 functions as a tumor suppressor partly through upregulation of CDH1 and downregulation of THBS1. Promoter hypermethylation-mediated suppression of PAX6 reduces the tumor suppressor function in the progression of liver cancer.
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Affiliation(s)
- Ching-Hua Yeh
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Rou-Yu Chen
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Ti-Hui Wu
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shan-Yueh Chang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Lueng Shih
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Ya-Wen Lin
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, 11490, Taiwan.
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
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18
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Saber S, Abdelhady R, Elhemely MA, Elmorsy EA, Hamad RS, Abdel-Reheim MA, El-Kott AF, AlShehri MA, Morsy K, AlSheri AS, Youssef ME. PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond. Front Pharmacol 2024; 15:1475998. [PMID: 39564119 PMCID: PMC11573589 DOI: 10.3389/fphar.2024.1475998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 10/22/2024] [Indexed: 11/21/2024] Open
Abstract
Heat shock protein 90 (HSP90) is a pivotal molecular chaperone with multifaceted roles in cellular health and disease. Herein, we explore how HSP90 orchestrates cellular stress responses, particularly through its partnership with heat shock factor 1 (HSF-1). PU-H71, a selective inhibitor of HSP90, demonstrates significant potential in cancer therapy by targeting a wide array of oncogenic pathways. By inducing the degradation of multiple client proteins, PU-H71 disrupts critical signaling pathways such as MAPK, PI3K/Akt, JAK/STAT, EGFR, and mTOR, which are essential for cancer cell survival, proliferation, and metastasis. We examined its impact on combating triple-negative breast cancer and enhancing the effectiveness of carbon-ion beam therapy, offering new avenues for cancer treatment. Furthermore, the dual inhibition of HSP90A and HSP90B1 by PU-H71 proves highly effective in the context of myeloma, providing fresh hope for patients with this challenging malignancy. We delve into its potential to induce apoptosis in B-cell lymphomas that rely on Bcl6 for survival, highlighting its relevance in the realm of hematologic cancers. Shifting our focus to hepatocellular carcinoma, we explore innovative approaches to chemotherapy. Moreover, the current review elucidates the potential capacity of PU-H71 to suppress glial cell activation paving the way for developing novel therapeutic strategies for neuroinflammatory disorders. Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes.
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Affiliation(s)
- Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Rasha Abdelhady
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Chinese University, Cairo, Egypt
| | - Mai A Elhemely
- School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Elsayed A Elmorsy
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, Saudi Arabia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
| | - Attalla F El-Kott
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Mohammed A AlShehri
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Kareem Morsy
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt
| | - Ali S AlSheri
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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19
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Zhou X, Chen Z, Yu Y, Li M, Cao Y, Prochownik EV, Li Y. Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8 + T Cell Activation and Allow Tumor Immune Escape. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403629. [PMID: 39325640 DOI: 10.1002/advs.202403629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 08/27/2024] [Indexed: 09/28/2024]
Abstract
Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti-tumor immunity mediated by CD8+ T cells. In HCCs, depletion of PMVK is required to facilitate CD8+ T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ-aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl-CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4-acetaminobutyric acid (4-Ac-GABA), which is released into the TME. There, 4-Ac-GABA activates the GABAA receptor (GABAAR) on CD8+ T cells, which inhibits AKT1 signaling. This in turn suppresses CD8+ T cell activation, intratumoral infiltration, and the anti-tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti-PD-1 immune checkpoint therapy. These findings reveal non-canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8+ T cell inhibitor 4-Ac-GABA. Blocking 4-Ac-GABA signaling in CD8+ T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.
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Affiliation(s)
- Xinyi Zhou
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Zhiqiang Chen
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yijiang Yu
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Mengjiao Li
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yu Cao
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Edward V Prochownik
- Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The Department of Microbiology and Molecular Genetics, The Pittsburgh Liver Research Center and The Hillman Cancer Center of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15224, USA
| | - Youjun Li
- Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
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20
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Musa Y, Ifeorah IM, Maiyaki AS, Almustapha RM, Maisuna YA, Saleh HT, Yakubu A. Liver cell cancer surveillance practice in Nigeria: Pitfalls and future prospects. World J Hepatol 2024; 16:1132-1141. [PMID: 39474579 PMCID: PMC11514613 DOI: 10.4254/wjh.v16.i10.1132] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/24/2024] [Accepted: 09/20/2024] [Indexed: 10/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a disease of public health concern in Nigeria, with chronic hepatitis B and C infections contributing most to the disease burden. Despite the increasing incidence of HCC, surveillance practices for early diagnosis and possible cure are not deeply rooted in the country. This article aims to review the current status of HCC surveillance in Nigeria, stressing the encounters, breaches, and potential prospects. Several factors, such as limited tools for screening and diagnostics, insufficient infrastructure, and low cognizance among the doctors, and the general public affect the surveillance practices for HCC in Nigeria. Moreover, the lack of standardized guidelines and protocols for HCC surveillance further intensifies the suboptimal diagnosis and treatment. Nevertheless, there are opportunities for refining surveillance practices in the country. This would be achieved through boosted public health sensitization campaigns, integrating HCC screening into routine clinical services, and leveraging technological developments for early detection and monitoring. Furthermore, collaboration between government agencies, healthcare providers, and international organizations can facilitate the development of comprehensive HCC surveillance programs personalized to the Nigerian setting. Thus, HCC surveillance practice faces substantial challenges. By addressing the drawbacks and leveraging prospects, Nigeria can improve HCC surveillance, with subsequent improved outcomes for individuals at risk of developing the disease.
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Affiliation(s)
- Yusuf Musa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Federal Teaching Hospital Katsina, Katsina 820101, Nigeria
| | - Ijeoma M Ifeorah
- Department of Medical Laboratory Sciences, College of Medicine University of Nigeria Enugu Campus, Enugu 400102, Nigeria
| | - Abubakar Sadiq Maiyaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840283, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University Teaching Hospital Sokoto, Sokoto 840101, Nigeria
| | - Rahama Mohammad Almustapha
- Infection Prevention and Control Unit, Department of Community Medicine, Federal Teaching Hospital, Katsina 820101, Katsina, Nigeria
| | - Yussuf Abdulkadir Maisuna
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bayero University Kano, Kano 700101, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Habib Tijjani Saleh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Federal Teaching Hospital Katsina, Katsina 820101, Nigeria
| | - Abdulmumini Yakubu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University, Sokoto 840283, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto 840283, Nigeria
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21
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Musa Y, Ifeorah IM, Maiyaki AS, Almustapha RM, Maisuna YA, Saleh HT, Yakubu A. Liver cell cancer surveillance practice in Nigeria: Pitfalls and future prospects. World J Hepatol 2024; 16:1312-1321. [DOI: 10.4254/wjh.v16.i10.1312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/24/2024] [Accepted: 09/20/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a disease of public health concern in Nigeria, with chronic hepatitis B and C infections contributing most to the disease burden. Despite the increasing incidence of HCC, surveillance practices for early diagnosis and possible cure are not deeply rooted in the country. This article aims to review the current status of HCC surveillance in Nigeria, stressing the encounters, breaches, and potential prospects. Several factors, such as limited tools for screening and diagnostics, insufficient infrastructure, and low cognizance among the doctors, and the general public affect the surveillance practices for HCC in Nigeria. Moreover, the lack of standardized guidelines and protocols for HCC surveillance further intensifies the suboptimal diagnosis and treatment. Nevertheless, there are opportunities for refining surveillance practices in the country. This would be achieved through boosted public health sensitization campaigns, integrating HCC screening into routine clinical services, and leveraging technological developments for early detection and monitoring. Furthermore, collaboration between government agencies, healthcare providers, and international organizations can facilitate the development of comprehensive HCC surveillance programs personalized to the Nigerian setting. Thus, HCC surveillance practice faces substantial challenges. By addressing the drawbacks and leveraging prospects, Nigeria can improve HCC surveillance, with subsequent improved outcomes for individuals at risk of developing the disease.
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Affiliation(s)
- Yusuf Musa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Federal Teaching Hospital Katsina, Katsina 820101, Nigeria
| | - Ijeoma M Ifeorah
- Department of Medical Laboratory Sciences, College of Medicine University of Nigeria Enugu Campus, Enugu 400102, Nigeria
| | - Abubakar Sadiq Maiyaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840283, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University Teaching Hospital Sokoto, Sokoto 840101, Nigeria
| | - Rahama Mohammad Almustapha
- Infection Prevention and Control Unit, Department of Community Medicine, Federal Teaching Hospital, Katsina 820101, Katsina, Nigeria
| | - Yussuf Abdulkadir Maisuna
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bayero University Kano, Kano 700101, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Habib Tijjani Saleh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Federal Teaching Hospital Katsina, Katsina 820101, Nigeria
| | - Abdulmumini Yakubu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University, Sokoto 840283, Nigeria
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto 840283, Nigeria
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22
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Chahine JJ, Davis SS, Culfaci S, Kallakury BV, Tuma PL. Chromosome 8q24 amplification associated with human hepatocellular carcinoma predicts MYC/ZEB1/MIZ1 transcriptional regulation. Sci Rep 2024; 14:24488. [PMID: 39424877 PMCID: PMC11489779 DOI: 10.1038/s41598-024-75219-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 10/03/2024] [Indexed: 10/21/2024] Open
Abstract
Genomic instability is associated with late stage carcinomas and the epithelial mesenchymal transition (EMT). Of note is chromosome 8q24 amplification that has been documented in many epithelial-derived carcinomas. On this amplified region is the potent oncogene, c-myc. Not only does MYC overexpression activate targets that promote cell proliferation, it also activates transcription factors that drive EMT, including ZEB1. Further reinforcing EMT, overexpressed MYC also represses tumor suppressors involved in promoting the epithelial phenotype, including MIZ1. We predict that as carcinomas progress, chromosome 8q24 is amplified leading to high MYC levels that leads to ZEB1 expression and MIZ1 repression driving cells through EMT. To interrogate this clinically, limited cohorts of human epithelial-derived carcinomas were examined for MYC/ZEB1/MIZ1 expression patterns across increasing carcinoma grades. Interestingly, the predicted temporal patterns were only observed in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinomas. Yet MIZ1 proved to be an excellent marker to assess carcinoma progression across types. We expanded the HCC cohort and determined that c-myc amplification was restricted to grade III/IV HCC that also exhibited increased MYC and ZEB1 nuclear expression whereas cytosolic MIZ1 expression was lost and only nuclear expression retained. These same resections were obtained from only individuals who had histories of alcohol consumption that were also diagnosed with cirrhosis, metastasis and had viral hepatitis suggesting etiology-specific mechanisms of cancer progression. Finally, analysis performed in Hep3B cells determined that alterations in MYC expression promoted the predicted changes in ZEB1 and MIZ1 expression and/or distributions and in markers for EMT further suggesting a relationship among these three transcription factors in HCC and their correlation to driving EMT.
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Affiliation(s)
- Joeffrey J Chahine
- Department of Pathology, MedStar Georgetown University Hospital, 20007, Washington, DC, USA
| | - Saniya S Davis
- Department of Biology, The Catholic University of America, 620 Michigan Avenue, NE, 103 McCort-Ward, 20064, Washington, DC, USA
| | - Sumeyye Culfaci
- Department of Pathology, MedStar Georgetown University Hospital, 20007, Washington, DC, USA
| | - Bhaskar V Kallakury
- Department of Pathology, MedStar Georgetown University Hospital, 20007, Washington, DC, USA
| | - Pamela L Tuma
- Department of Biology, The Catholic University of America, 620 Michigan Avenue, NE, 103 McCort-Ward, 20064, Washington, DC, USA.
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23
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Więckowska M, Cichon N, Szelenberger R, Gorniak L, Bijak M. Ochratoxin A and Its Role in Cancer Development: A Comprehensive Review. Cancers (Basel) 2024; 16:3473. [PMID: 39456567 PMCID: PMC11506779 DOI: 10.3390/cancers16203473] [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: 09/13/2024] [Revised: 10/05/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Ochratoxin A (OTA) is widely recognized for its broad spectrum of toxic effects and is classified as a potential human carcinogen, placed in group 2B by the International Agency for Research on Cancer (IARC). Its presence in food and beverages poses a significant health hazard. Extensive research has documented the efficient absorption and distribution of OTA throughout the body via the bloodstream and tissues, underscoring the associated health risk. Additionally, ongoing studies aim to clarify the link between OTA exposure and carcinogenesis. The obtained results indicate a strong correlation between OTA and renal cell carcinoma (RCC), with potential associations with other malignancies, including hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and squamous cell carcinoma (SCC). OTA is implicated in oxidative stress, lipid peroxidation, apoptosis, DNA damage, adduct formation, miRNA deregulation, and distributions in the cell cycle, all of which may contribute to carcinogenesis. Conclusions: Despite significant research efforts, the topic remains inexhaustible and requires further investigation. The obtained results do not yield definitive conclusions, potentially due to species-specific differences in the animal models used and challenges in extrapolating these results to humans. In our review, we delve deeper into the potential mechanisms underlying OTA-induced carcinogenesis and discuss existing limitations, providing directions for future research.
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Affiliation(s)
| | - Natalia Cichon
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; (M.W.); (R.S.); (L.G.); (M.B.)
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24
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Kazi IA, Jahagirdar V, Kabir BW, Syed AK, Kabir AW, Perisetti A. Role of Imaging in Screening for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3400. [PMID: 39410020 PMCID: PMC11476228 DOI: 10.3390/cancers16193400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/22/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening.
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Affiliation(s)
- Irfan A. Kazi
- Department of Radiology, University of Missouri Columbia, Columbia, MO 65212, USA;
| | - Vinay Jahagirdar
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Bareen W. Kabir
- Department of Internal Medicine, University of Missouri Columbia, Columbia, MO 65212, USA;
| | - Almaan K. Syed
- Blue Valley Southwest High School, Overland Park, KS 6622, USA;
| | | | - Abhilash Perisetti
- Division of Gastroenterology and Hepatology, Kansas City Veteran Affairs, Kansas City, MO 64128, USA
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25
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Wang K, Chen XY, Zhang RWY, Yue Y, Wen XL, Yang YS, Han CY, Ma Y, Liu HJ, Zhu HL. Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions. Biomaterials 2024; 310:122635. [PMID: 38810386 DOI: 10.1016/j.biomaterials.2024.122635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 05/17/2024] [Accepted: 05/26/2024] [Indexed: 05/31/2024]
Abstract
Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.
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Affiliation(s)
- Kai Wang
- Affiliated Children's Hospital of Jiangnan University, Wuxi, 214023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Xu-Yang Chen
- Affiliated Children's Hospital of Jiangnan University, Wuxi, 214023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Ren-Wei-Yang Zhang
- Affiliated Children's Hospital of Jiangnan University, Wuxi, 214023, China
| | - Ying Yue
- Affiliated Children's Hospital of Jiangnan University, Wuxi, 214023, China
| | - Xiao-Lin Wen
- Affiliated Children's Hospital of Jiangnan University, Wuxi, 214023, China
| | - Yu-Shun Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Chen-Yang Han
- The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314001, China
| | - Yuan Ma
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.
| | - Hong-Ji Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
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Asgharzadeh F, Moradi Binabaj M, Fanoudi S, C. Cho W, Yang YJ, Azarian M, Shafiee Ardestani M, Nasiri N, Ramezani Farani M, Huh YS. Nanomedicine Strategies Utilizing Lipid-Based Nanoparticles for Liver Cancer Therapy: Exploring Signaling Pathways and Therapeutic Modalities. Adv Pharm Bull 2024; 14:513-523. [PMID: 39494254 PMCID: PMC11530870 DOI: 10.34172/apb.2024.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/03/2024] [Accepted: 07/29/2024] [Indexed: 11/05/2024] Open
Abstract
Liver cancer, specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related deaths, following pancreatic cancer. The 5-year overall survival rate for HCC remains relatively low. Currently, there are multiple treatment options available for HCC, including systemic drugs, minimally invasive local therapies such as radiofrequency ablation, transarterial chemoembolization (TACE), and arterial radioembolization (TARE), as well as surgical interventions like liver resection or transplantation. However, the effectiveness of drug delivery to the cancerous liver is hindered by pathophysiological changes in the organ. In order to address this challenge, lipid-based nanoparticles (LNPs) have emerged as promising platforms for delivering a diverse range of therapeutic drugs. LNPs offer various structural configurations that enhance their physical stability and enable them to accommodate different types of cargo with varying mechanical properties and degrees of hydrophobicity. In this article, we provide a comprehensive review of the current applications of LNPs in the development of anti-HCC therapies. By examining the existing research, we aim to shed light on the potential future directions and advancements in this field.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Moradi Binabaj
- Department of Nutrition, Food Sciences and Clinical Biochemistry, School of Medicine, Social Determinants of Health Research Center, Gonabad University of Medical Science, Gonabad, Iran
| | - Sahar Fanoudi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Yu-jeong Yang
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
| | - Maryam Azarian
- Department of Radiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Mehdi Shafiee Ardestani
- Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Nasiri
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Marzieh Ramezani Farani
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
| | - Yun Suk Huh
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
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Yang JK, Kim J, Ahn YH, Bae SH, Baek MJ, Lee SH, Moon JS. Inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human hepatocellular carcinoma. BMB Rep 2024; 57:459-464. [PMID: 39219047 PMCID: PMC11524825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/07/2024] [Accepted: 09/01/2024] [Indexed: 09/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. HCC occurs people with chronic liver diseases. The purinergic receptor P2X 7 (P2RX7) is involved in tumor proliferation and growth. Also, P2RX7 is associated with tumor invasion and metastatic dissemination. High glucose utilization is important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellular survival of HCC remains unclear. Here, our results show that the gene and protein levels of P2RX7 were elevated in tumor cells of patients with HCC. The pharmacological inhibition of P2RX7 by A-804598, a selective P2RX7 antagonist, and genetic inhibition by P2RX7 knockdown suppressed the glycolytic activity by reduction of hexokinase 2 (HK2), a key enzyme of the glycolysis pathway, in human HCC cells. Also, both A-804598 treatment and P2RX7 knockdown induced cytotoxicity via inhibition of AKT activation which is critical for tumor cell survival in human HCC cells. Moreover, A-804598 treatment and P2RX7 knockdown increased cytotoxicity and caspase-3 activation in human HCC cells. These results suggest that inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human HCC. [BMB Reports 2024; 57(10): 459-464].
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Affiliation(s)
- Jae Kook Yang
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Junhyung Kim
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Korea
| | - Young Hyeon Ahn
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Sang Ho Bae
- Department of Surgery, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Moo-Jun Baek
- Department of Surgery, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan 31151, Korea
| | - Jong-Seok Moon
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Korea
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
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Hao P, Li Q, Zhao H. Mucin 1 expression is regulated by hsa_circ_0055054/microRNA‑122‑5p and promotes hepatocellular carcinoma development. Oncol Lett 2024; 28:404. [PMID: 38983125 PMCID: PMC11228922 DOI: 10.3892/ol.2024.14537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/29/2024] [Indexed: 07/11/2024] Open
Abstract
The abnormal expression of mucin 1 (MUC1) is a major cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Competitive endogenous RNA demonstrates a novel regulatory mechanism that can affect the biological behavior of tumors. In the present study, the regulatory functions of hsa_circ_0055054 as well as those of microRNA (miR/miRNA) 122-5p on MUC1 expression and its role in HCC cell proliferation, migration and invasion, were evaluated. MUC1 expression was assessed using western blotting and reverse transcription-quantitative PCR. The phenotypic functions of the HCC cell lines were evaluated following MUC1 knockdown using Cell Counting Kit-8, wound healing and Transwell assays. Bioinformatics tools were used to identify specific miRNAs and circular (circ)RNAs that interact with and can regulate MUC1. The stability of circRNAs was assessed using a Ribonuclease R assay. The binding of circRNA/miRNA/MUC1 was assessed using dual-luciferase reporter assays and cellular function tests. Finally, in vivo experiments were performed using animal models. The results demonstrated that in MHCC97L cells, MUC1 and hsa_circ_0055054 were expressed at high levels while miR-122-5p was downregulated. The proliferation, migration and invasion of MHCC97L cells were suppressed by low MUC1 expression. hsa_circ_0055054 knockdown or miR-122-5p overexpression both led to a decrease in MUC1 expression. In MHCC97L cells with a low MUC1 expression caused by hsa_circ_0055054 knockdown, miR-122-5p inhibition resulted in the increased proliferation, migration and invasion of MHCC97L cells. In combination, the results of the present study indicate that hsa_circ_0055054 knockdown in MHCC97L cells leads to an increased expression of miR-122-5p and decreased expression of MUC1, which results in the inhibition of MHCC97L cell proliferation, migration and invasion.
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Affiliation(s)
- Pengfei Hao
- Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Qi Li
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, P.R. China
| | - Haoliang Zhao
- Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi 030032, P.R. China
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29
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Rivera-Esteban J, Muñoz-Martínez S, Higuera M, Sena E, Bermúdez-Ramos M, Bañares J, Martínez-Gomez M, Cusidó MS, Jiménez-Masip A, Francque SM, Tacke F, Minguez B, Pericàs JM. Phenotypes of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2024; 22:1774-1789.e8. [PMID: 38604295 DOI: 10.1016/j.cgh.2024.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 04/13/2024]
Abstract
Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.
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Affiliation(s)
- Jesús Rivera-Esteban
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sergio Muñoz-Martínez
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain; Universitat de Barcelona, Barcelona, Spain
| | - Mónica Higuera
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - Elena Sena
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - María Bermúdez-Ramos
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain; Liver Unit, Department of Digestive Diseases, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Juan Bañares
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - María Martínez-Gomez
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - M Serra Cusidó
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain
| | - Alba Jiménez-Masip
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Sven M Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Beatriz Minguez
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Madrid, Spain.
| | - Juan M Pericàs
- Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Campus Hospitalari, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Madrid, Spain.
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Liang J, Liao Y, Tu Z, Liu J. Revamping Hepatocellular Carcinoma Immunotherapy: The Advent of Microbial Neoantigen Vaccines. Vaccines (Basel) 2024; 12:930. [PMID: 39204053 PMCID: PMC11359864 DOI: 10.3390/vaccines12080930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Immunotherapy has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC). However, its efficacy varies significantly with each patient's genetic composition and the complex interactions with their microbiome, both of which are pivotal in shaping anti-tumor immunity. The emergence of microbial neoantigens, a novel class of tumor vaccines, heralds a transformative shift in HCC therapy. This review explores the untapped potential of microbial neoantigens as innovative tumor vaccines, poised to redefine current HCC treatment modalities. For instance, neoantigens derived from the microbiome have demonstrated the capacity to enhance anti-tumor immunity in colorectal cancer, suggesting similar applications in HCC. By harnessing these unique neoantigens, we propose a framework for a personalized immunotherapeutic response, aiming to deliver a more precise and potent treatment strategy for HCC. Leveraging these neoantigens could significantly advance personalized medicine, potentially revolutionizing patient outcomes in HCC therapy.
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Affiliation(s)
| | | | | | - Jinping Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (J.L.); (Y.L.); (Z.T.)
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31
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Kotulkar M, Paine-Cabrera D, Apte U. Role of Hepatocyte Nuclear Factor 4 Alpha in Liver Cancer. Semin Liver Dis 2024; 44:383-393. [PMID: 38901435 DOI: 10.1055/a-2349-7236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the incidence of HCC is on the rise. Liver cancers in general and HCC in particular do not respond to chemotherapy. Radiological ablation, surgical resection, and liver transplantation are the only medical therapies currently available. Hepatocyte nuclear factor 4 α (HNF4α) is an orphan nuclear receptor expressed only in hepatocytes in the liver. HNF4α is considered the master regulator of hepatic differentiation because it regulates a significant number of genes involved in various liver-specific functions. In addition to maintaining hepatic differentiation, HNF4α also acts as a tumor suppressor by inhibiting hepatocyte proliferation by suppressing the expression of promitogenic genes and inhibiting epithelial to mesenchymal transition in hepatocytes. Loss of HNF4α expression and function is associated with rapid progression of chronic liver diseases that ultimately lead to liver cirrhosis and HCC, including metabolism-associated steatohepatitis, alcohol-associated liver disease, and hepatitis virus infection. This review summarizes the role of HNF4α in liver cancer pathogenesis and highlights its potential as a potential therapeutic target for HCC.
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Affiliation(s)
- Manasi Kotulkar
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Diego Paine-Cabrera
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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Li J, Wang H, Lu Q, Han J, Xu H, Sun P, Xu Q, Huang J, Ji J. Lysosome-Related Genes and RNF19B as Prognostic Markers for Survival and Immunotherapy Efficacy in Hepatocellular Carcinoma. Clin Transl Gastroenterol 2024; 15:e1. [PMID: 38546132 PMCID: PMC11196081 DOI: 10.14309/ctg.0000000000000701] [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: 10/19/2023] [Accepted: 03/18/2024] [Indexed: 06/26/2024] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) poses a considerable worldwide health concern due to its associated high risk of death. The heterogeneity of HCC poses challenges in developing practical risk stratification tools and identifying prognostic markers for personalized targeted treatments. Recently, lysosomes were shown to be crucial contributors to numerous cellular activities, including tumor initiation and immune response regulation. We aimed to construct a reliable prognostic signature based on lysosome-related genes and determine its association with the immune microenvironment. METHODS We comprehensively analyzed lysosome-related genes in HCC to investigate their influence on patient survival and the tumor immune microenvironment. A prognostic signature comprising 14 genes associated with lysosomes was created to estimate the survival outcomes of individuals with HCC. In addition, we verified the prognostic importance of Ring Finger Protein 19B (RNF19B) in patients with HCC through multiplex immunohistochemistry analysis. RESULTS Our constructed lysosome-related prediction model could significantly discriminate between HCC patients with good and poor survival outcomes ( P < 0.05). We also found that elevated RNF19B expression was linked to unfavorable prognostic outcomes and showed a connection with specific clinicopathological characteristics. Moreover, it was observed that RNF19B could facilitate the transformation of macrophages into M2-polarized macrophages and showed a significant positive correlation with PD-1 and CTLA-4. DISCUSSION In summary, our study proposes that the expression of lysosome-related genes is associated with the immune microenvironment, serving as a predictor for HCC patient survival. Meanwhile, RNF19B was identified as a novel prognostic marker for predicting overall survival and immunotherapy effects in patients with HCC.
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Affiliation(s)
- Jieying Li
- Department of Pathology, Medical School of Nantong University & Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Hui Wang
- Department of Pathology, Medical School of Nantong University & Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Qian Lu
- Department of General Surgery, Tongzhou People's Hospital, Nantong, Jiangsu Province, China
| | - Jiayi Han
- Department of Pathology, Medical School of Nantong University & Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Haiyan Xu
- Department of Pathology, Medical School of Nantong University & Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, China
| | - Pingping Sun
- Department of Clinical Biobank & The Institute of Oncology, the Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Qiang Xu
- Department of Pathology, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, China
| | - Jianfei Huang
- Department of Clinical Biobank & The Institute of Oncology, the Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu Province, China
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Peruhova M, Banova-Chakarova S, Miteva DG, Velikova T. Genetic screening of liver cancer: State of the art. World J Hepatol 2024; 16:716-730. [PMID: 38818292 PMCID: PMC11135278 DOI: 10.4254/wjh.v16.i5.716] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria
| | - Sonya Banova-Chakarova
- Department of Gastroenterology, University Hospital "Heart and Brain", Burgas 8000, Bulgaria.
| | - Dimitrina Georgieva Miteva
- Department of Genetics, Faculty of Biology, Sofia University" St. Kliment Ohridski, Sofia 1164, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Ali FEM, Ibrahim IM, Althagafy HS, Hassanein EHM. Role of immunotherapies and stem cell therapy in the management of liver cancer: A comprehensive review. Int Immunopharmacol 2024; 132:112011. [PMID: 38581991 DOI: 10.1016/j.intimp.2024.112011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/08/2024]
Abstract
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan.
| | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
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35
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Hu Z, Kurihara T, Sun Y, Cetin Z, Florentino RM, Faccioli LAP, Liu Z, Yang B, Ostrowska A, Soto-Gutierrez A, Delgado ER. A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.18.590120. [PMID: 38712079 PMCID: PMC11071316 DOI: 10.1101/2024.04.18.590120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis and well-differentiated HCC, characterized by increased fibrosis, altered liver architecture, and enhanced hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and HCC rat model successfully replicates the clinical progression of human HCC, including liver function impairment and early-stage liver cancer characteristics. It presents a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.
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Chen C, Wang C, Li Y, Jiang S, Yu N, Zhou G. Prognosis and chemotherapy drug sensitivity in liver hepatocellular carcinoma through a disulfidptosis-related lncRNA signature. Sci Rep 2024; 14:7157. [PMID: 38531953 DOI: 10.1038/s41598-024-57954-7] [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: 10/12/2023] [Accepted: 03/23/2024] [Indexed: 03/28/2024] Open
Abstract
Disulfidptosis, a new type of regulated cell death associated with the actin cytoskeleton, provides a new therapeutic tool for cancers. The direct relationship between disulfidptosis-related lncRNAs(DRLs) in liver hepatocellular carcinoma(HCC) remains unclear. We acquired transcriptomic data, corresponding clinical data, and tumor mutation data of HCC from the TCGA database. First of all, DRLs were determined through correlation analysis. Then, a prognostic model containing six DRLs was created by adopting univariate Cox regression, LASSO algorithm and multivariate Cox regression analysis. Based on the model, 424 HCC patients were divided into high- and low-risk groups. Next, we structured ROC curves and PCA through combining the model and clinical data. Enrichment analysis and immune infiltration analysis were adopted to further explore the relationship between the model and prognosis. In addition, we explored the relationship between the model and tumor mutation burden (TMB). There were significant differences between high- and low- risk groups, and patients in the high-risk group showed poor prognosis. Enrichment analysis suggested that metabolic progress was obviously different between the two groups. According to the analysis of immune infiltration, there were several differences in immune cells, function, and checkpoints. Patients with high-risk and high TMB demonstrated the least favorable prognosis. The two risk groups both manifested visiblly in chemotherapy drug sensitivity. To sum up, we set up a DRL-based signature and that may provide a predictable value for the prognosis and use of chemotherapy drugs for HCC patients.
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Affiliation(s)
- Chao Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Chaoyang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Yi Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Shanshan Jiang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ningjun Yu
- Department of Radiology, Sichuan Science Hospital, Mianyang, 621022, Sichuan, China
| | - Guofeng Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Yu X, Zhang H, Li J, Gu L, Cao L, Gong J, Xie P, Xu J. Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening. Front Cell Dev Biol 2024; 12:1237445. [PMID: 38374893 PMCID: PMC10875080 DOI: 10.3389/fcell.2024.1237445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.
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Affiliation(s)
- Xiang Yu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Hao Zhang
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jinze Li
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lu Gu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Cao
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jun Gong
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ping Xie
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jian Xu
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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Rawal P, Tripathi DM, Hemati H, Kumar J, Tyagi P, Sarin SK, Nain V, Kaur S. Targeted HBx gene editing by CRISPR/Cas9 system effectively reduces epithelial to mesenchymal transition and HBV replication in hepatoma cells. Liver Int 2024; 44:614-624. [PMID: 38105495 DOI: 10.1111/liv.15805] [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: 08/03/2022] [Revised: 10/28/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND AND AIMS Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. METHODOLOGY AND RESULTS We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both two- and three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. CONCLUSION Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC.
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Affiliation(s)
- Preety Rawal
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Dinesh Mani Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Hamed Hemati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Jitendra Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Purnima Tyagi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Vikrant Nain
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
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Kong Y, Wang Y, Yang Q, Ye S. Immunotherapy and liver cancer research trends and the 100 most cited articles: A bibliometric analysis. Technol Health Care 2024; 32:5141-5155. [PMID: 39093101 PMCID: PMC11613086 DOI: 10.3233/thc-241111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 07/10/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Bibliometric analysis of liver cancer research, particularly in immunotherapy, reveals crucial insights. The US leads in liver cancer mortality but ranks fifth globally. OBJECTIVE Scopus database analysis identified 2,349 papers, with the top 100 ranging from 127 to 4,959 citations. Notably, "Microenvironmental Regulation of Tumours Progression and Metastasis" in the Journal of Nature Medicine garnered the highest citations. METHODS Journals like the Journal of Hepatology, Hepatology, and Nature Reports Clinical Oncology contributed significantly. Understanding molecular mechanisms and prognostic indicators is paramount for advancing combination therapies. RESULTS For better patient outcomes, research trends in liver cancer immunotherapy point to improved treatment protocols, knowledge of the tumor microenvironment, combining therapies, predicting disease course, international cooperation, sophisticated surgical techniques, early detection, oncolytic virotherapy, and patient-centered care. CONCLUSIONS This research underscores immunotherapy's pivotal role and encourages further exploration, offering valuable insights into liver cancer treatment trends.
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Affiliation(s)
- Yang Kong
- Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yizhi Wang
- Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Qifan Yang
- Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Song Ye
- Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Li X, Zheng N, Yu Y, Zhang W, Sun S, An Q, Li Z, Ji Y, Wang S, Shi Y, Li W. Individual and combined effects of phthalate metabolites on eczema in the United States population. ENVIRONMENTAL RESEARCH 2024; 240:117459. [PMID: 37914015 DOI: 10.1016/j.envres.2023.117459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/22/2023] [Accepted: 10/19/2023] [Indexed: 11/03/2023]
Abstract
Phthalates might trigger immune dysregulation. The relationship between a phthalate mixture exposure and eczema remains unclear. To address this research gap, four statistical models were used to investigate the individual, combined, and interaction relationships between monoesters of phthalates (MPAEs) and eczema, including the logistic regression, weighted quantile sum regression (WQS), quantile g computation (qg-computation), and bayesian kernel machine regression (BKMR). Moreover, subgroup analyses were performed by sex and age. After adjusting for all covariates, the logistic regression model suggested a positive correlation between mono-(3-carboxypropyl) phthalate (MCPP) and eczema. Subgroup analysis suggested that the effect of the MPAEs on eczema was predominantly present in men and children. In the WQS model, the joint effect of 11 MPAEs on eczema was marginally significant [odds ratio = 1.36, 95% confidence interval: 0.97-1.90]. Moreover, a positive association was observed between the combined exposure to 11 MPAEs and eczema in the BKMR model. MCPP and mono-(carboxynonyl) phthalate were the most substantial risk factors based on the results of WQS and qg-computation models. The exposure to a mixture of MPAEs may lead to an elevated prevalence of eczema in the United States population, with men and children being particularly vulnerable to their effects.
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Affiliation(s)
- Xiaoqian Li
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Na Zheng
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China.
| | - Yan Yu
- Department of Dermatology, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Wenhui Zhang
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Siyu Sun
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Qirui An
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Zimeng Li
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Yining Ji
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Sujing Wang
- Key Laboratory of Groundwater Resources and Environment of the Ministry of Education, College of New Energy and Environment, Jilin University, Changchun, 130012, Jilin, China
| | - Ying Shi
- Department of Dermatology, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Wanlei Li
- Department of Dermatology, First Hospital of Jilin University, Changchun, 130021, Jilin, China
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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Chen H, Durand S, Bawa O, Bourgin M, Montégut L, Lambertucci F, Motiño O, Li S, Nogueira-Recalde U, Anagnostopoulos G, Maiuri MC, Kroemer G, Martins I. Biomarker Identification in Liver Cancers Using Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) Imaging: An Approach for Spatially Resolved Metabolomics. Methods Mol Biol 2024; 2769:199-209. [PMID: 38315399 DOI: 10.1007/978-1-0716-3694-7_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Liver cancers are characterized by interindividual and intratumoral heterogeneity, which makes early diagnosis and the development of therapies challenging. Desorption electrospray ionization mass spectrometry (DESI-MS) imaging is a potent and sensitive MS ionization technique for direct, unaltered 2D and 3D imaging of metabolites in complex biological samples. Indeed, DESI gently desorbs and ionizes analyte molecules from the sample surface using an electrospray source of highly charged aqueous spray droplets in ambient conditions. DESI-MS imaging of biological samples allows untargeted analysis and characterization of metabolites in liver cancers to identify new biomarkers of malignancy. In this chapter, we described a detailed protocol using liver cancer samples collected and stored for histopathology examination, either as frozen or as formalin-fixed, paraffin-embedded specimens. Such hepatocellular carcinoma samples can be subjected to DESI-MS analyses, illustrating the capacity of spatially resolved metabolomics to distinguish malignant lesions from adjacent normal liver tissue.
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Affiliation(s)
- Hui Chen
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France
| | - Sylvère Durand
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Olivia Bawa
- PETRA, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Mélanie Bourgin
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Léa Montégut
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France
| | - Flavia Lambertucci
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Omar Motiño
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Sijing Li
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France
| | - Uxía Nogueira-Recalde
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Rheumatology Research Group (GIR), Biomedical Research Institute of A Coruña (INIBIC), Professor Novoa Santos Foundation, A Coruña, Spain
| | - Gerasimos Anagnostopoulos
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
| | - Maria Chiara Maiuri
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Department of Molecular Medicine and Medical Biotechnologies, University of Napoli Federico II, Naples, Italy
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Isabelle Martins
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, UMS AMICCa, Gustave Roussy, Villejuif, France.
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Cao K, Wang R, Li L, Liao Y, Hu X, Li R, Liu X, Xiong XD, Wang Y, Liu X. Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination. Oncogene 2024; 43:35-46. [PMID: 38007537 DOI: 10.1038/s41388-023-02898-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 11/27/2023]
Abstract
Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9-mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.
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Affiliation(s)
- Kun Cao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China.
| | - Ruonan Wang
- Scientific Research Platform Service Management Center, Guangdong Medical University, Dongguan, 523808, China
| | - Lianhai Li
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China
| | - Yuting Liao
- Department of Radiotherapy, General Hospital of Southern Theater Command of the Chinese People's Liberation Army, Guangzhou, 510016, China
| | - Xiao Hu
- Department of Surgery, The Second People's Hospital of Guangdong Province, Guangzhou, 510317, China
| | - Ruixue Li
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China
| | - Xiuwen Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China
| | - Xing-Dong Xiong
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China.
| | - Yanjie Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China.
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44
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Cuesta ÁM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, Porras A. New and Old Key Players in Liver Cancer. Int J Mol Sci 2023; 24:17152. [PMID: 38138981 PMCID: PMC10742790 DOI: 10.3390/ijms242417152] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.
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Affiliation(s)
- Ángel M. Cuesta
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Nerea Palao
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Paloma Bragado
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alvaro Gutierrez-Uzquiza
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Blanca Herrera
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Aránzazu Sánchez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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45
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Wu Y, Yang Y, Yi X, Song L. The circSNX14 functions as a tumor suppressor via the miR-562/ LATS2 pathway in hepatocellular carcinoma cells. J Mol Histol 2023; 54:593-607. [PMID: 37861952 DOI: 10.1007/s10735-023-10157-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/17/2023] [Indexed: 10/21/2023]
Abstract
Circular RNAs (circRNAs) play critical roles in the initiation and progression of various cancers. However, the potential functional roles of circSNX14 in hepatocellular carcinoma (HCC) remain largely unknown. CircSNX14 expression pattern was analyzed in HCC tissues and cell lines via qRT-PCR. The effects of circSNX14 on cell proliferation, invasion, angiogenesis, and Epithelial-mesenchymal transition (EMT) were investigated by overexpression experiments. The role of circSNX14 in the tumorigenesis of HCC cells was examined using in vivo xenograft mouse model. The interaction between circSNX14, miR-562, and Large Tumor Suppressor Kinase 2 (LATS2) mRNA was confirmed by Luciferase reporter assay and RNA immunoprecipitation (RIP) analysis. CircSNX14 was significantly down-regulated in HCC tissues and cell lines, and its down-regulation was correlated with a poor prognosis in HCC patients. In the following functional experiments, circSNX14 overexpression remarkably suppressed the proliferation and invasion of HCC cells, and attenuated the mesenchymall status. circSNX14 overexpression also suppressed the tumorigenesis of HCC cells in the mouse model. We further revealed the interaction of circSNX14 and miR-562, and miR-562 could suppress the expression of LATS2 by interacting with its mRNA. The negative correlation of circSNX14 and miR-562, negative correlation of miR-562 and LATS2, and positive correlation of circSNX14 and LATS2 have been confirmed by Pearson correlation in the HCC samples. Collectively, these results reveal a novel role of circSNX14/miR-562/LATS2 axis in regulating the malignant progression of HCC cancer progression, indicating the tumor suppressor role of circSNX14 and its potential as a prognostic biomarker.
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Affiliation(s)
- Yan Wu
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, No.55 University Town Middle Road, Shapingba District, Chongqing, 401331, China
| | - Yaowei Yang
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, No.55 University Town Middle Road, Shapingba District, Chongqing, 401331, China
| | - Xin Yi
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, No.55 University Town Middle Road, Shapingba District, Chongqing, 401331, China
| | - Liwen Song
- Department of General Surgery, University-Town Hospital of Chongqing Medical University, No.55 University Town Middle Road, Shapingba District, Chongqing, 401331, China.
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46
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Takao S, Fukushima H, King AP, Kato T, Furusawa A, Okuyama S, Kano M, Choyke PL, Escorcia FE, Kobayashi H. Near-infrared photoimmunotherapy in the models of hepatocellular carcinomas using cetuximab-IR700. Cancer Sci 2023; 114:4654-4663. [PMID: 37817415 PMCID: PMC10727998 DOI: 10.1111/cas.15965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/22/2023] [Accepted: 09/01/2023] [Indexed: 10/12/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in many cancers, and overexpression of EGFR is frequently observed in hepatocellular carcinomas (HCCs). Near-infrared photoimmunotherapy (NIR-PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells after NIR light-induced photochemical reaction of IR700, which is bound to a targeting antibody on the cell membrane. NIR-PIT using cetuximab-IR700 has already been approved in Japan, is under review by the US Food and Drug Administration (FDA) for advanced head and neck cancers, and its safety has been established. However, EGFR has not been investigated as a target in NIR-PIT in HCCs. Here, we investigate the application of NIR-PIT using cetuximab-IR700 to HCCs using xenograft mouse models of EGFR-expressing HCC cell lines, Hep3B, HuH-7, and SNU-449. In vitro NIR-PIT using EGFR-targeted cetuximab-IR700 killed cells in a NIR light dose-dependent manner. In vivo NIR-PIT resulted in a delayed growth compared with untreated controls. In addition, in vivo NIR-PIT in both models showed histological signs of cancer cell damage, such as cytoplasmic vacuolation and nuclear dysmorphism. A significant decrease in Ki-67 positivity was also observed after NIR-PIT, indicating decreased cancer cell proliferation. This study suggests that NIR-PIT using cetuximab-IR700 has potential for the treatment of EGFR-expressing HCCs.
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Affiliation(s)
- Seiichiro Takao
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Hiroshi Fukushima
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - A. Paden King
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Takuya Kato
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Aki Furusawa
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Shuhei Okuyama
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Makoto Kano
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Peter L. Choyke
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Freddy E. Escorcia
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaMarylandUSA
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47
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Wu Q, Wang P, Peng Q, Kang Z, Deng Y, Li J, Chen Y, Li J, Ge F. Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker. Int J Mol Sci 2023; 24:16986. [PMID: 38069309 PMCID: PMC10707058 DOI: 10.3390/ijms242316986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Adhesion G protein-coupled receptor G2 (ADGRG2) is an orphan adhesion G protein-coupled receptor (GPCR), which performs a tumor-promoting role in certain cancers; however, it has not been systematically investigated in hepatocellular carcinoma (HCC). In the current study, we utilized multiple databases to analyze the expression and diagnostic and prognostic value of ADGRG2 in HCC and its correlation with immune infiltration and inflammatory factors. The function and upstream regulatory miRNA of ADGRG2 were validated through qPCR, Western blot, CCK8, wound healing, and dual luciferase assays. It turned out that ADGRG2 was significantly higher in HCC and had a poor survival rate, especially in AFP ≤ 400 ng/mL subgroups. Functional enrichment analysis suggested that ADGRG2 may be involved in cancer pathways and immune-related pathways. In vitro, siRNA-mediated ADGRG2 silencing could inhibit the proliferation and migration of Huh7 and HepG2 cells. There was a highly significant positive correlation between ADGRG2 and neutrophils. Moreover, NET-related genes were filtered and confirmed, such as ENO1 and S100A9. Meanwhile, the high expression of ADGRG2 was also accompanied by the highest number of inflammatory cytokines, chemokines, and chemokine receptors and good immunotherapy efficacy. Finally, AGDGR2 may be sensitive to two drugs (PIK-93 and NPK76-II-72-1) and can be targeted by miR-326. In conclusion, ADGRG2 may serve as a novel biomarker and drug target for HCC diagnosis, immunotherapy, and prognosis and was related to neutrophils and the inflammatory process of liver cancer development.
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Affiliation(s)
- Qian Wu
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Pei Wang
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Qihang Peng
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Zhongcui Kang
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Yiting Deng
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Jiayi Li
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Ying Chen
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Jin Li
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Feng Ge
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
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48
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Wang Y, Shi C, Guo J, Zhang Y, Gong Z. Distinct Types of Cell Death and Implications in Liver Diseases: An Overview of Mechanisms and Application. J Clin Transl Hepatol 2023; 11:1413-1424. [PMID: 37719956 PMCID: PMC10500292 DOI: 10.14218/jcth.2023.00132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/17/2023] [Accepted: 07/12/2023] [Indexed: 09/19/2023] Open
Abstract
Cell death is associated with a variety of liver diseases, and hepatocyte death is a core factor in the occurrence and progression of liver diseases. In recent years, new cell death modes have been identified, and certain biomarkers have been detected in the circulation during various cell death modes that mediate liver injury. In this review, cell death modes associated with liver diseases are summarized, including some cell death modes that have emerged in recent years. We described the mechanisms associated with liver diseases and summarized recent applications of targeting cell death in liver diseases. It provides new ideas for the diagnosis and treatment of liver diseases. In addition, multiple cell death modes can contribute to the same liver disease. Different cell death modes are not isolated, and they interact with each other in liver diseases. Future studies may focus on exploring the regulation between various cell death response pathways in liver diseases.
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Affiliation(s)
- Yukun Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jin Guo
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yanqiong Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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49
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Yamaguchi M. Regucalcin Is a Potential Regulator in Human Cancer: Aiming to Expand into Cancer Therapy. Cancers (Basel) 2023; 15:5489. [PMID: 38001749 PMCID: PMC10670417 DOI: 10.3390/cancers15225489] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/24/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Regucalcin, a calcium-binding protein lacking the EF-hand motif, was initially discovered in 1978. Its name is indicative of its function in calcium signaling regulation. The rgn gene encodes for regucalcin and is situated on the X chromosome in both humans and vertebrates. Regucalcin regulates pivotal enzymes involved in signal transduction and has an inhibitory function, which includes protein kinases, protein phosphatases, cysteinyl protease, nitric oxide dynthetase, aminoacyl-transfer ribonucleic acid (tRNA) synthetase, and protein synthesis. This cytoplasmic protein is transported to the nucleus where it regulates deoxyribonucleic acid and RNA synthesis as well as gene expression. Overexpression of regucalcin inhibits proliferation in both normal and cancer cells in vitro, independent of apoptosis. During liver regeneration in vivo, endogenous regucalcin suppresses cell growth when overexpressed. Regucalcin mRNA and protein expressions are significantly downregulated in tumor tissues of patients with various types of cancers. Patients exhibiting upregulated regucalcin in tumor tissue have shown prolonged survival. The decrease of regucalcin expression is linked to the advancement of cancer. Overexpression of regucalcin carries the potential for preventing and treating carcinogenesis. Additionally, extracellular regucalcin has displayed control over various types of human cancer cells. Regucalcin may hold a prominent role as a regulatory factor in cancer development. Supplying the regucalcin gene could prove to be a valuable asset in cancer treatment. The therapeutic value of regucalcin suggests its potential significance in treating cancer patients. This review delves into the most recent research on the regulatory role of regucalcin in human cancer development, providing a novel approach for treatment.
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Affiliation(s)
- Masayoshi Yamaguchi
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, 701 Ilalo Street, Hawaii, HI 96813, USA
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50
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Asahina Y, Takatori H, Nio K, Okada H, Hayashi T, Hayashi T, Hashiba T, Suda T, Nishitani M, Sugimoto S, Honda M, Kaneko S, Yamashita T. Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression. Int J Mol Sci 2023; 24:16283. [PMID: 38003473 PMCID: PMC10671815 DOI: 10.3390/ijms242216283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/05/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs.
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Affiliation(s)
| | - Hajime Takatori
- Department of Gastroenterology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan
| | - Kouki Nio
- Department of Gastroenterology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan
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