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Li YH, Zheng CR, Liu Y, Wang K, Zhou FF, Dong X, Yuan T, He QJ, Zhu H, Yang B. The role of calcium signaling in organotropic metastasis of cancer. Acta Pharmacol Sin 2025:10.1038/s41401-025-01537-3. [PMID: 40133629 DOI: 10.1038/s41401-025-01537-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/09/2025] [Indexed: 03/27/2025]
Abstract
Tumor metastasis is an important event in cancer progression, representing an enduring and irrevocable hallmark of cancers. The causes of tumor metastasis are complex and diverse. Arising evidence shows that the dysregulation of calcium signaling plays a crucial role in its initiation and progress. Calcium is an essential secondary messenger that regulates signaling pathways associated with tumor metastasis. The transient accumulation of calcium potentially promotes the advancement of tumor metastasis, while calcium-dependent proteins and calcium-related channels also significantly contribute to such malignant process. Thus, compounds specially targeting calcium channels, transporters or pumps may be therapeutic approaches prohibiting tumor metastasis. This review focuses on exploring the roles of calcium ions, calcium-dependent proteins and calcium-related channels in organotropic metastasis of cancer and its clinical applications in the treatment of metastatic cancers.
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Affiliation(s)
- Yong-Hao Li
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Chu-Run Zheng
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yue Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ke Wang
- National Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 210000, China
| | - Fan-Fan Zhou
- Sydney Pharmacy School, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Xin Dong
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310015, China
| | - Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310015, China
| | - Qiao-Jun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310015, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310015, China.
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
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Yang HM, Zhao XN, Li XL, Wang X, Pu Y, Wei DK, Li Z. A pan-cancer analysis of the oncogenic function of HMGB1 in human tumors. Biochem Biophys Rep 2024; 40:101851. [PMID: 39582753 PMCID: PMC11584604 DOI: 10.1016/j.bbrep.2024.101851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 09/30/2024] [Accepted: 10/16/2024] [Indexed: 11/26/2024] Open
Abstract
Background Although high mobility group box protein 1 (HMGB1) has been researched in relation to cancer in many investigations, a thorough investigation of its role in pan-cancer has yet to be conducted. With the objective of bridging this gap, we delved into the functions of HMGB1 in various tumors. Methods This investigation employed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to examine HMGB1 gene expression differences and correlation with survival across various human tumors. Then, genetic alterations of HMGB1 were analyzed by tool cBioPortal, and immune cell infiltration was assessed. Finally, we gathered clinial samples from 95 patients with various types of solid tumor and performed somatic mutation analysis using panel sequencing. This further highlighted the role of HMGB1 in different solid tumors. Results There was a notable elevation of HMGB1 gene expression in tumor tissues as opposed to non-cancerous tissues across the bulk of tumor types. Elevated HMGB1 gene expression had a connection with shorter overall survival, progression-free survival, and disease-free survival in specific tumor types. Genetic alterations of HMGB1 suggested that the amplifications and mutations of HMGB1 may impact the prognosis of breast cancer (BRCA) and liver hepatocellular carcinoma (LIHC). Both BRCA and mesothelioma (MESO) displayed a connection between the infiltration of cancer-associated fibroblasts (CAFs) and HMGB1 gene expression. Moreover, HMGB1 co-expression analysis revealed its association with genes involved in RNA splicing, mRNA processing, and modulation of mRNA metabolic processes. Additionally, a pathway analysis by use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) unveiled that HMGB1 was implicated in the pathogenic mechanisms of "Hepatitis B," "Viral Carcinogenesis," and "Hepatocellular Carcinoma." Based on somatic mutation analysis of 95 patients with different solid tumors, we found that the frequency of HMGB1 mutations was higher in Liver cancer patients compared to other solid tumors. This finding is consistent with our in-silico study results. Additionally, we discovered that the frequency of HMGB1 mutations ranked among the top 20 mutated genes in the 95 patients' data, indicating that HMGB1 plays an important role in the development and prognosis of various solid tumors. Conclusion This pan-cancer study of HMGB1 underscores its potential as a signature marker and target for the management of various tumor types.
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Affiliation(s)
- Hui-min Yang
- Shanghai Singlera Medical Laboratory, 1rst Floor, No. 20 Building, 500 Furonghua Road, Pudong New District, Shanghai, China
| | - Xiang-ning Zhao
- Department of Surgical Oncology, Shanghai Mengchao Cancer Hospital, 118 Qianyang Road, Jiading District, Shanghai, China
| | | | - Xi Wang
- Suzhou Func Biotech Inc, Suzhou, Jiangsu, China
| | - Yu Pu
- Suzhou Func Biotech Inc, Suzhou, Jiangsu, China
| | | | - Zhe Li
- Department of Breast Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New District, Shanghai, China
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Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: Viruses and metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189179. [PMID: 39299491 DOI: 10.1016/j.bbcan.2024.189179] [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: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/22/2024]
Abstract
Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Golestani
- Department of ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Motlaghzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aidin Lalehzadeh
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Le C, Liu C, Lu B, Zhou X, Jiamaliding Y, Jin T, Dai S, Li J, Ding K, Xiao Q. Association between Hepatitis B virus infection and liver metastasis in colorectal cancer. MedComm (Beijing) 2024; 5:e584. [PMID: 38887467 PMCID: PMC11181900 DOI: 10.1002/mco2.584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 03/18/2024] [Accepted: 04/04/2024] [Indexed: 06/20/2024] Open
Abstract
The association between Hepatitis B virus (HBV) infection and colorectal liver metastases (CRLM) remains ambiguous in current population-based evidence. To clarify this, we present a retrospective analysis of 5871 colorectal cancer (CRC) patients. Propensity score matching (PSM) was applied to harmonize age and sex disparities within HBV+ (n = 1696) and HBV- (n = 4175) groups and further within HBV+ subgroups of chronic (CHB, n = 474) and occult (OHB, n = 1222) infections. Our initial results indicated a significant association between HBV infection and synchronous colorectal liver metastasis (SYN-CRLM); however, this association dissipated after PSM was employed to adjust for confounding variables. No significant association was observed between HBV infection and metachronous colorectal liver metastases (MET-CRLM) both before and after PSM. Further analysis revealed that HBV replication status did not influence the incidence of CRLM. However, HBV+ participants demonstrated an increased incidence of metachronous extrahepatic metastases, particularly to the lungs. Our findings imply that neither past nor present HBV infection is significantly correlated with the occurrence of SYN-CRLM or MET-CRLM. The absence of an association between HBV replication status and CRLM incidence highlights the importance of incorporating a broader range of factors in the clinical management of CRLM beyond the status of HBV infection.
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Affiliation(s)
- Chenqin Le
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Chengcheng Liu
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Bin Lu
- Nursing DepartmentThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
| | - Xinbin Zhou
- Nursing DepartmentThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
| | - Yeernaer Jiamaliding
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Tian Jin
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Siqi Dai
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Jun Li
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
| | - Qian Xiao
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Center for Medical Research and Innovation in Digestive System TumorsMinistry of EducationHangzhouChina
- Zhejiang Provincial Clinical Research Center for CANCERHangzhouChina
- Cancer Center of Zhejiang UniversityHangzhouChina
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Yao M, Fang RF, Xie Q, Xu M, Sai WL, Yao DF. Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2350-2361. [PMID: 38994143 PMCID: PMC11236219 DOI: 10.4251/wjgo.v16.i6.2350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/02/2024] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Rong-Fei Fang
- Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qun Xie
- Department of Infectious Diseases, Haian People’s Hospital, Haian 226600, Jiangsu Province, China
| | - Min Xu
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Yao M, Fang RF, Xie Q, Xu M, Sai WL, Yao DF. Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2814-2825. [DOI: 10.4251/wjgo.v16.i6.2814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/02/2024] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Rong-Fei Fang
- Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qun Xie
- Department of Infectious Diseases, Haian People’s Hospital, Haian 226600, Jiangsu Province, China
| | - Min Xu
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Rawal P, Tripathi DM, Hemati H, Kumar J, Tyagi P, Sarin SK, Nain V, Kaur S. Targeted HBx gene editing by CRISPR/Cas9 system effectively reduces epithelial to mesenchymal transition and HBV replication in hepatoma cells. Liver Int 2024; 44:614-624. [PMID: 38105495 DOI: 10.1111/liv.15805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/28/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND AND AIMS Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. METHODOLOGY AND RESULTS We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both two- and three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. CONCLUSION Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC.
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Affiliation(s)
- Preety Rawal
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Dinesh Mani Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Hamed Hemati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Jitendra Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Purnima Tyagi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Vikrant Nain
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
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Chen R, Zou J, Zhong X, Li J, Kang R, Tang D. HMGB1 in the interplay between autophagy and apoptosis in cancer. Cancer Lett 2024; 581:216494. [PMID: 38007142 DOI: 10.1016/j.canlet.2023.216494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/25/2023] [Accepted: 11/08/2023] [Indexed: 11/27/2023]
Abstract
Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.
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Affiliation(s)
- Ruochan Chen
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Ju Zou
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Xiao Zhong
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Jie Li
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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Tang D, Kang R, Zeh HJ, Lotze MT. The multifunctional protein HMGB1: 50 years of discovery. Nat Rev Immunol 2023; 23:824-841. [PMID: 37322174 DOI: 10.1038/s41577-023-00894-6] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2023] [Indexed: 06/17/2023]
Abstract
Fifty years since the initial discovery of HMGB1 in 1973 as a structural protein of chromatin, HMGB1 is now known to regulate diverse biological processes depending on its subcellular or extracellular localization. These functions include promoting DNA damage repair in the nucleus, sensing nucleic acids and inducing innate immune responses and autophagy in the cytosol and binding protein partners in the extracellular environment and stimulating immunoreceptors. In addition, HMGB1 is a broad sensor of cellular stress that balances cell death and survival responses essential for cellular homeostasis and tissue maintenance. HMGB1 is also an important mediator secreted by immune cells that is involved in a range of pathological conditions, including infectious diseases, ischaemia-reperfusion injury, autoimmunity, cardiovascular and neurodegenerative diseases, metabolic disorders and cancer. In this Review, we discuss the signalling mechanisms, cellular functions and clinical relevance of HMGB1 and describe strategies to modify its release and biological activities in the setting of various diseases.
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Affiliation(s)
- Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Herbert J Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Michael T Lotze
- Departments of Surgery, Immunology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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11
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You H, Wang X, Ma L, Zhang F, Zhang H, Wang Y, Pan X, Zheng K, Kong F, Tang R. Insights into the impact of hepatitis B virus on hepatic stellate cell activation. Cell Commun Signal 2023; 21:70. [PMID: 37041599 PMCID: PMC10088164 DOI: 10.1186/s12964-023-01091-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/26/2023] [Indexed: 04/13/2023] Open
Abstract
During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-β and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. Video abstract.
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Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xing Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lihong Ma
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Huanyang Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yuxin Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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12
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Zhang M, Ding Q, Bian C, Su J, Xin Y, Jiang X. Progress on the molecular mechanism of portal vein tumor thrombosis formation in hepatocellular carcinoma. Exp Cell Res 2023; 426:113563. [PMID: 36944406 DOI: 10.1016/j.yexcr.2023.113563] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/01/2023] [Accepted: 03/18/2023] [Indexed: 03/22/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with poor prognosis and high mortality. Early-stage HCC has no obvious clinical symptoms, and most patients are already at an advanced stage when they are diagnosed. Portal vein tumor thrombus (PVTT) is the most common complication and a poor prognostic factor for HCC, which frequently leads to portal vein hypertension, ascites, gastrointestinal bleeding, and tumor metastasis. The formation of PVTT is related to the complex structure and hemodynamic changes of the portal vein and is closely related to changes at the cellular and molecular levels. The differentially-expressed genes (DEGs) between PVTT and primary tumor (PT) suggest that the two tissues may have different clonal origins. Epigenetic and proteomic analyses also suggest complex and diverse mechanisms for the formation of PVTT. In addition, the tumor microenvironment and energy metabolism pathways are interrelated in regulating the invasion and progression of PVTT. Aerobic glycolysis and the tumor immune microenvironment have been the focus of recent studies on PVTT. In this review, we summarize the mechanism of PVTT formation at the cellular and molecular levels to provide information to guide better prevention and treatment of PVTT in the clinic.
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Affiliation(s)
- Min Zhang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130021, China.
| | - Qiuhui Ding
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130021, China.
| | - Chenbin Bian
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130021, China.
| | - Jing Su
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130021, China.
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
| | - Xin Jiang
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, 130021, China; Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China; NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130021, China.
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13
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Mo Y, Chen K. Review: The role of HMGB1 in spinal cord injury. Front Immunol 2023; 13:1094925. [PMID: 36713448 PMCID: PMC9877301 DOI: 10.3389/fimmu.2022.1094925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/19/2022] [Indexed: 01/13/2023] Open
Abstract
High mobility group box 1 (HMGB1) has dual functions as a nonhistone nucleoprotein and an extracellular inflammatory cytokine. In the resting state, HMGB1 is mainly located in the nucleus and regulates key nuclear activities. After spinal cord injury, HMGB1 is rapidly expressed by neurons, microglia and ependymal cells, and it is either actively or passively released into the extracellular matrix and blood circulation; furthermore, it also participates in the pathophysiological process of spinal cord injury. HMGB1 can regulate the activation of M1 microglia, exacerbate the inflammatory response, and regulate the expression of inflammatory factors through Rage and TLR2/4, resulting in neuronal death. However, some studies have shown that HMGB1 is beneficial for the survival, regeneration and differentiation of neurons and that it promotes the recovery of motor function. This article reviews the specific timing of secretion and translocation, the release mechanism and the role of HMGB1 in spinal cord injury. Furthermore, the role and mechanism of HMGB1 in spinal cord injury and, the challenges that still need to be addressed are identified, and this work will provide a basis for future studies.
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14
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Liu H, Yan Y, Lin J, He C, Liao H, Li H, Zhou Z, Wang J, Mao K, Xiao Z. Circular RNA circSFMBT2 downregulation by HBx promotes hepatocellular carcinoma metastasis via the miR-665/TIMP3 axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:788-802. [PMID: 36159591 PMCID: PMC9463182 DOI: 10.1016/j.omtn.2022.08.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 08/02/2022] [Indexed: 04/30/2023]
Abstract
Hepatitis B virus X protein (HBx) is considered as an oncogene in tumorigenesis and progression of hepatocellular carcinoma (HCC). In recent years, the important role of circular RNAs (circRNAs) in HCC has been increasingly demonstrated. However, the regulatory mechanisms of HBx on circRNAs remains largely unknown. In this study, we identified that a novel circRNA, circSFMBT2, was markedly downregulated by HBx. Low expression of circSFMBT2 was correlated with poor prognosis and vascular invasion. Functionally, overexpression of circSFMBT2 significantly inhibited HCC metastasis both in vitro and in vivo. The mechanism of circSFMBT2 was to as a sponge of miR-665, which is a negative regulator of tissue inhibitor of metalloproteinases 3 (TIMP3). However, HBx downregulated circSFMBT2 via the interaction with DExH-box helicase 9 (DHX9), which binds to flanking circRNA-forming introns. In conclusion, circSFMBT2, which is downregulated by HBx, acts as a tumor suppressor to inhibit tumor metastasis through the miR-665/TIMP3 axis. Our study suggests that circSFMBT2 could be a potential prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Haohan Liu
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Corresponding author Yongcong Yan, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road #107, Guangzhou 510120, China.
| | - Jianhong Lin
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Chuanchao He
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Hao Liao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Huoming Li
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Zhenyu Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Kai Mao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of General Surgery, Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei 516600, China
- Corresponding author Kai Mao, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road #107, Guangzhou 510120, China.
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Department of General Surgery, Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei 516600, China
- Corresponding author Zhiyu Xiao, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road #107, Guangzhou 510120, China.
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15
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Chen R, Kang R, Tang D. The mechanism of HMGB1 secretion and release. Exp Mol Med 2022; 54:91-102. [PMID: 35217834 PMCID: PMC8894452 DOI: 10.1038/s12276-022-00736-w] [Citation(s) in RCA: 393] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/13/2021] [Accepted: 11/04/2021] [Indexed: 02/08/2023] Open
Abstract
High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage. A nuclear protein that gets released after cell death or is actively secreted by immune cells offers a promising therapeutic target for treating diseases linked to excessive inflammation. Daolin Tang from the University of Texas Southwestern Medical Center in Dallas, USA, and colleagues review how cellular stresses can trigger the accumulation of HMGB1, a type of alarm signal protein that promotes the recruitment and activation of inflammation-promoting immune cells. The researchers discuss various mechanisms that drive both passive and active release of HMGB1 into the space around cells. These processes, which include enzymatic modifications of the HMGB1 protein, cell–cell interactions and molecular pathways of cell death, could be targeted by drugs to lessen tissue damage and inflammatory disease caused by HMGB1-induced immune responses
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Affiliation(s)
- Ruochan Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. .,Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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16
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Intracellular translocation of HMGB1 is important for Zika virus replication in Huh7 cells. Sci Rep 2022; 12:1054. [PMID: 35058496 PMCID: PMC8776752 DOI: 10.1038/s41598-022-04955-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/04/2022] [Indexed: 12/11/2022] Open
Abstract
Neonatal microcephaly and adult Guillain-Barré syndrome are severe complications of Zika virus (ZIKV) infection. The robustly induced inflammatory cytokine expressions in ZIKV-infected patients may constitute a hallmark for severe disease. In the present study, the potential role of high mobility group box 1 protein (HMGB1) in ZIKV infection was investigated. HMGB1 protein expression was determined by the enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. HMGB1's role in ZIKV infection was also explored using treatment with dexamethasone, an immunomodulatory drug, and HMGB1-knockdown (shHMGB1) Huh7 cells. Results showed that the Huh7 cells were highly susceptible to ZIKV infection. The infection was found to induce HMGB1 nuclear-to-cytoplasmic translocation, resulting in a > 99% increase in the cytosolic HMGB1 expression at 72-h post-infection (h.p.i). The extracellular HMGB1 level was elevated in a time- and multiplicity of infection (MOI)-dependent manner. Treatment of the ZIKV-infected cells with dexamethasone (150 µM) reduced HMGB1 extracellular release in a dose-dependent manner, with a maximum reduction of 71 ± 5.84% (P < 0.01). The treatment also reduced virus titers by over 83 ± 0.50% (P < 0.01). The antiviral effects, however, were not observed in the dexamethasone-treated shHMGB1 cells. These results suggest that translocation of HMGB1 occurred during ZIKV infection and inhibition of the translocation by dexamethasone coincided with a reduction in ZIKV replication. These findings highlight the potential of targeting the localization of HMGB1 in affecting ZIKV infection.
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17
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Kim MJ, Kim J, Im JS, Kang I, Ahn JK. Hepatitis B virus X protein enhances liver cancer cell migration by regulating calmodulin-associated actin polymerization. BMB Rep 2021. [PMID: 34488928 PMCID: PMC8728542 DOI: 10.5483/bmbrep.2021.54.12.084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, plays pivotal roles in the development and metastasis of HCC. It has been reported that HBx induces liver cancer cell migration and reorganizes actin cytoskeleton, however the molecular basis for actin cytoskeleton reorganization remains obscure. In this study, we for the first time report that HBx promotes actin polymerization and liver cancer cell migration by regulating calcium modulated protein, calmodulin (CaM). HBx physically interacts with CaM to control the level of phosphorylated cofilin, an actin depolymerizing factor. Mechanistically, HBx interacts with CaM, liberates Hsp90 from its inhibitory partner CaM, and increases the activity of Hsp90, thus activating LIMK1/cofilin pathway. Interestingly, the interaction between HBx and CaM is calcium-dependent and requires the CaM binding motif on HBx. These results indicate that HBx modulates CaM which plays a regulatory role in Hsp90/LIMK1/cofilin pathway of actin reorganization, suggesting a new mechanism of HBV-induced HCC metastasis specifically derived by HBx.
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Affiliation(s)
- Mi-jee Kim
- Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Jinchul Kim
- Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Jin-su Im
- Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Inho Kang
- Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Korea
| | - Jeong Keun Ahn
- Department of Microbiology & Molecular Biology, College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Korea
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18
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Wei Y, Tang X, Ren Y, Yang Y, Song F, Fu J, Liu S, Yu M, Chen J, Wang S, Zhang K, Tan Y, Han Z, Wei L, Zhang B, Cheng Z, Li L, Wang H. An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity. Signal Transduct Target Ther 2021; 6:421. [PMID: 34916485 PMCID: PMC8677721 DOI: 10.1038/s41392-021-00801-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/25/2021] [Accepted: 10/09/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged involving RNA–RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA–RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV+ early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3′untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1+ exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1+ exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.
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Affiliation(s)
- Yanping Wei
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Xuewu Tang
- National Center for Liver Cancer, Shanghai, China.,Hepato-Pancreato-biliary center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yibin Ren
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Yun Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Fengliang Song
- National Center for Liver Cancer, Shanghai, China.,School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Jingbo Fu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Shuowu Liu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Miao Yu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jing Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Suyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Kecheng Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yexiong Tan
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Zhipeng Han
- National Center for Liver Cancer, Shanghai, China.,Tumor Immunology and Gene Therapy Center, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Lixin Wei
- National Center for Liver Cancer, Shanghai, China.,Tumor Immunology and Gene Therapy Center, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhangjun Cheng
- Hepato-Pancreato-biliary center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
| | - Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China. .,National Center for Liver Cancer, Shanghai, China.
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-Biliary Surgery Institute, Second Military Medical University, Shanghai, China. .,National Center for Liver Cancer, Shanghai, China. .,National Laboratory for Oncogenes and Related Genes, Cancer Institute, RenJi Hospital, Shanghai Jiao Tong University, 200441, Shanghai, China.
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19
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Zhang H, Chen B, Zou Z, Feng J, Li Y, Wang Y, He X, Xu C, Wang H, Guo S, Jin L, Li Q, Wang J, Xiao M, Li F, Wu J. Associations Between CAMKK1 Polymorphism rs7214723 and the Prognosis of Patients With Lung Cancer. Front Oncol 2021; 11:757484. [PMID: 34868969 PMCID: PMC8640188 DOI: 10.3389/fonc.2021.757484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/26/2021] [Indexed: 11/18/2022] Open
Abstract
Background The 5-year survival rate of patients with lung cancer in China is less than 20% and predicting their prognosis is challenging. We investigated the association between a common non-synonymous single nucleotide polymorphism (SNP), rs7214723, in the Ca2+/calmodulin-dependent protein kinase kinase 1 (CAMKK1) gene and the prognosis of patients with lung cancer. Methods Genomic DNA was extracted from the blood samples of 839 patients with lung cancer, recruited from Changhai Hospital (n = 536) and Taizhou Institute of Health Sciences (n = 352), and genotyped using the SNPscan technique. The association between patient prognosis and the genotypic data for CAMKK1 was analyzed using a multivariate Cox proportional hazards model adjusted for multiple potential confounders. The CRISPR/Cas9 gene-editing system was used to introduce point mutations in the CAMKK1 rs7214723 of A549 and NCI-H358 cells. Subsequently, Cell proliferation and migration ability were assessed with the Cell Counting Kit-8 and scratch assay. The Annexin V-FITC apoptosis detection kit was used to detect cell apoptosis. Results The CAMKK1 rs7214723 recessive CC genotype conferred significantly better overall survival (CC vs. TT + TC: adjusted hazard ratio = 0.78, 95% confidence interval [CI], 0.61-1.00, P = 0.049) than the TT + TC genotypes. Stratified analysis showed that the CAMKK1 rs7214723 CC genotype and recessive CC genotype conferred a significantly decreased risk of death in patients who were male, had a smoking history, or had stage III + IV cancer, compared with the TT and TT + TC genotypes. Relative to the TT + TC genotypes, the rs7214723 recessive CC genotype was also associated with a decreased risk of death in patients aged < 60 years (CC vs. TT + TC: adjusted hazard ratio = 0.59, 95% CI, 0.37-0.93, P = 0.024) and patients with squamous cell carcinoma (CC vs. TT + TC: adjusted hazard ratio = 0.65, 95% CI, 0.44-0.98, P = 0.038). Remarkably, CRISPR/Cas9-guided single nucleotide editing demonstrated that CAMKK1 rs7214723 T > C mutation significantly inhibits cell proliferation and migration and promotes cell apoptosis. Conclusions CAMKK1 SNP rs7214723 may be a significant prognostic factor for the risk of death among patients with lung cancer.
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Affiliation(s)
- Haorui Zhang
- Department of Ophthalmology, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - Bocen Chen
- Department of Biochemistry and Molecular Biology, Hainan Medical University, Haikou, China
| | - Zixiu Zou
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jian Feng
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yutao Li
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Yi Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Xing He
- Department of Urology, Navy Military Medical University Affiliated Changhai Hospital, Shanghai, China
| | - Chang Xu
- Clinical College, Xiangnan University, Chenzhou, China
| | - Haijian Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Shicheng Guo
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Qiang Li
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Man Xiao
- Department of Biochemistry and Molecular Biology, Hainan Medical University, Haikou, China
| | - Feng Li
- Department of Respiratory Disease, Shanghai Public Health Clinical Center, Shanghai, China
| | - Junjie Wu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Department of Infectious Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Respiratory and Critical Care Medicine, Changhai Hospital, Navy Military Medical University, Shanghai, China
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20
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Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma. Angiogenesis 2021; 25:181-203. [PMID: 34617194 PMCID: PMC8494172 DOI: 10.1007/s10456-021-09819-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 08/04/2021] [Indexed: 01/15/2023]
Abstract
Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.
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21
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Ni YA, Chen H, Nie H, Zheng B, Gong Q. HMGB1: An overview of its roles in the pathogenesis of liver disease. J Leukoc Biol 2021; 110:987-998. [PMID: 33784425 DOI: 10.1002/jlb.3mr0121-277r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 01/06/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is an abundant architectural chromosomal protein that has multiple biologic functions: gene transcription, DNA replication, DNA-damage repair, and cell signaling for inflammation. HMGB1 can be released passively by necrotic cells or secreted actively by activated immune cells into the extracellular milieu after injury. Extracellular HMGB1 acts as a damage-associated molecular pattern to initiate the innate inflammatory response to infection and injury by communicating with neighboring cells through binding to specific cell-surface receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). Numerous studies have suggested HMGB1 to act as a key protein mediating the pathogenesis of chronic and acute liver diseases, including nonalcoholic fatty liver disease, hepatocellular carcinoma, and hepatic ischemia/reperfusion injury. Here, we provide a detailed review that focuses on the role of HMGB1 and HMGB1-mediated inflammatory signaling pathways in the pathogenesis of liver diseases.
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Affiliation(s)
- Yuan-Ao Ni
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hui Chen
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei Province, People's Republic of China
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22
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Zhou X, Chi Y, Dong Z, Tao T, Zhang X, Pan W, Wang Y. A nomogram combining PPARγ expression profiles and clinical factors predicts survival in patients with hepatocellular carcinoma. Oncol Lett 2021; 21:319. [PMID: 33692851 PMCID: PMC7933753 DOI: 10.3892/ol.2021.12581] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in the development of various tumor types. However, its role in hepatocellular carcinoma (HCC) remains unclear. Multiple databases including The Cancer Genome Atlas, Gene Expression Omnibus and Kaplan-Meier plotter were used for bioinformatics analysis of the PPARγ gene or protein. Immunohistochemical labeling of tumor and adjacent normal tissues obtained from 125 patients with HCC was performed to analyze the relationship between PPARγ expression and overall survival (OS) rate. PPARγ was evaluated using functional enrichment analyses and Lasso regression was used to conduct a dimensionality reduction analysis of 43 clinical factors for HCC. An OS prognostic nomogram was then established using seven independent risk factors screened via Lasso regression. PPARγ expression in HCC tumor tissues was higher compared with that in normal liver tissues, and its high expression was associated with poor prognosis, as indicated by bioinformatics analysis. However, opposite results were obtained using the clinical specimens. Functional enrichment analysis indicated that PPARγ was enriched in the 'fatty acid metabolism' pathway. Lasso regression identified seven clinical factors associated with prognosis, including Tumor-Node-Metastasis stage, grade, vascular invasion, α fetoprotein, carbohydrate antigen 199, γ-glutamyl transpeptidase and the PPARγ protein. These seven clinical factors were to construct an OS prognostic nomogram. Overall, PPARγ was highly expressed in the livers of patients with HCC and can be included in an OS prognostic nomogram. However, the factors underlying the differential association of PPARγ expression with HCC prognosis in different datasets should be further investigated.
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Affiliation(s)
- Xiaolu Zhou
- Department of Clinical Medicine, The Medical College of Qingdao University, Qingdao, Shandong 266071, P.R. China.,Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yajing Chi
- Department of Clinical Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 271016, P.R. China
| | - Zhiyuan Dong
- Department of Clinical Medicine, The Medical College of Qingdao University, Qingdao, Shandong 266071, P.R. China.,Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Tao Tao
- Hithink Flush Information Network Co., Ltd., Hangzhou, Zhejiang 310000, P.R. China
| | - Xin Zhang
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Wensheng Pan
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yemeng Wang
- Department of Hepatobiliary Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji, Zhejiang 311800, P.R. China
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23
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Yang N, Wang T, Li Q, Han F, Wang Z, Zhu R, Zhou J. HBXIP drives metabolic reprogramming in hepatocellular carcinoma cells via METTL3-mediated m6A modification of HIF-1α. J Cell Physiol 2020; 236:3863-3880. [PMID: 33305825 DOI: 10.1002/jcp.30128] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/10/2020] [Accepted: 10/15/2020] [Indexed: 12/17/2022]
Abstract
Cancer cells sustain high levels of glycolysis and glutaminolysis via reprogramming of intracellular metabolism, which represents a driver of hepatocellular carcinoma (HCC) progression. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. Herein, we collected HCC tissues and noncancerous liver tissues and found hepatitis B virus X-interacting protein (HBXIP) was found to be upregulated in HCC tissues and associated with poor prognosis. The N6-methyladenosine (m6A) level of hypoxia-inducible factor-1α (HIF-1α) in HCC cells was evaluated after the intervention of METTL3. The possible m6A site of HIF-1α was queried and the binding relationship between METTL3 and HIF-1α was verified. The interference of HBXIP suppressed HCC malignant behaviors and inhibited the Warburg effect in HCC cells. METTL3 was upregulated in HCC tissues and positively regulated by HBXIP. Overexpression of METTL3 restored cell metabolic reprogramming in HCC cells with partial loss of HBXIP. HBXIP mediated METTL3 to promote the metabolic reprogramming and malignant biological behaviors of HCC cells. The levels of total m6A in HCC cells and m6A in HIF-1α were increased. METTL3 had a binding relationship with HIF-1α and mediated the m6A modification of HIF-1α. In conclusion, HBXIP drives metabolic reprogramming in HCC cells via METTL3-mediated m6A modification of HIF-1α.
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Affiliation(s)
- Nanmu Yang
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tao Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qingjun Li
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Feng Han
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhengzheng Wang
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ruili Zhu
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinxue Zhou
- Department of Hepatopancreatobiliary Surgery, Henan Cancer Hospital, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
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24
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Yin J, Yin LY, Freedman ND, Li TY, Dawsey SM, Cui JF, Taylor PR, Liu B, Fan JH, Chen W, Abnet CC, Qiao YL. Independent and Joint Associations between Serum Calcium, 25-Hydroxy Vitamin D, and the Risk of Primary Liver Cancer: A Prospective Nested Case-Control Study. Cancer Epidemiol Biomarkers Prev 2020; 29:2057-2064. [PMID: 32856608 PMCID: PMC8594771 DOI: 10.1158/1055-9965.epi-20-0417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/27/2020] [Accepted: 07/31/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Accumulating evidence has shown that serum calcium and vitamin D may be associated with or influence various cancer risks. However, no prospective studies have evaluated the independent and joint associations between prediagnostic levels of serum calcium and vitamin D and future risk of incident primary liver cancer. METHODS We used a nested case-control design to evaluate subjects over 22 years of follow-up. Serum calcium, 25-hydroxy vitamin D [25(OH)D], and three markers of hepatitis B virus and hepatitis C virus were measured in baseline serum from 226 incident primary liver cancer cases and 1,061 matched controls. We calculated ORs and 95% confidence intervals (CI) using logistic regression to estimate the associations between calcium, 25(OH)D, and primary liver cancer risk. RESULTS Multivariable adjusted models showed that subjects with both low (ORLow/Medium = 1.48, 95% CI = 1.01-2.17) or high (ORHigh/Medium = 1.92, 95% CI = 1.34-2.76) calcium had an increased primary liver cancer risk, while those with high 25(OH)D had a decreased risk of primary liver cancer (ORHigh/Medium = 0.54, 95% CI = 0.35-0.82). In joint analyses, when compared with subjects with medium calcium and 25(OH)D, subjects with high calcium and medium 25(OH)D had elevated odds of developing primary liver cancer (OR = 1.89, 95% CI = 1.17-3.05); those with medium calcium and high 25(OH)D had reduced odds of developing primary liver cancer (OR = 0.34, 95% CI = 0.17-0.67); and subjects in other classifications of calcium and serum 25(OH)D levels had no change in the odds of developing primary liver cancer (all P > 0.05). CONCLUSIONS In a nutrient-deficient population, we found that serum calcium and serum 25(OH)D could potentially be modifiable risk or protective factors. IMPACT Our findings provide potential targets for primary liver cancer prevention and control.
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Affiliation(s)
- Jian Yin
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liang-Yu Yin
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Department of Clinical Nutrition, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Ting-Yuan Li
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sanford M Dawsey
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Jian-Feng Cui
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Philip R Taylor
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Bin Liu
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin-Hu Fan
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen Chen
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Christian C Abnet
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - You-Lin Qiao
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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25
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Cámara-Quílez M, Barreiro-Alonso A, Rodríguez-Bemonte E, Quindós-Varela M, Cerdán ME, Lamas-Maceiras M. Differential Characteristics of HMGB2 Versus HMGB1 and their Perspectives in Ovary and Prostate Cancer. Curr Med Chem 2020; 27:3271-3289. [PMID: 30674244 DOI: 10.2174/0929867326666190123120338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/28/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023]
Abstract
We have summarized common and differential functions of HMGB1 and HMGB2 proteins with reference to pathological processes, with a special focus on cancer. Currently, several "omic" approaches help us compare the relative expression of these 2 proteins in healthy and cancerous human specimens, as well as in a wide range of cancer-derived cell lines, or in fetal versus adult cells. Molecules that interfere with HMGB1 functions, though through different mechanisms, have been extensively tested as therapeutic agents in animal models in recent years, and their effects are summarized. The review concludes with a discussion on the perspectives of HMGB molecules as targets in prostate and ovarian cancers.
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Affiliation(s)
- María Cámara-Quílez
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Aida Barreiro-Alonso
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Esther Rodríguez-Bemonte
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - María Quindós-Varela
- Translational Cancer Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Carretera del Pasaje s/n, 15006 A Coruña, Spain
| | - M Esperanza Cerdán
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
| | - Mónica Lamas-Maceiras
- EXPRELA Group, Centro de Investigacions Cientificas Avanzadas (CICA), Departamento de Bioloxia. Facultade de Ciencias, INIBIC- Universidade da Coruna, Campus de A Zapateira, 15071, A Coruna, Spain
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26
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PCV2 Induces Reactive Oxygen Species To Promote Nucleocytoplasmic Translocation of the Viral DNA Binding Protein HMGB1 To Enhance Its Replication. J Virol 2020; 94:JVI.00238-20. [PMID: 32321806 DOI: 10.1128/jvi.00238-20] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023] Open
Abstract
Porcine circovirus type 2 (PCV2) is an important swine pathogen that causes significant economic losses to the pig industry. PCV2 interacts with host cellular factors to regulate its replication. High-mobility-group box 1 (HMGB1) protein, a major nonhistone protein in the nucleus, was recently discovered to participate in viral infections. Here, we demonstrate that nuclear HMGB1 negatively regulated PCV2 replication as shown by overexpression of HMGB1 or blockage of its nucleocytoplasmic translocation with ethyl pyruvate. The B box domain was essential in restricting PCV2 replication. Nuclear HMGB1 restricted PCV2 replication by sequestering the viral genome via binding to the Ori region. However, PCV2 infection induced translocation of HMGB1 from cell nuclei to the cytoplasmic compartment. Elevation of reactive oxygen species (ROS) induced by PCV2 infection was closely associated with cytosolic translocation of nuclear HMGB1. Treatment of PCV2-infected cells with ethyl pyruvate or N-acetylcysteine downregulated PCV2-induced ROS production, suppressed nucleocytoplasmic HMGB1 translocation, and decreased PCV2 replication. Collectively, these findings offer new insight into the mechanism of the PCV2 evasion strategy: PCV2 manages to escape restriction of its replication by nuclear HMGB1 by inducing ROS to trigger the nuclear-to-cytoplasmic translocation of HMGB1.IMPORTANCE Porcine circovirus type 2 (PCV2) is a small DNA virus that depends heavily on host cells for its infection. This study reports the close relationship between subcellular localization of host high-mobility-group box 1 (HMGB1) protein and viral replication during PCV2 infection. Restriction of PCV2 replication by nuclear HMGB1 is the early step of host defense at the host-pathogen interface. PCV2 then upregulates host reactive oxygen species (ROS) to prevent sequestration of its genome by expelling nuclear HMGB1 into the cytosol. It will be interesting to study if a similar evasion strategy is employed by other circoviruses such as beak and feather disease virus, recently discovered PCV3, and geminiviruses in plants. This study also provides insight into the justification and pharmacological basis of antioxidants as an adjunct therapy in PCV2 infection or possibly other diseases caused by the viruses that deploy the ROS-HMGB1 interaction favoring their replication.
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27
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Shi X, Yu L, Zhang Y, Liu Z, Zhang H, Zhang Y, Liu P, Du P. Glycyrrhetinic acid alleviates hepatic inflammation injury in viral hepatitis disease via a HMGB1-TLR4 signaling pathway. Int Immunopharmacol 2020; 84:106578. [PMID: 32416454 PMCID: PMC7205693 DOI: 10.1016/j.intimp.2020.106578] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/24/2020] [Accepted: 05/06/2020] [Indexed: 12/24/2022]
Abstract
Licorice defect in TCM recipes leads to the hepatotoxicity in administrated mice. GA inhibits viral hepatitis by suppressing HMGB1 release and cytokine activity. GA treatment effect on infected mice is similar with HMGB1 neutralizing antibody. HMGB1-TLR4 axis is involved in murine hepatic injury during MHV infection. Various human disorders are cured by the use of licorice, a key ingredient of herbal remedies. Glycyrrhizic acid (GL), a triterpenoid glycoside, is the aqueous extract from licorice root. Glycyrrhetinic acid (GA) has been reported to be a major bioactive hydrolysis product of GL and has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis. However, the mechanism by which GA inhibits viral hepatic inflammatory injury is not completely understood. In this study, we found that, by consecutively treating mice with a traditional herbal recipe, licorice plays an important role in the detoxification of mice. We also employed a murine hepatitis virus (MHV) infection model to illustrate that GA treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity. Furthermore, decreased HMGB1 levels and downstream signaling triggered by injection of a neutralizing HMGB1 antibody or TLR4 gene deficiency, also significantly protected against MHV-induced severe hepatic injury. Thus, our findings characterize GA as a hepatoprotective therapy agent in hepatic infectious disease not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via an underlying viral-induced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm. The present study provides a new therapy strategy for the treatment of acute viral hepatitis in the clinical setting.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Cell Line
- Cytokines/genetics
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Female
- Glycyrrhetinic Acid/pharmacology
- Glycyrrhetinic Acid/therapeutic use
- Glycyrrhiza
- HMGB1 Protein/immunology
- Hepatitis, Viral, Animal/drug therapy
- Hepatitis, Viral, Animal/genetics
- Hepatitis, Viral, Animal/immunology
- Liver/drug effects
- Liver/immunology
- Mice, Inbred C57BL
- Mice, Knockout
- Murine hepatitis virus
- Signal Transduction/drug effects
- Toll-Like Receptor 4/genetics
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Affiliation(s)
- Xiaodong Shi
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China.
| | - Lijia Yu
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Yinglin Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Zequan Liu
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Huawei Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Yansong Zhang
- National Center for Occupational Safety and Health, National Health Commission of the People's Republic of China, Beijing 102308, China
| | - Ping Liu
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Peishuang Du
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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28
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Nikolaou S, Qiu S, Fiorentino F, Simillis C, Rasheed S, Tekkis P, Kontovounisios C. The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review. Cell Commun Signal 2020; 18:68. [PMID: 32336282 PMCID: PMC7183616 DOI: 10.1186/s12964-020-00569-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
Background Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell proliferation, migration, DNA synthesis has been studied in a wide range of cancers. Expression of Neurotensin and its receptors has also been correlated to prognosis and prediction to treatment. Main body The effects of NT are mediated through mitogen-activated protein kinases, epidermal growth factor receptors and phosphatidylinositol-3 kinases amongst others. This review is a comprehensive summary of the molecular pathways by which Neurotensin and its receptors act in cancer cells. Conclusion Identifying the role of Neurotensin in the underlying molecular mechanisms in various cancers can give way to developing new agnostic drugs and personalizing treatment according to the genomic structure of various cancers.
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