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Ding DY, Jiang SY, Zu YX, Yang Y, Gan XJ, Yuan SX, Zhou WP. Collagen in hepatocellular carcinoma: A novel biomarker and therapeutic target. Hepatol Commun 2024; 8:e0489. [PMID: 38967581 PMCID: PMC11227359 DOI: 10.1097/hc9.0000000000000489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/22/2024] [Indexed: 07/06/2024] Open
Abstract
HCC is globally recognized as a major health threat. Despite significant progress in the development of treatment strategies for liver cancer, recurrence, metastasis, and drug resistance remain key factors leading to a poor prognosis for the majority of liver cancer patients. Thus, there is an urgent need to develop effective biomarkers and therapeutic targets for HCC. Collagen, the most abundant and diverse protein in the tumor microenvironment, is highly expressed in various solid tumors and plays a crucial role in the initiation and progression of tumors. Recent studies have shown that abnormal expression of collagen in the tumor microenvironment is closely related to the occurrence, development, invasion, metastasis, drug resistance, and treatment of liver cancer, making it a potential therapeutic target and a possible diagnostic and prognostic biomarker for HCC. This article provides a comprehensive review of the structure, classification, and origin of collagen, as well as its role in the progression and treatment of HCC and its potential clinical value, offering new insights into the diagnosis, treatment, and prognosis assessment of liver cancer.
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Affiliation(s)
- Dong-yang Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
| | - Shu-ya Jiang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
| | - Yun-xi Zu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
| | - Xiao-jie Gan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, P. R. China
| | - Sheng-xian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
| | - Wei-ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, P. R. China
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Pan X, Ni S, Hu K. Nanomedicines for reversing immunosuppressive microenvironment of hepatocellular carcinoma. Biomaterials 2024; 306:122481. [PMID: 38286109 DOI: 10.1016/j.biomaterials.2024.122481] [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: 09/08/2023] [Revised: 01/18/2024] [Accepted: 01/20/2024] [Indexed: 01/31/2024]
Abstract
Although immunotherapeutic strategies such as immune checkpoint inhibitors (ICIs) have gained promising advances, their limited efficacy and significant toxicity remain great challenges for hepatocellular carcinoma (HCC) immunotherapy. The tumor immunosuppressive microenvironment (TIME) with insufficient T-cell infiltration and low immunogenicity accounts for most HCC patients' poor response to ICIs. Worse still, the current immunotherapeutics without precise delivery may elicit enormous autoimmune side effects and systemic toxicity in the clinic. With a better understanding of the TIME in HCC, nanomedicines have emerged as an efficient strategy to achieve remodeling of the TIME and superadditive antitumor effects via targeted delivery of immunotherapeutics or multimodal synergistic therapy. Based on the typical characteristics of the TIME in HCC, this review summarizes the recent advancements in nanomedicine-based strategies for TIME-reversing HCC treatment. Additionally, perspectives on the awaiting challenges and opportunities of nanomedicines in modulating the TIME of HCC are presented. Acquisition of knowledge of nanomedicine-mediated TIME reversal will provide researchers with a better opportunity for clinical translation of HCC immunotherapy.
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Affiliation(s)
- Xier Pan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shuting Ni
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Kaili Hu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Wang J, Chen C, Huang J, Xie Z, Chen X, Zheng Z, Li E, Zou H. The possibilities of LOXL4 as a prognostic marker for carcinomas. Amino Acids 2023; 55:1519-1529. [PMID: 37814029 DOI: 10.1007/s00726-023-03343-9] [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: 05/16/2022] [Accepted: 09/25/2023] [Indexed: 10/11/2023]
Abstract
Lysyl oxidase-like 4 (LOXL4), a member of lysyl oxidase family, is a copper and lysine tyrosylquinone-dependent amine oxidase that serves the role of catalyzing the cross-linking of elastin and collagen in the extracellular matrix. Numerous studies have shown a significant association between LOXL4 expression levels and tumor proliferation, migration, invasion and patients' prognosis and overall survival in different types of tumors. Here we review their relationship and the molecular pathogenesis behind them, aiming to explore the possibilities of LOXL4 as a prognostic marker for diverse carcinomas and provide some indications for further research in this field.
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Affiliation(s)
- Jiaming Wang
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Chaojian Chen
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Jiayi Huang
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Ziman Xie
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Xiaoxue Chen
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Ziqi Zheng
- Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Enmin Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China
| | - Haiying Zou
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China.
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, People's Republic of China.
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Chen S, Duan Y, Zhang Y, Cheng L, Cai L, Hou X, Li W. Associations Between Single Nucleotide Polymorphisms of Hypoxia-Related Genes and Capsule Formation in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:1785-1797. [PMID: 37841371 PMCID: PMC10576505 DOI: 10.2147/jhc.s417830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/12/2023] [Indexed: 10/17/2023] Open
Abstract
Purpose Tumor capsule is an independent prognostic factor for patients with hepatocellular carcinoma (HCC) and used increasingly to guide clinical decision-making. Considering the genetic complexity for capsule formation and its potential association with hypoxia, the significance of the polymorphisms of hypoxia-related genes in capsule formation and HCC prognosis remains to be elucidated. Patients and Methods Peripheral blood samples from HCC patients were collected in this study. Single nucleotide polymorphism (SNP) genotyping was conducted by the iPLEX chemistry on a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (Sequenom, Inc.). The demographic and clinical data for the patients were obtained through medical chart review and/or consultation with the treating physicians. SPSS 25.0, R 4.1.1, and PLINK toolset were used to perform statistical analysis. Results A total of 183 patients were enrolled, including 88 patients assigned to the capsule group and 95 to the non-capsule group. SLC2A1 rs841858 T allele, SLC2A1 rs2297977 T allele, STAT1 rs1547550 C allele, and STAT1 rs34997637 G allele were associated with significantly increased risk of capsule formation. The genotypes of SLC2A1 rs841858, SLC2A1 rs2297977, STAT1 rs34997637, and STAT1 rs1914408 were significantly associated with the formation of HCC capsule. The polymorphisms of STAT1 rs2066802, STAT1 rs12693591, and HIF1A rs2057482 showed close relationship with the prognosis of HCC patients in the capsule group, while the genotype distributions of CTNNB1 rs4135385, IFNG rs1861494, and SERPINE1 rs2227631 were closely related to the survival of patients in the non-capsule group. Further haplotype analysis suggested that SLC2A1 block 1 and STAT1 block 2 were related to the susceptibility of HCC capsule. Conclusion The polymorphisms of the hypoxia-related genes (HIF1A, SERPINE1, IFNG, STAT1, CTNNB1, and SLC2A1) were correlated with the formation of HCC capsule. Several SNPs in these genes also showed association with HCC prognosis except SLC2A1. Further functional studies are warranted to explore the underlying mechanisms.
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Affiliation(s)
- Shanshan Chen
- Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Youjia Duan
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yongchao Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Long Cheng
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Liang Cai
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xiaopu Hou
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Wei Li
- Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
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Cano A, Eraso P, Mazón MJ, Portillo F. LOXL2 in Cancer: A Two-Decade Perspective. Int J Mol Sci 2023; 24:14405. [PMID: 37762708 PMCID: PMC10532419 DOI: 10.3390/ijms241814405] [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: 07/28/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
Lysyl Oxidase Like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises five lysine tyrosylquinone (LTQ)-dependent copper amine oxidases in humans. In 2003, LOXL2 was first identified as a promoter of tumour progression and, over the course of two decades, numerous studies have firmly established its involvement in multiple cancers. Extensive research with large cohorts of human tumour samples has demonstrated that dysregulated LOXL2 expression is strongly associated with poor prognosis in patients. Moreover, investigations have revealed the association of LOXL2 with various targets affecting diverse aspects of tumour progression. Additionally, the discovery of a complex network of signalling factors acting at the transcriptional, post-transcriptional, and post-translational levels has provided insights into the mechanisms underlying the aberrant expression of LOXL2 in tumours. Furthermore, the development of genetically modified mouse models with silenced or overexpressed LOXL2 has enabled in-depth exploration of its in vivo role in various cancer models. Given the significant role of LOXL2 in numerous cancers, extensive efforts are underway to identify specific inhibitors that could potentially improve patient prognosis. In this review, we aim to provide a comprehensive overview of two decades of research on the role of LOXL2 in cancer.
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Affiliation(s)
- Amparo Cano
- Departamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28029 Madrid, Spain; (A.C.); (P.E.); (M.J.M.)
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz—IdiPAZ, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red, Área de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Pilar Eraso
- Departamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28029 Madrid, Spain; (A.C.); (P.E.); (M.J.M.)
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz—IdiPAZ, 28029 Madrid, Spain
| | - María J. Mazón
- Departamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28029 Madrid, Spain; (A.C.); (P.E.); (M.J.M.)
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz—IdiPAZ, 28029 Madrid, Spain
| | - Francisco Portillo
- Departamento de Bioquímica UAM, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28029 Madrid, Spain; (A.C.); (P.E.); (M.J.M.)
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz—IdiPAZ, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red, Área de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Löser R, Kuchar M, Wodtke R, Neuber C, Belter B, Kopka K, Santhanam L, Pietzsch J. Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging. ChemMedChem 2023; 18:e202300331. [PMID: 37565736 DOI: 10.1002/cmdc.202300331] [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: 06/28/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/12/2023]
Abstract
The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.
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Affiliation(s)
- Reik Löser
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Manuela Kuchar
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Robert Wodtke
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Christin Neuber
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Birgit Belter
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Klaus Kopka
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Lakshmi Santhanam
- Departments of Anesthesiology and Critical Care Medicine and Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Jens Pietzsch
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
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Radić J, Kožik B, Nikolić I, Kolarov-Bjelobrk I, Vasiljević T, Vranjković B, Despotović S. Multiple Roles of LOXL2 in the Progression of Hepatocellular Carcinoma and Its Potential for Therapeutic Targeting. Int J Mol Sci 2023; 24:11745. [PMID: 37511503 PMCID: PMC10380739 DOI: 10.3390/ijms241411745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with an aggressive phenotype and represents a poor prognostic factor. Here, we focus on the mechanisms through which LOXL2 orchestrates multiple oncogenic functions in HCC development. We performed a review of the current knowledge on the roles LOXL2 performs in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial-mesenchymal transition. We also highlighted the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize the current LOXL2 inhibitors and discuss their potential in HCC precision treatment.
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Affiliation(s)
- Jelena Radić
- Faculty of Medicine, University of Novi Sad, 21137 Novi Sad, Serbia
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11100 Belgrade, Serbia
| | - Ivan Nikolić
- Faculty of Medicine, University of Novi Sad, 21137 Novi Sad, Serbia
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Ivana Kolarov-Bjelobrk
- Faculty of Medicine, University of Novi Sad, 21137 Novi Sad, Serbia
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Tijana Vasiljević
- Faculty of Medicine, University of Novi Sad, 21137 Novi Sad, Serbia
- Department of Pathology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Bojana Vranjković
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Sanja Despotović
- Institute of Histology and Embryology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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Gong L, Zhang Y, Yang Y, Yan Q, Ren J, Luo J, Tiu YC, Fang X, Liu B, Lam RHW, Lam K, Lee AW, Guan X. Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment. Hepatol Commun 2022; 6:3194-3211. [PMID: 35894804 PMCID: PMC9592791 DOI: 10.1002/hep4.1966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/13/2022] [Accepted: 02/27/2022] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross-linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial-to-mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen-enriched TME and revealed that collagen enrichment could induce 5-fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia-induced up-regulation of lysyl oxidase-like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross-linking, enhances cell adhesion-mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/rho-associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen-enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2-targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis.
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Affiliation(s)
- Lanqi Gong
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Yu Zhang
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
- Department of Pediatric OncologySun Yat‐sen University Cancer CenterGuangzhouChina
- State Key Laboratory of Oncology in Southern ChinaSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yuma Yang
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
| | - Qian Yan
- Department of Colorectal SurgeryGuangdong Institute Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Jifeng Ren
- Department of Biomedical EngineeringCity University of Hong KongHong KongChina
- School of Biomedical EngineeringCapital Medical UniversityBeijingChina
| | - Jie Luo
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
| | - Yuen Chak Tiu
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
| | - Xiaona Fang
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Beilei Liu
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
| | - Raymond Hiu Wai Lam
- Department of Biomedical EngineeringCity University of Hong KongHong KongChina
| | - Ka‐On Lam
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
| | - Anne Wing‐Mui Lee
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- Advanced Energy Science and Technology Guangdong LaboratoryHuizhouChina
| | - Xin‐Yuan Guan
- Department of Clinical OncologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- Department of Clinical OncologyLi Ka Shing Faculty of MedicineHong KongChina
- State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina
- State Key Laboratory of Oncology in Southern ChinaSun Yat‐sen University Cancer CenterGuangzhouChina
- Advanced Energy Science and Technology Guangdong LaboratoryHuizhouChina
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9
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Nayak A, Warrier NM, Kumar P. Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems. Stem Cell Rev Rep 2022; 18:2209-2233. [PMID: 35876959 PMCID: PMC9489588 DOI: 10.1007/s12015-022-10426-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2022] [Indexed: 11/25/2022]
Abstract
The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates-nanocarriers (NCs) especially-have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Central role of CSCs in regulation of cellular components within the TME.
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Affiliation(s)
- Aadya Nayak
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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10
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Epremyan KK, Goleva TN, Rogov AG, Lavrushkina SV, Zinovkin RA, Zvyagilskaya RA. The First Yarrowia lipolytica Yeast Models Expressing Hepatitis B Virus X Protein: Changes in Mitochondrial Morphology and Functions. Microorganisms 2022; 10:microorganisms10091817. [PMID: 36144419 PMCID: PMC9501646 DOI: 10.3390/microorganisms10091817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic hepatitis B virus infection is the dominant cause of hepatocellular carcinoma, the main cause of cancer death. HBx protein, a multifunctional protein, is essential for pathogenesis development; however, the underlying mechanisms are not fully understood. The complexity of the system itself, and the intricate interplay of many factors make it difficult to advance in understanding the mechanisms underlying these processes. The most obvious solution is to use simpler systems by reducing the number of interacting factors. Yeast cells are particularly suitable for studying the relationships between oxidative stress, mitochondrial dynamics (mitochondrial fusion and fragmentation), and mitochondrial dysfunction involved in HBx-mediated pathogenesis. For the first time, genetically modified yeast, Y. lipolytica, was created, expressing the hepatitis B virus core protein HBx, as well as a variant fused with eGFP at the C-end. It was found that cells expressing HBx experienced stronger oxidative stress than the control cells. Oxidative stress was alleviated by preincubation with the mitochondria-targeted antioxidant SkQThy. Consistent with these data, in contrast to the control cells (pZ-0) containing numerous mitochondrial forming a mitochondrial reticulum, in cells expressing HBx protein, mitochondria were fragmented, and preincubation with SkQThy partially restored the mitochondrial reticulum. Expression of HBx had a significant influence on the bioenergetic function of mitochondria, making them loosely coupled with decreased respiratory rate and reduced ATP formation. In sum, the first highly promising yeast model for studying the impact of HBx on bioenergy, redox-state, and dynamics of mitochondria in the cell and cross-talk between these parameters was offered. This fairly simple model can be used as a platform for rapid screening of potential therapeutic agents, mitigating the harmful effects of HBx.
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Affiliation(s)
- Khoren K. Epremyan
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
- Correspondence: (K.K.E.); (R.A.Z.); Tel.: +7-(917)-575-3560 (K.K.E.)
| | - Tatyana N. Goleva
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
| | - Anton G. Rogov
- National Research Center “Kurchatov Institute”, Akademika Kurchatova pl. 1, 123182 Moscow, Russia
| | - Svetlana V. Lavrushkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, Russia
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskye Gory 1/73, 119234 Moscow, Russia
| | - Roman A. Zinovkin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, Russia
| | - Renata A. Zvyagilskaya
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
- Correspondence: (K.K.E.); (R.A.Z.); Tel.: +7-(917)-575-3560 (K.K.E.)
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11
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Li Z, Shi L, Li X, Wang X, Wang H, Liu Y. RNF144A-AS1, a TGF-β1- and hypoxia-inducible gene that promotes tumor metastasis and proliferation via targeting the miR-30c-2-3p/LOX axis in gastric cancer. Cell Biosci 2021; 11:177. [PMID: 34583752 PMCID: PMC8480077 DOI: 10.1186/s13578-021-00689-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/11/2021] [Indexed: 01/19/2023] Open
Abstract
Background Although recent molecular analyses have improved our knowledge regarding gastric cancer (GC) biology, the molecular mechanisms that confer metastatic potential to GC remain poorly understood. In this study, we intend to explore the function and characterize the underlying mechanism of long noncoding RNA RNF144A-AS1 in GC metastasis and outgrowth. Methods The expression of RNF144A-AS1, miR-30c-2-3p, and Lysyl oxidase (LOX) was detected by quantitative real-time PCR assay. Fluorescence in situ hybridization and subcellular fractionation assay determined the cellular localization of RNF144A-AS1. Cell counting kit 8 assay, transwell assay, and tube formation assay were performed to detect the effect on cell proliferation, migration, invasion, and angiogenesis, respectively. Animal models were also applied to verify the effect on tumor metastasis, outgrowth, and angiogenesis. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation (RIP) assay explored the interactions among RNF144A-AS1, miR-30c-2-3p, and LOX. Gene regulation was further validated by knockdown of Dicer or mutating the miRNA binding sites on RNF144A-AS1 and LOX 3ʹUTR. Cells were treated with recombinant human TGF-β1 (Transforming Growth Factor β1) to explore the effect of TGF-β1 on RNF144A-AS1. Western blot and immunohistochemistry were used to detect protein expression. Results The expression of RNF144A-AS1 was significantly upregulated in GC tissues and was associated with poor prognosis and later-stage diseases. Hypoxia stimulated the expression of RNF144A-AS1 in a HIF-1α-independent manner. Additionally, RNF144A-AS1 was also induced by TGF-β1. Loss and gain of function assays revealed that RNF144A-AS1 promoted tumor metastasis, angiogenesis, and proliferation. Mechanism exploration indicated RNF144A-AS1 served as a microRNA decoy of miR-30c-2-3p to release LOX. Gene Set Enrichment Analysis further suggested LOX and RNF144A-AS1 were enriched in the same gene sets, emphasizing the internal mechanism connection between these two genes. Conclusions TGF-β1- and hypoxia-inducible RNF144A-AS1 promoted tumor metastasis, angiogenesis, and proliferation through targeting the miR-30c-2-3p/LOX axis in GC, highlighting the value of the RNF144A-AS1/miR-30c-2-3p/LOX axis in therapeutic interventions of GC. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00689-z.
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Affiliation(s)
- Zengliang Li
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Liang Shi
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Xiangwei Li
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Xiaopeng Wang
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Haixiao Wang
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Yeliu Liu
- Department of Gastroenterological Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 1 Huanghe West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China.
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12
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Zhao F, Xie X, Tan X, Yu H, Tian M, Lv H, Qin C, Qi J, Zhu Q. The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis. Front Immunol 2021; 12:691766. [PMID: 34456908 PMCID: PMC8387624 DOI: 10.3389/fimmu.2021.691766] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.
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Affiliation(s)
- Fenglin Zhao
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Xiaoyu Xie
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xu Tan
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hongli Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Miaomiao Tian
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huanran Lv
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengyong Qin
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianni Qi
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Zhu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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13
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Pfisterer K, Shaw LE, Symmank D, Weninger W. The Extracellular Matrix in Skin Inflammation and Infection. Front Cell Dev Biol 2021; 9:682414. [PMID: 34295891 PMCID: PMC8290172 DOI: 10.3389/fcell.2021.682414] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) is an integral component of all organs and plays a pivotal role in tissue homeostasis and repair. While the ECM was long thought to mostly have passive functions by providing physical stability to tissues, detailed characterization of its physical structure and biochemical properties have uncovered an unprecedented broad spectrum of functions. It is now clear that the ECM not only comprises the essential building block of tissues but also actively supports and maintains the dynamic interplay between tissue compartments as well as embedded resident and recruited inflammatory cells in response to pathologic stimuli. On the other hand, certain pathogens such as bacteria and viruses have evolved strategies that exploit ECM structures for infection of cells and tissues, and mutations in ECM proteins can give rise to a variety of genetic conditions. Here, we review the composition, structure and function of the ECM in cutaneous homeostasis, inflammatory skin diseases such as psoriasis and atopic dermatitis as well as infections as a paradigm for understanding its wider role in human health.
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Affiliation(s)
- Karin Pfisterer
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | | | - Wolfgang Weninger
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
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14
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Rashid M, Zadeh LR, Baradaran B, Molavi O, Ghesmati Z, Sabzichi M, Ramezani F. Up-down regulation of HIF-1α in cancer progression. Gene 2021; 798:145796. [PMID: 34175393 DOI: 10.1016/j.gene.2021.145796] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/19/2022]
Abstract
Hypoxia induicible factor-1 alpha (HIF-1α) is a key transcription factor in cancer progression and target therapy in cancer. HIF-1α acts differently depending on presence or absence of Oxygen. In an oxygen-immersed environment, HIF-1α completely deactivated and destroyed by the ubiquitin proteasome pathway (UPP). In contrast, in the oxygen-free environment, it escapes destruction and enters to the nucleus of cells then upregulates many genes involved in cancer progression. Overexpressed HIF-1α and downstream genes support cancer progression through various mechanisms including angiogenesis, proliferation and survival of cells, metabolism reprogramming, invasion and metastasis, cancer stem cell maintenance, induction of genetic instability, and treatment resistance. HIF-1α can be provoked by signaling pathways unrelated to hypoxia during cancer progression. Therefore, cancer development and progression can be modulated by targeting HIF-1α and its downstream signaling molecules. In this regard, HIF-1α inhibitors which are categorized into the agents that regulate HIF-1α in gene, mRNA and protein levels used as an efficient way in cancer treatment. Also, HIF-1α expression can be negatively affected by the agents suppressing the activation of mTOR, PI3k/Akt and MAPK pathways.
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Affiliation(s)
- Mohsen Rashid
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Rostami Zadeh
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ommoleila Molavi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Ghesmati
- Department of Medical Biotechnology, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Sabzichi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Fatemeh Ramezani
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Kui X, Wang Y, Zhang C, Li H, Li Q, Ke Y, Wang L. Prognostic value of SH3PXD2B (Tks4) in human hepatocellular carcinoma: a combined multi-omics and experimental study. BMC Med Genomics 2021; 14:115. [PMID: 33906640 PMCID: PMC8080318 DOI: 10.1186/s12920-021-00963-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers worldwide. HCC invasion and metastasis are crucial for its poor prognosis. SH3PXD2B is a scaffold protein and critical for intravascular and extravascular invasion and metastasis of various types of tumors. However, the role of SH3PXD2B in HCC progression remains unclear. METHODS The levels of SH3PXD2B mRNA transcripts in the TCGA database and SH3PXD2B protein expression in the Human Protein Atlas were analyzed. Furthermore, the levels of SH3PXD2B expression in clinical samples were analyzed by quantitative RT-PCR and immunohistochemistry. The potential association of the levels of SH3PXD2B expression with clinicopathological characteristics, overall survival (OS), and recurrence-free survival (RFS) of HCC patients was analyzed. The impact of SH3PXD2B silencing by shRNA-based lentivirus transduction on the proliferation and invasion of human HCC Hep3B and Huh7 cells was determined. RESULTS SH3PXD2B expression was up-regulated in HCC tissues in the TCGA and Human Protein Atlas as well as clinical samples, relative to that of non-tumor liver samples. The levels of SH3PXD2B expression in HCC tissues were significantly associated with higher HBV infection rate, higher HCC grades and TNM stages, higher Ki-67 expression, higher serum α-fetoprotein (AFP), a shorter OS and RFS of HCC patients. Functionally, SH3PXD2B silencing significantly inhibited the formation and function of invadopodia and the invasion of Hep3B and Huh7 cells, but did not affect their proliferation in vitro. CONCLUSIONS Our data suggest that SH3PXD2B may promote the invasion and metastasis of HCC and be a valuable therapeutic target and biomarker for treatment and prognosis of HCC.
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Affiliation(s)
- Xiang Kui
- Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Yan Wang
- Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Cheng Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
- Department of Hepatobiliary Surgery, The Sixth People's Hospital of Chengdu, Chengdu, 610051, China
| | - Hai Li
- School of Medicine, Kunming University, Kunming, 650214, China
| | - Qingfeng Li
- Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Yang Ke
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China.
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16
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Lei Y, Xu X, Liu H, Chen L, Zhou H, Jiang J, Yang Y, Wu B. HBx induces hepatocellular carcinogenesis through ARRB1-mediated autophagy to drive the G 1/S cycle. Autophagy 2021; 17:4423-4441. [PMID: 33866937 DOI: 10.1080/15548627.2021.1917948] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The hepatitis B virus X protein (HBx) is involved in the process of hepatocellular carcinoma via the activation of various oncogenes. Our previous study indicated that ARBB1 (arrestin beta 1) promotes hepatocellular carcinogenesis (HCC). However, the role of ARRB1 in HBx-related HCC remains unclear. Herein, we identified that ARRB1 was upregulated by HBx in vivo and in vitro. Arrb1 deficiency suppressed HBx-induced hepatocellular carcinogenesis in several mouse models. Furthermore, knockdown of ARRB1 blocked HBx-induced macroautophagic/autophagic flux and disrupted the formation of autophagosomes. ARRB1 interacted with HBx, and the autophagic core protein MAP1LC3/LC3, a scaffolding protein, was essential for complete autophagy. Inhibition of autophagy by 3-methyladenine or interference of ATG5 or ATG7 attenuated HBx-induced cell cycle acceleration and the subsequent proliferative response via the induction of G1/S arrest. The absence of autophagy abolished the phosphorylation of CDK2 and the activity of the CDK2-CCNE1 complex. Our results demonstrate that ARRB1 plays a critical role in HBV-related HCC via modulating autophagy and the CDKN1B-CDK2-CCNE1-E2F1 axis and indicate that ARRB1 may be a potential therapeutic target for HCC.
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Affiliation(s)
- Yiming Lei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Xuan Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Lingjun Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Haoxiong Zhou
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Yidong Yang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
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17
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Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. J Clin Transl Hepatol 2021; 9:90-98. [PMID: 33604259 PMCID: PMC7868706 DOI: 10.14218/jcth.2020.00104] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease. ALDH2 gene mutations exist in about 8% of the world's population, with the incidence reaching 45% in East Asia. The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde, facilitating the progression of other liver diseases, including non-alcoholic fatty liver diseases, viral hepatitis and hepatocellular carcinoma, through adduct formation and inflammatory responses. In this review, we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases, with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.
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Affiliation(s)
- Qiaoling Wang
- Peking University, 302 Clinical Medical School, Beijing, China
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Binxia Chang
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Li
- Anhui Medical University, Hefei, Anhui, China
| | - Zhengsheng Zou
- Peking University, 302 Clinical Medical School, Beijing, China
- Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Correspondence to: Zhengsheng Zou, The Center for Diagnosis and Treatment of Non-Infectious Liver Disease, The General Hospital of Chinese People’s Liberation Army No. 5 Medical Science Center, No. 100 Xisihuan Middle Road, Beijing 100039, China. E-mail:
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18
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Nishihara K, Hori K, Saito T, Omori T, Sunakawa H, Minamide T, Suyama M, Yamamoto Y, Yoda Y, Shinmura K, Ikematsu H, Yano T. A study of evaluating specific tissue oxygen saturation values of gastrointestinal tumors by removing adherent substances in oxygen saturation imaging. PLoS One 2021; 16:e0243165. [PMID: 33411775 PMCID: PMC7790263 DOI: 10.1371/journal.pone.0243165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 11/16/2020] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Oxygen saturation (OS) imaging is a new method of endoscopic imaging that has clinical applications in oncology which can directly measure tissue oxygen saturation (Sto2) of the surface of gastrointestinal tract without any additional drugs or devices. This imaging technology is expected to contribute to research into cancer biology which leads to clinical benefit such as prediction to efficacy of chemotherapy or radiotherapy. However, adherent substances on tumors such as blood and white coating, pose a challenge for accurate measurements of the StO2 values in tumors. The aim of this study was to develop algorithms for discriminating between the tumors and their adherent substances, and to investigate whether it is possible to evaluate the tumor specific StO2 values excluding adherent substances during OS imaging. METHODS We plotted areas of tumors and their adherent substances using white-light images of 50 upper digestive tumors: blood (68 plots); reddish tumor (83 plots); white coating (89 plots); and whitish tumor (79 plots). Scatter diagrams and discriminating algorithms using spectrum signal intensity values were constructed and verified using validation datasets. StO2 values were compared between the tumors and tumor adherent substances using OS images of gastrointestinal tumors. RESULTS The discriminating algorithms and their accuracy rates (AR) were as follows: blood vs. reddish tumor: Y> - 4.90X+7.13 (AR: 95.9%) and white coating vs. whitish tumor: Y< -0.52X+0.17 (AR: 96.0%). The StO2 values (median, [range]) were as follows: blood, 79.3% [37.8%-100.0%]; reddish tumor, 74.5% [62.0%-86.9%]; white coating, 73.8% [42.1%-100.0%]; and whitish tumor, 65.7% [53.0%-76.3%]. CONCLUSIONS OS imaging is strongly influenced by adherent substances for evaluating the specific StO2 value of tumors; therefore, it is important to eliminate the information of adherent substances for clinical application of OS imaging.
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Affiliation(s)
- Keiichiro Nishihara
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Keisuke Hori
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Takaaki Saito
- Imaging Technology Center, FUJIFILM Corporation, Tokyo, Japan
| | - Toshihiko Omori
- Medical Systems Research & Development Center, Research & Development, Management Headquarters, FUJIFILM Corporation, Tokyo Japan
| | - Hironori Sunakawa
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Tatsunori Minamide
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Masayuki Suyama
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Yoichi Yamamoto
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Yusuke Yoda
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Kensuke Shinmura
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Hiroaki Ikematsu
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
| | - Tomonori Yano
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital, Kashiwanoha, Kashiwa, Japan
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19
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Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer. Int J Mol Sci 2020; 21:ijms21249751. [PMID: 33371259 PMCID: PMC7766343 DOI: 10.3390/ijms21249751] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/08/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022] Open
Abstract
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.
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Ye M, Song Y, Pan S, Chu M, Wang ZW, Zhu X. Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy. Pharmacol Ther 2020; 215:107633. [PMID: 32693113 DOI: 10.1016/j.pharmthera.2020.107633] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022]
Abstract
The lysyl oxidase (LOX) family is comprised of LOX and four LOX-like proteins (LOXL1, LOXL2, LOXL3, and LOXL4), and mainly functions in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic fibers. Recently, a growing body of research has demonstrated that LOX family is critically involved in the regulation of cancer cell proliferation, migration, invasion and metastasis. In this review, we discuss the roles of LOX family members in the development and progression of different types of human cancers. Furthermore, we also describe the potential inhibitors of LOX family proteins and highlight that LOX family might be an important therapeutic target for cancer therapy.
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Affiliation(s)
- Miaomiao Ye
- Departmant of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Yizuo Song
- Departmant of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Shuya Pan
- Departmant of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Man Chu
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Zhi-Wei Wang
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China..
| | - Xueqiong Zhu
- Departmant of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
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21
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Maali Y, Journo C, Mahieux R, Dutartre H. Microbial Biofilms: Human T-cell Leukemia Virus Type 1 First in Line for Viral Biofilm but Far Behind Bacterial Biofilms. Front Microbiol 2020; 11:2041. [PMID: 33042035 PMCID: PMC7523422 DOI: 10.3389/fmicb.2020.02041] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/03/2020] [Indexed: 12/25/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To date, it is the unique published example of a virus able to form a biofilm at the surface of infected cells. Deeply studied in bacteria, bacterial biofilms represent multicellular assemblies of bacteria in contact with a surface and shielded by the extracellular matrix (ECM). Microbial lifestyle in biofilms, either viral or bacterial, is opposed structurally and physiologically to an isolated lifestyle, in which viruses or bacteria freely float in their environment. HTLV-1 biofilm formation is believed to be promoted by viral proteins, mainly Tax, through remodeling of the ECM of the infected cells. HTLV-1 biofilm has been linked to cell-to-cell transmission of the virus. However, in comparison to bacterial biofilms, very little is known on kinetics of viral biofilm formation or dissemination, but also on its pathophysiological roles, such as escape from immune detection or therapeutic strategies, as well as promotion of leukemogenesis. The switch between production of cell-free isolated virions and cell-associated viral biofilm, although not fully apprehended yet, remains a key step to understand HTLV-1 infection and pathogenesis.
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Affiliation(s)
- Yousef Maali
- CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France
| | - Chloé Journo
- CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France
| | - Renaud Mahieux
- CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France
| | - Hélène Dutartre
- CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France
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Yao B, Li Y, Niu Y, Wang L, Chen T, Guo C, Liu Q. Hypoxia-induced miR-3677-3p promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by suppressing SIRT5. J Cell Mol Med 2020; 24:8718-8731. [PMID: 32596968 PMCID: PMC7412699 DOI: 10.1111/jcmm.15503] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 05/08/2020] [Accepted: 05/24/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), with life‐threatening malignant behaviours, often develops distant metastases and is the fourth most common primary cancer in the world, having taken millions of lives in Asian countries such as China. The novel miR‐3677‐3p is involved in a high‐expression‐related poor prognosis in HCC tissues and cell lines, indicating oncogenesis functions in vitro and in vivo. Initially, we confirmed the inhibition of proliferation, migration and invasion in miR‐3677‐3p knock‐down MHCC‐97H and SMMC‐7721 cell lines, which are well known for their high degree of invasiveness. Then, we reversed the functional experiments in the low‐miR‐3677‐3p‐expression Hep3B cell line via overexpressing miR‐3677‐3p. In nude mice xenograft and lung metastasis assays, we found suppressor behaviours, smaller nodules and low density of organ spread, after injection of cells transfected with shRNA‐miR‐3677‐3p. A combination of databases (Starbase, TargetScan and MiRgator) illustrated miR‐3677‐3p targets, and it was shown to suppress the expression of SIRT5 in a dual‐luciferase reporter system. To clarify the conclusions of previous ambiguous research, we up‐regulated SIRT5 in Hep3B cells, and rescue tests were established for confirmation that miR‐3677‐3p suppresses SIRT5 to enhance the migration and invasion of HCC. Interestingly, we discovered hypoxia‐induced miR‐3677‐3p up‐regulation benefited HCC malignancy and invasiveness. In conclusion, the overexpression of miR‐3677‐3p mediated SIRT5 inhibition, which could increase proliferation, migration and invasion of HCC in hypoxic microenvironments.
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Affiliation(s)
- Bowen Yao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yazhao Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yongshen Niu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tianxiang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Cheng Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice. Eur J Vasc Endovasc Surg 2019; 59:1000-1010. [PMID: 31879145 DOI: 10.1016/j.ejvs.2019.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 09/26/2019] [Accepted: 10/18/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. METHODS β-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n = 30) (21%-5% O2, 90 s/cycle, 10 h/day, IH + BAPN group) or normoxia (n = 30) (21% O2, 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O2)/re-oxygenation (30 min, 21% O2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1α and LOX via HIF-1α-siRNA. RESULTS It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1β, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1α. CONCLUSION The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.
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Guo Y, Xiao Z, Yang L, Gao Y, Zhu Q, Hu L, Huang D, Xu Q. Hypoxia‑inducible factors in hepatocellular carcinoma (Review). Oncol Rep 2019; 43:3-15. [PMID: 31746396 PMCID: PMC6908932 DOI: 10.3892/or.2019.7397] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022] Open
Abstract
Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia-inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.
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Affiliation(s)
- Yang Guo
- Graduate Department, BengBu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Zunqiang Xiao
- The Second Clinical Medical Department, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, P.R. China
| | - Liu Yang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
| | - Yuling Gao
- Department of Genetics, Shaoxing Women and Children Hospital, Shaoxin, Zhejiang 312030, P.R. China
| | - Qiaojuan Zhu
- The Second Clinical Medical Department, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, P.R. China
| | - Linjun Hu
- Medical Department, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China
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Xu S, Xu H, Wang W, Li S, Li H, Li T, Zhang W, Yu X, Liu L. The role of collagen in cancer: from bench to bedside. J Transl Med 2019; 17:309. [PMID: 31521169 PMCID: PMC6744664 DOI: 10.1186/s12967-019-2058-1] [Citation(s) in RCA: 482] [Impact Index Per Article: 80.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/06/2019] [Indexed: 02/06/2023] Open
Abstract
Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.
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Affiliation(s)
- Shuaishuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Huaxiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Tianjiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wuhu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People's Republic of China.
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Ding X, Lei Q, Li T, Li L, Qin B. Hepatitis B core antigen can regulate NLRP3 inflammasome pathway in HepG2 cells. J Med Virol 2019; 91:1528-1536. [PMID: 31017673 DOI: 10.1002/jmv.25490] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 03/04/2019] [Accepted: 03/27/2019] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) has four open reading frames (ORFs) of which ORF C is consists of the pre Core and Core genes encodes the Hepatitis B core antigen (HBcAg) and Hepatitis B e antigen (HBeAg). Studies have shown that HBeAg significantly inhibits the NLRP3 inflammasome activation and interleukin-1β (IL-1β) production. However, the role of HBcAg and ORF C proteins (in this paper, ORF C proteins = HBcAg + HBeAg) were remain unclear. Our study aims to assess whether HBcAg and ORF C proteins can affect the NLRP3 inflammasome pathway. Vectors expressing ORF C proteins and HBcAg were designed and transfected into HepG2 cells. And then, cells were stimulated with lipopolysaccharide (LPS). Activation of the NLRP3 inflammasome and the levels of IL-1β and IL-18 were evaluated by Western blot analysis, quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. The expression of NLRP3 and IL-1β peaked when HepG2 cells were stimulated with 1000 ng/mL LPS for 18 to 24 hours. HBcAg, but not ORF C proteins, promoted LPS-induced NLRP3 inflammasome activation and IL-1β production. These findings provide a novel mechanism on how the HBV causes liver inflammation and may provide insights into the search for new therapeutic strategies.
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Affiliation(s)
- Xiaolin Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qingsong Lei
- Department of Oncology, Chongqing Cancer Hospital, Chongqing, People's Republic of China
| | - Tianju Li
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Li
- Department of Liver Diseases, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People's Republic of China
| | - Bo Qin
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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27
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Han YL, Chen L, Qin R, Wang GQ, Lin XH, Dai GH. Lysyl oxidase and hypoxia-inducible factor 1α: biomarkers of gastric cancer. World J Gastroenterol 2019; 25:1828-1839. [PMID: 31057297 PMCID: PMC6478611 DOI: 10.3748/wjg.v25.i15.1828] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/21/2019] [Accepted: 03/02/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the main causes of cancer mortality worldwide. Recent studies on tumor microenvironments have shown that tumor metabolism exerts a vital role in cancer progression.
AIM To investigate whether lysyl oxidase (LOX) and hypoxia-inducible factor 1α (HIF1α) are prognostic and predictive biomarkers in GC.
METHODS A total of 80 tissue and blood samples were collected from 140 patients admitted to our hospital between August 2008 and March 2012. Immunohistochemical staining was performed to measure the expression of LOX and HIF1α in tumor and adjacent tissues collected from patients with GC. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was used to detect the mRNA expression levels of LOX and HIF1α in patients with GC. In addition, single-factor analysis was applied to analyze the relationship between LOX, HIF1α and prognosis of GC.
RESULTS Immunohistochemical staining suggested that the expression levels of LOX and HIF1α increased in tumor tissues from patients with GC. QRT-PCR analysis indicated that mRNA expression of LOX and HIF1α was also upregulated in tumor tissues, which was in accordance with the above results. We also detected expression of these two genes in blood samples. The expression level of LOX and HIF1α was higher in patients with GC than in healthy controls. Additional analysis showed that the expression level of LOX and HIF1α was related to the clinicopathological characteristics of GC. Expression of LOX and HIF1α increased with the number of lymph node metastases, deeper infiltration depth and later tumor–node–metastasis stages. Single-factor analysis showed that high expression of LOX and HIF1α led to poor prognosis of patients with GC.
CONCLUSION LOX and HIF1α can be used as prognostic and predictive biomarkers for GC.
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Affiliation(s)
- Ya-Lin Han
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Li Chen
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Rui Qin
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Guan-Qing Wang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Xiao-Hua Lin
- Department of Oncology, the General Hospital of PLA Rocket Force, Beijing 100088, China
| | - Guang-Hai Dai
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
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Yang M, Liu J, Wang F, Tian Z, Ma B, Li Z, Wang B, Zhao W. Lysyl oxidase assists tumor‑initiating cells to enhance angiogenesis in hepatocellular carcinoma. Int J Oncol 2019; 54:1398-1408. [PMID: 30720077 DOI: 10.3892/ijo.2019.4705] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/14/2018] [Indexed: 11/06/2022] Open
Abstract
A highly tumorigenic and malignant sub‑population of HCC containing tumor‑initiating cells (TICs) are defined by high self‑renewal and sphere formation ability. Lysyl oxidase (LOX) regulates various factors involved in extracellular matrix (ECM) maintenance, migration and angiogenesis. Certain reports have demonstrated the role of LOX in ECM crosslinking, however, the cancer‑promoting effects of LOX in HCC remain unclear, and whether LOX has a role in the regulation of angiogenesis in HCC TICs has not been elucidated. In the current study, RNA sequencing using next‑generation sequencing technology and bioinformatics analyses revealed that LOX gene expression was significantly upregulated in cell spheres. Sphere cells may form tumors with more vascular enrichment compared with tumors produced from adherent cells, as observed in a mouse xenograft model. LOX expression is correlated with increased vascular endothelial growth factor (VEGF) and platelet‑derived growth factor, as demonstrated by analyses of The Cancer Genome Atlas and Gene Expression Omnibus databases. Conditioned media obtained from LOX‑overexpressing tumor cells stimulated angiogenesis via secreted VEGF and enhanced the tube formation capacity of endothelial cells. Furthermore, these functional behaviors were blocked by the LOX inhibitor β‑aminopropionitrile. These findings provide novel mechanistic insight into the pivotal role of LOX in the regulation of TICs in HCC. Combination of LOX inhibitor with sorafenib is a potentially advantageous strategy for HCC therapy.
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Affiliation(s)
- Min Yang
- Department of Gerontology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
| | - Jingtao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pharmacy, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Fei Wang
- Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Unit 0853, Houston, TX 77030, USA
| | - Zhihua Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Central Laboratory, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Bo Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Boqing Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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