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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Yan X, Wang M, Ji L, Li X, Gao B. Machine learning and molecular subtyping reveal the impact of diverse patterns of cell death on the prognosis and treatment of hepatocellular carcinoma. Comput Biol Chem 2025; 115:108360. [PMID: 39874853 DOI: 10.1016/j.compbiolchem.2025.108360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/27/2024] [Accepted: 01/19/2025] [Indexed: 01/30/2025]
Abstract
Programmed cell death (PCD) is a significant factor in the progression of hepatocellular carcinoma (HCC) and might serve as a crucial marker for predicting HCC prognosis and therapy response. However, the classification of HCC based on diverse PCD patterns requires further investigation. This study identified a novel molecular classification named PCD subtype (C1, C2, and C3) based on the genes associated with 19 PCD patterns, distinguished by clinical, biological functional pathways, mutations, immune characteristics, and drug sensitivity. Validated in 4 independent datasets, diverse cell death pathways were enriched in the C3 subtype, including apoptosis, pyroptosis, and autophagy, it also exhibited a highly infiltrative immunosuppressive microenvironment and demonstrated higher sensitivity to compounds such as Paclitaxel, Bortezomib, and YK-4-279, while C1 subtype was significantly enriched in cuproptosis and metabolism-related pathways, suggesting that it may be more suitable for cuproptosis-inducing agent therapy. Subsequently, utilizing the machine learning algorithms, we constructed a cell death-related index (CDRI) with 22 gene features and constructed prognostic nomograms with high predictive performance by combining CDRI with clinical features. Notably, we found that CDRI effectively predicted the response of HCC patients to therapeutic strategies, where patients with high CDRI were more suitable for sorafenib drug therapy and patients with low CDRI were more ideal for transarterial chemoembolization (TACE). In conclusion, the PCD subtype and CDRI demonstrate significant efficacy in predicting the prognosis and therapeutic outcomes for patients with HCC. These findings offer valuable insights for the development of precise, individualized treatment strategies.
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Affiliation(s)
- Xinyue Yan
- College of Chemistry and Life Science of Beijing University of Technology, Beijing 100124, China
| | - Meng Wang
- College of Chemistry and Life Science of Beijing University of Technology, Beijing 100124, China
| | - Lurao Ji
- College of Chemistry and Life Science of Beijing University of Technology, Beijing 100124, China
| | - Xiaoqin Li
- College of Chemistry and Life Science of Beijing University of Technology, Beijing 100124, China.
| | - Bin Gao
- College of Chemistry and Life Science of Beijing University of Technology, Beijing 100124, China
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3
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Gao S, Zhang W, Dai J, Hu W, Xu Y, Yang H, Ye B, Ouyang H, Tang Q, Zhao G, Zhu J. Icariin mediates autophagy and apoptosis of hepatocellular carcinoma cells induced by the β-catenin signaling pathway through lncRNA LOXL1-AS1. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03692-6. [PMID: 39812768 DOI: 10.1007/s00210-024-03692-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025]
Abstract
To investigate the effect of icariin (ICA) on hepatocellular carcinoma (HCC) and its autophagy/apoptosis mechanism in HCC. The anti-HCC mechanism of ICA was investigated using HCC cells treated with 20 µmol/L ICA. Cell viability and proliferation were assessed using CCK-8 and colony formation assays, respectively, while TUNEL staining evaluated anti-apoptotic effects. DHE staining quantified intracellular ROS levels, and JC-1 staining assessed mitochondrial membrane potential. The expression of LC3 was detected by immunofluorescence staining. Additionally, HepG2 cells (2.0 × 106) were implanted into the thymus of BALB/c nude mice, which received intraperitoneal injections of 40 mg/kg ICA. Western blotting was used to evaluate the expression of proteins related to apoptosis and autophagy. ICA effectively inhibited the proliferation and invasion of HCC cells, enhancing autophagy and apoptosis. Silencing of lncRNA LOXL1-AS1 reduced β-catenin expression and downregulated PI3K/AKT/mTOR pathway phosphorylation. Targeting β-catenin with siRNA augmented apoptosis in HepG2 cells through elevated levels of Bax and caspase-3/8/9 and boosted autophagy via increased expression of LC3-II, Atg5, Atg7, Atg8, and Beclin-1. ICA reversed this autophagic effect, while rapamycin enhanced ICA's efficacy. In vivo, ICA suppressed tumor growth and promoted autophagy and apoptosis in mice. Icariin induces autophagy and apoptosis in HCC cells via the β-catenin signaling pathway mediated by lncRNA LOXL1-AS1, offering a novel approach to HCC clinical management.
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Affiliation(s)
- Sicheng Gao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Wanyi Zhang
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
- Shanghai Zhongshan Community Health Center of Songjiang District, Shanghai, China
| | - Jinhua Dai
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Weiye Hu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Yongyun Xu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Hailin Yang
- Changzheng Hospital Affiliated to Naval Medical University, Department of Traditional Chinese Medicine, Shanghai, 200003, China
| | - Baiyang Ye
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Hao Ouyang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Qinlin Tang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Gang Zhao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China.
| | - Junfeng Zhu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China.
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4
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Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy. Front Immunol 2024; 15:1450487. [PMID: 39315094 PMCID: PMC11416969 DOI: 10.3389/fimmu.2024.1450487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
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Affiliation(s)
- Beibei Liu
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ling Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Senavirathna L, Hasapes C, Chen R, Pan S. Accumulation of Intracellular Protein Advanced Glycation End Products Alters Cellular Homeostasis for Protein Clearance in Pancreatic Ductal Epithelial Cells. Biochemistry 2024; 63:1723-1729. [PMID: 38941592 PMCID: PMC11446404 DOI: 10.1021/acs.biochem.4c00250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein clearance. Here, we investigated the formation particulars of intracellular protein AGEs and sought to elucidate the molecular events implicated in the impact of cellular clearance systems. The formation and accumulation of intracellular protein AGEs increased protein aggregation and protease resistance, potentially overwhelming the ubiquitin-proteasome system (UPS). At high levels of protein AGEs, the abundance of many E3 ligases decreased and the overall ubiquitination level was reduced, all of which indicated decreased UPS activity. On the other hand, autophagy activity was stimulated, as evidenced by the upregulation of autophagy marker LC3II and important proteins in autophagosome and autolysosome formation, as well as downregulation of mTOR. Understanding the functional impacts of intracellular protein AGEs on the UPS and autophagy could pave the way for the future development of pharmaceutical agents targeting AGE-related diseases.
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Affiliation(s)
- Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Christopher Hasapes
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ru Chen
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Wang G, Jiang X, Torabian P, Yang Z. Investigating autophagy and intricate cellular mechanisms in hepatocellular carcinoma: Emphasis on cell death mechanism crosstalk. Cancer Lett 2024; 588:216744. [PMID: 38431037 DOI: 10.1016/j.canlet.2024.216744] [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: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/05/2024]
Abstract
Hepatocellular carcinoma (HCC) stands as a formidable global health challenge due to its prevalence, marked by high mortality and morbidity rates. This cancer type exhibits a multifaceted etiology, prominently linked to viral infections, non-alcoholic fatty liver disease, and genomic mutations. The inherent heterogeneity of HCC, coupled with its proclivity for developing drug resistance, presents formidable obstacles to effective therapeutic interventions. Autophagy, a fundamental catabolic process, plays a pivotal role in maintaining cellular homeostasis, responding to stressors such as nutrient deprivation. In the context of HCC, tumor cells exploit autophagy, either augmenting or impeding its activity, thereby influencing tumorigenesis. This comprehensive review underscores the dualistic role of autophagy in HCC, acting as both a pro-survival and pro-death mechanism, impacting the trajectory of tumorigenesis. The anti-carcinogenic potential of autophagy is evident in its ability to enhance apoptosis and ferroptosis in HCC cells. Pertinently, dysregulated autophagy fosters drug resistance in the carcinogenic context. Both genomic and epigenetic factors can regulate autophagy in HCC progression. Recognizing the paramount importance of autophagy in HCC progression, this review introduces pharmacological compounds capable of modulating autophagy-either inducing or inhibiting it, as promising avenues in HCC therapy.
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Affiliation(s)
- Gang Wang
- Department of Interventional, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110020, PR China
| | - Pedram Torabian
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada; Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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Lv G, Yang M, Gai K, Jia Q, Wang Z, Wang B, Li X. Multiple functions of HMGB1 in cancer. Front Oncol 2024; 14:1384109. [PMID: 38725632 PMCID: PMC11079206 DOI: 10.3389/fonc.2024.1384109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.
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Affiliation(s)
- Guangyao Lv
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Menglin Yang
- Quality Management Department, Marine Biomedical Research Institute of Qingdao, Qingdao, China
| | - Keke Gai
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Qiong Jia
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Zhenzhen Wang
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Bin Wang
- Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xueying Li
- School of Health, Binzhou Polytechnic, Binzhou, China
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8
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Xi P, Zhu W, Zhang Y, Wang M, Liang H, Wang H, Tian D. Upregulation of hypothalamic TRPV4 via S100a4/AMPKα signaling pathway promotes the development of diet-induced obesity. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166883. [PMID: 37683711 DOI: 10.1016/j.bbadis.2023.166883] [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: 06/07/2023] [Revised: 08/26/2023] [Accepted: 09/05/2023] [Indexed: 09/10/2023]
Abstract
Obesity is associated with abnormal regulation of energy metabolism in the hypothalamus. Transient receptor potential vanilloid 4 (TRPV4) is involved in regulating osmotic pressure, temperature and mechanical force transmission, but little is known about its role in obesity. Herein, the present study aimed to elucidate the effect of hypothalamic TRPV4 on high-fat diet-induced obesity (DIO) and evaluate its potential for regulating energy metabolism. Here we show that hypothalamic TRPV4 content is increased in DIO rats. Central administration of adeno-associated virus expressing TRPV4 in these animals remarkably increased body weight and fat mass by activating the S100a4/AMPKα signaling pathway, thereby promoting positive energy metabolism. Overexpressed hypothalamic TRPV4 impaired glucose tolerance, while promoting the accumulation of fat in liver cells, resulting in hepatic steatosis. In addition, the upregulation of hypothalamic TRPV4 reduces high-fat induced central inflammation. This study provides evidence that hypothalamic TRPV4 plays a significant role in regulating homeostasis. Hypothalamic TRPV4 emerges as a target for therapeutic intervention against obesity.
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Affiliation(s)
- Pengjiao Xi
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Wenjuan Zhu
- Department of Nuclear Medicine, Third Hospital of Nanchang, Nanchang, Jiangxi 330008, China
| | - Yan Zhang
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Meng Wang
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Huimin Liang
- Department of School of Nursing, Tianjin Medical University, Tianjin 300070, China
| | - Haomin Wang
- Department of Human Anatomy and Histology, Tianjin Medical University, Tianjin 300070, China.
| | - Derun Tian
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China; Department of Human Anatomy and Histology, Tianjin Medical University, Tianjin 300070, China.
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Hashemi M, Nadafzadeh N, Imani MH, Rajabi R, Ziaolhagh S, Bayanzadeh SD, Norouzi R, Rafiei R, Koohpar ZK, Raei B, Zandieh MA, Salimimoghadam S, Entezari M, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches. Cell Commun Signal 2023; 21:32. [PMID: 36759819 PMCID: PMC9912665 DOI: 10.1186/s12964-023-01053-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 01/15/2023] [Indexed: 02/11/2023] Open
Abstract
Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Niloufar Nadafzadeh
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Hassan Imani
- Department of Clinical Science, Faculty of Veterinary Medicine, Shahr-E Kord Branch, Islamic Azad University, Tehran, Chaharmahal and Bakhtiari, Iran
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Setayesh Ziaolhagh
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Raheleh Norouzi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Reihaneh Rafiei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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10
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RAGE Inhibitors for Targeted Therapy of Cancer: A Comprehensive Review. Int J Mol Sci 2022; 24:ijms24010266. [PMID: 36613714 PMCID: PMC9820344 DOI: 10.3390/ijms24010266] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/28/2022] [Accepted: 12/16/2022] [Indexed: 12/28/2022] Open
Abstract
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment.
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11
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Lv JH, Chen WZ, Li YN, Wang JX, Fu YK, Zeng ZX, Wu JY, Wang SJ, Huang XX, Huang LM, Huang RF, Wei YG, Yan ML. Should associating liver partition and portal vein ligation for staged hepatectomy be applied to hepatitis B virus-related hepatocellular carcinoma patients with cirrhosis? A multi-center study. HPB (Oxford) 2022; 24:2175-2184. [PMID: 36280426 DOI: 10.1016/j.hpb.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 06/30/2022] [Accepted: 10/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND It is unclear whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be performed in hepatitis B virus-related hepatocellular carcinoma (HCC) patients with cirrhosis. We explored the efficacy of ALPPS in HCC patients. METHODS Data of 54 patients who underwent ALPPS between August 2014 and July 2020 at three centers were collected. Adverse factors affecting their prognosis were analyzed and subsequently compared with 184 patients who underwent transcatheter arterial chemoembolization (TACE). RESULTS Overall survival rates of the ALPPS group at 1, 3, and 5 years were 70.6%, 38.4%, and 31.7%, respectively; corresponding disease-free survival rates were 50.5%, 22.4%, and 19.2%, respectively. The ALPPS group had a significantly greater long-term survival rate than the TACE group (before propensity score matching, P < 0.001; after propensity score matching, P = 0.002). Multivariate analysis demonstrated that multifocal lesions (P = 0.018) and macroscopic vascular invasion (P = 0.001) were prognostic factors for HCC patients who underwent ALPPS. After the propensity score matching, the multifocal lesions (P = 0.031), macroscopic vascular invasion (P = 0.003), and treatment type (ALPPS/TACE) (P = 0.026) were the factors adversely affecting the prognosis of HCC patients. CONCLUSION ALPPS was feasible in hepatitis B virus-related HCC patients with cirrhosis and resulted in better survival than TACE.
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Affiliation(s)
- Jia-Hui Lv
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Wei-Zhao Chen
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Yi-Nan Li
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Jin-Xiu Wang
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Yang-Kai Fu
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Zhen-Xin Zeng
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Jia-Yi Wu
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Shuang-Jia Wang
- Department of Hepatobiliary Pancreatic Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Xiao-Xiao Huang
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Li-Ming Huang
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Rong-Fa Huang
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Yong-Gang Wei
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China.
| | - Mao-Lin Yan
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China.
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12
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Yue Q, Song Y, Liu Z, Zhang L, Yang L, Li J. Receptor for Advanced Glycation End Products (RAGE): A Pivotal Hub in Immune Diseases. Molecules 2022; 27:molecules27154922. [PMID: 35956875 PMCID: PMC9370360 DOI: 10.3390/molecules27154922] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/21/2022] [Accepted: 07/31/2022] [Indexed: 02/07/2023] Open
Abstract
As a critical molecule in the onset and sustainment of inflammatory response, the receptor for advanced glycation end products (RAGE) has a variety of ligands, such as advanced glycation end products (AGEs), S100/calcium granule protein, and high-mobility group protein 1 (HMGB1). Recently, an increasing number studies have shown that RAGE ligand binding can initiate the intracellular signal cascade, affect intracellular signal transduction, stimulate the release of cytokines, and play a vital role in the occurrence and development of immune-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Alzheimer’s disease. In addition, other RAGE signaling pathways can play crucial roles in life activities, such as inflammation, apoptosis, autophagy, and endoplasmic reticulum stress. Therefore, the strategy of targeted intervention in the RAGE signaling pathway may have significant therapeutic potential, attracting increasing attention. In this paper, through the systematic induction and analysis of RAGE-related signaling pathways and their regulatory mechanisms in immune-related diseases, we provide theoretical clues for the follow-up targeted intervention of RAGE-mediated diseases.
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Affiliation(s)
- Qing Yue
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan 063210, China; (Q.Y.); (Y.S.); (Z.L.); (L.Y.)
| | - Yu Song
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan 063210, China; (Q.Y.); (Y.S.); (Z.L.); (L.Y.)
| | - Zi Liu
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan 063210, China; (Q.Y.); (Y.S.); (Z.L.); (L.Y.)
| | - Lin Zhang
- Department of Internal Medicine Nursing, School of Nursing, Wannan Medical College, 22 Wenchang West Road, Higher Education Park, Wuhu 241002, China;
| | - Ling Yang
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan 063210, China; (Q.Y.); (Y.S.); (Z.L.); (L.Y.)
| | - Jinlong Li
- Hebei Key Laboratory for Organ Fibrosis Research, School of Public Health, North China University of Science and Technology, Tangshan 063210, China; (Q.Y.); (Y.S.); (Z.L.); (L.Y.)
- Correspondence: ; Tel.: +86-0315-8805572
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13
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CircFMN2 Boosts Sorafenib Resistance in Hepatocellular Carcinoma Cells via Upregulating CNBP by Restraining Ubiquitination. JOURNAL OF ONCOLOGY 2022; 2022:2674163. [PMID: 35909906 PMCID: PMC9334069 DOI: 10.1155/2022/2674163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/25/2022] [Accepted: 06/29/2022] [Indexed: 12/11/2022]
Abstract
Purpose Noncoding RNAs exert critical biological effects in hepatocellular carcinoma (HCC). The role of circFMN2, a newly discovered functional RNA in prostate cancer and colorectal cancer, was investigated for the first time in sorafenib-resistance HCC cells. Methods The level of circFMN2 was assessed via quantitative real-time PCR (qRT-PCR). Cell proliferation was detected via CCK-8 and colony formation assay. Cell apoptosis was measured via the TUNEL assay and flow cytometry analysis. A Western blot assay was conducted to detect the CCHC-type zinc finger nucleic acid binding protein (CNBP) level and ubiquitination. RNA pull-down assay and RNA immunoprecipitation were carried out to explore the interaction between circFMN2 and CNBP. Results CircFMN2 was highly expressed in multidrug-resistant (MDR) cells. CircFMN2 overexpression exerted pro-proliferation effects in sorafenib-treated HCC cells, while depletion of circFMN2 displayed negative effect on sorafenib-treated MDR cells. Moreover, CNBP was verified as the binding protein of circFMN2. CNBP was upregulated in MDR cells, which was achieved by inhibition of ubiquitination by circFMN2. Besides, CNBP overexpression was found to boost sorafenib resistance in HCC cells. Conclusions CircFMN2 is aberrantly expressed in sorafenib-resistant HCC cells and contributes to sorafenib resistance in HCC cells via upregulation of CNBP by restraining ubiquitination.
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14
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Li D, Yao Y, Rao Y, Huang X, Wei L, You Z, Zheng G, Hou X, Su Y, Varghese Z, Moorhead JF, Chen Y, Ruan XZ. Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:116. [PMID: 35354475 PMCID: PMC8966370 DOI: 10.1186/s13046-022-02306-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/28/2022] [Indexed: 01/08/2023]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted. Methods We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice. Results Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo. Conclusions SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02306-4.
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Affiliation(s)
- Danyang Li
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Yingcheng Yao
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Yuhan Rao
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Xinyu Huang
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Li Wei
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Zhimei You
- Department of General Medicine, Affiliated Cancer Hospital of Chongqing University, Chongqing, 400016, China
| | - Guo Zheng
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Xiaoli Hou
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Yu Su
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Zac Varghese
- John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, NW3 2PF, UK
| | - John F Moorhead
- John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, NW3 2PF, UK
| | - Yaxi Chen
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China.
| | - Xiong Z Ruan
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China. .,John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, NW3 2PF, UK.
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Xie Y, Wang Y, Xue W, Zou H, Li K, Liu K, Zhao W, Zhu C, Cao J. Profiling and Integrated Analysis of Differentially Expressed MicroRNAs as Novel Biomarkers of Hepatocellular Carcinoma. Front Oncol 2022; 11:770918. [PMID: 35174066 PMCID: PMC8841844 DOI: 10.3389/fonc.2021.770918] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/29/2021] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease that has multiple etiologies. It is the most common primary liver cancer, the sixth highest cause of cancer incidences, and the fourth highest cause of cancer-related deaths. The discovery of new biomarkers for the early detection, treatment, and prognosis of HCC would therefore be extremely useful. This study investigated differentially expressed ribonucleic acid (RNA) profiles by constructing a genome-wide profile of clinical samples. Differential expression analysis identified 1,280 differentially expressed messenger RNAs (dif-mRNAs), 99 differentially expressed microRNAs (dif-miRNAs), 181 differentially expressed long non-coding RNAs (dif-lncRNAs), and 31 differentially expressed circular RNAs (dif-circRNAs). Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) path analysis were then conducted on these differentially expressed RNAs, revealing that they were clearly related to cell division, foreign body metabolism, and ribosome assembly. A competing endogenous RNA (ceRNA) network was then constructed based on the regulatory dif-miRNA-dif-mRNA and dif-miRNA-dif-lncRNA relationships. These results were also verified using HCC data from the Cancer Genome Atlas (TCGA); seven dif-miRNAs were verified in clinical samples by real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-Meier survival analysis revealed that the expression levels of Hsa-miR-1269a, Hsa-miR-421, and Hsa-miR-190b were correlated with overall survival. (P <0.05). Survival analysis of clinical samples showed that hsa-mir-1269a, hsa-mir-421 were associated with prognosis (p<0.05).This study revealed the general expression characteristics of specific differentially expressed miRNAs using a ceRNA network constructed from HCC samples. Hsa-mir-1269a, hsa-mir-421 may be promising candidates.
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Affiliation(s)
- Yuwei Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yixiu Wang
- Department of Hepatic Surgery, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weijie Xue
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hao Zou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Chengzhan Zhu, ; Jingyu Cao,
| | - Jingyu Cao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Chengzhan Zhu, ; Jingyu Cao,
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Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconj J 2022; 38:717-734. [PMID: 35064413 DOI: 10.1007/s10719-021-10031-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
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Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities. Cancers (Basel) 2021; 14:cancers14010048. [PMID: 35008212 PMCID: PMC8750350 DOI: 10.3390/cancers14010048] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 12/18/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The progression of liver tumors is highly influenced by the interactions between cancer cells and the surrounding environment, and, consequently, can determine whether the primary tumor regresses, metastasizes, or establishes micrometastases. In the context of liver cancer, cell death is a double-edged sword. On one hand, cell death promotes inflammation, fibrosis, and angiogenesis, which are tightly orchestrated by a variety of resident and infiltrating host cells. On the other hand, targeting cell death in advanced hepatocellular carcinoma could represent an attractive therapeutic approach for limiting tumor growth. Further studies are needed to investigate therapeutic strategies combining current chemotherapies with novel drugs targeting either cell death or the tumor microenvironment. Abstract Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution.
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Sionov RV. Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled. Cells 2021; 10:cells10092486. [PMID: 34572138 PMCID: PMC8465406 DOI: 10.3390/cells10092486] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/12/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
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Affiliation(s)
- Ronit Vogt Sionov
- Hadassah Medical School, The Hebrew University of Jerusalem, Ein Kerem Campus, P.O.B. 12272, Jerusalem 9112102, Israel
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19
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Zhang Z, Li JW, Zeng PH, Gao WH, Tian XF. Data Mining and Systems Pharmacology to Elucidate Effectiveness and Mechanisms of Chinese Medicine in Treating Primary Liver Cancer. Chin J Integr Med 2021; 28:636-643. [PMID: 34432201 DOI: 10.1007/s11655-021-3449-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To identify specific Chinese medicines (CM) that may benefit patients with primary liver cancer (PLC), and to explore the mechanism of action of these medicines. METHODS In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines. RESULTS Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis (P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling, steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6. CONCLUSIONS Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself.
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Affiliation(s)
- Zhen Zhang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine of Hunan University of Chinese Medicine, Changsha, 410208, China
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Jun-Wei Li
- Department of Pharmacy, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong Province, 518020, China
| | - Pu-Hua Zeng
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, 410006, China
| | - Wen-Hui Gao
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Xue-Fei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine of Hunan University of Chinese Medicine, Changsha, 410208, China.
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China.
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20
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García-Chávez JN, Vásquez-Garzón VR, López MG, Villa-Treviño S, Montiel R. Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma. PLoS One 2021; 16:e0256016. [PMID: 34383828 PMCID: PMC8360386 DOI: 10.1371/journal.pone.0256016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
Mitochondria participate in multiple functions in eukaryotic cells. Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. We also found that mitochondrial proteomic profiles from tissues adjacent to nodules or tumor are determined more by the stage of HCC development than by tissue type, and we evaluated two models to predict HCC stage of the samples using proteomic profiles. Finally, we propose an omics integration pipeline to massively identify molecular features that could be further evaluated as key regulators, biomarkers or therapeutic targets. As an example, we show a group of miRNAs and transcription factors as candidates, responsible for mitochondrial metabolic modification in HCC.
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Affiliation(s)
- J. Noé García-Chávez
- Langebio, Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
| | | | - Mercedes G. López
- Departamento de Biotecnología y Bioquímica, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
| | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies (CINVESTAV-IPN), Ciudad de México, Mexico
| | - Rafael Montiel
- Langebio, Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
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Dahiya M, Dureja H. Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms. J Chemother 2021; 34:286-301. [PMID: 34291704 DOI: 10.1080/1120009x.2021.1955202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most widespread typical therapy-resistant, unresectable type of malignant solid tumour with a high death rate constituting huge medical concern. Sorafenib is a small molecule oral multi-target kinase potent inhibitor that acts by suppressing/blocking the multiplication of the tumour cells, angiogenesis, and encouraging apoptosis of the tumour cells. Though, the precise mechanism of tumour cell death induction by sorafenib is yet under exploration. Furthermore, genetic heterogeneity plays a critical role in developing sorafenib resistance, which leads the way to identify the need for predictive biomarkers responsible for drug resistance. Therefore, it is essential to find out the fundamental resistance mechanisms to expand therapeutic plans. The authors summarize the molecular concepts of resistance, progression, potential molecular targets, HCC management therapies, and discussion on the advancements expected in the coming future, inclusive of biomarker-driven treatment strategies, which may provide the prospects to design innovative therapeutically targeted strategies for the HCC treatment and the clinical implementation of emerging targeted agents.
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Affiliation(s)
- Mandeep Dahiya
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
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22
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An Aptamer-Based Antagonist against the Receptor for Advanced Glycation End-Products (RAGE) Blocks Development of Colorectal Cancer. Mediators Inflamm 2021; 2021:9958051. [PMID: 34035661 PMCID: PMC8116144 DOI: 10.1155/2021/9958051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/23/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor angiogenesis plays a crucial role in colorectal cancer development. Dysregulation of the receptor for the advanced glycation end-products (RAGE) transmembrane signaling mediates inflammation, resulting in various cancers. However, the mechanism of the RAGE signaling pathway in modulating development of colorectal cancer has not been explored. In this study, an aptamer-based RAGE antagonist (Apt-RAGE) was used to inhibit interaction between RAGE and S100B, thus blocking downstream NFκB-mediated signal transduction. In vitro results showed that Apt-RAGE effectively inhibited S100B-dependent and S100B-independent RAGE/NFκB activation in colorectal HCT116 cancer cells, thus decreasing proliferation and migration of cells. Notably, expression and secretion of VEGF-A were inhibited, implying that Apt-RAGE can be used as an antiangiogenesis agent in tumor therapy. Moreover, Apt-RAGE inhibited tumor growth and microvasculature formation in colorectal tumor-bearing mice. Inhibition of angiogenesis by Apt-RAGE was positively correlated with suppression of the RAGE/NFκB/VEGF-A signaling. The findings of this study show that Apt-RAGE antagonist is a potential therapeutic agent for treatment of colorectal cancer.
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23
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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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24
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du Plessis M, Davis T, Loos B, Pretorius E, de Villiers WJS, Engelbrecht AM. Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A. Cytokine Growth Factor Rev 2021; 59:71-83. [PMID: 33727011 DOI: 10.1016/j.cytogfr.2021.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.
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Affiliation(s)
- M du Plessis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa.
| | - T Davis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - B Loos
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - E Pretorius
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - W J S de Villiers
- African Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
| | - A M Engelbrecht
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
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25
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Autophagy, an accomplice or antagonist of drug resistance in HCC? Cell Death Dis 2021; 12:266. [PMID: 33712559 PMCID: PMC7954824 DOI: 10.1038/s41419-021-03553-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal malignancy characterized by poor prognosis and a low 5-year survival rate. Drug treatment is proving to be effective in anti-HCC. However, only a small number of HCC patients exhibit sensitive responses, and drug resistance occurs frequently in advanced patients. Autophagy, an evolutionary process responsible for the degradation of cellular substances, is closely associated with the acquisition and maintenance of drug resistance for HCC. This review focuses on autophagic proteins and explores the intricate relationship between autophagy and cancer stem cells, tumor-derived exosomes, and noncoding RNA. Clinical trials involved in autophagy inhibition combined with anticancer drugs are also concerned.
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26
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Li J, Ren H, Wang J, Zhang P, Shi X. Extracellular HMGB1 promotes CD44 expression in hepatocellular carcinoma via regulating miR-21. Aging (Albany NY) 2021; 13:8380-8395. [PMID: 33661757 PMCID: PMC8034936 DOI: 10.18632/aging.202649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/12/2020] [Indexed: 04/11/2023]
Abstract
As a member of damage-associated molecular patterns (DAMPs), extracellular high-mobility group box 1 (HMGB1) plays a critical role in hepatocellular carcinoma (HCC) progression. Cluster differentiation 44 (CD44) has been demonstrated to participate in HCC progression. However, the relationship between extracellular HMGB1 and CD44 remains unclear. In this study, our results indicated that extracellular HMGB1 promoted the invasion, sphere formation and EMT process of HCC by increasing CD44 expression, which was dependent on miR-21. Moreover, miR-21 upregulated CD44 expression via activating OCT4/TGF-β1 signaling. Finally, we demonstrated the activation of Rage/JNK signaling caused by extracellular HMGB1 was responsible for miR-21 overexpression. Together, these findings reveal an important role of extracellular HMGB1 in HCC progression through upregulating miR-21/CD44.
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Affiliation(s)
- Jun Li
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Pengfei Zhang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
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27
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Zhu W, Li J, Zhang Y, Zhu Z, Liu H, Lin Y, Hu A, Zhou J, Ren H, Shi X. Inhibition of HMGB1 Suppresses Hepatocellular Carcinoma Progression via HIPK2-Mediated Autophagic Degradation of ZEB1. Front Oncol 2021; 11:599124. [PMID: 33747917 PMCID: PMC7969871 DOI: 10.3389/fonc.2021.599124] [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: 08/26/2020] [Accepted: 01/11/2021] [Indexed: 12/29/2022] Open
Abstract
Autophagy is a conserved catabolic process maintaining cellular homeostasis and reportedly plays a critical role in tumor progression. Accumulating data show that autophagic activity is inhibited in hepatocellular carcinoma. However, the underlying molecular basis of impaired autophagy in HCC remains unclear. In this study, we revealed that autophagic activity was suppressed by HMGB1 in a HIPK2-dependent way. Targeting HMGB1 could inhibit the degradation of HIPK2, as a result of which, autophagic degradation of ZEB1 was enhanced by reprogramming glucose metabolism/AMPK/mTOR axis. Moreover, we demonstrated that selectively degradation of ZEB1 was responsible for HCC growth inhibition in HMGB1 deficient cells. Lastly, we found the combination therapy of HMGB1 inhibitor and rapamycin achieved a better anti-HCC effect. These results demonstrate that impaired autophagy is controlled by HMGB1 and targeting HMGB1 could suppress HCC progression via HIPK2-mediated autophagic degradation of ZEB1.
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Affiliation(s)
- Wei Zhu
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuheng Zhang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhengyi Zhu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Hanyi Liu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yunzhen Lin
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Anyin Hu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jingchao Zhou
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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28
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Chu H, Wu C, Zhao Q, Sun R, Yang K, Zhao B, Liu Y, Liang Z, Zhong S, Zhang L, Zhang Y. Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells. Carcinogenesis 2021; 42:753-761. [PMID: 33677528 DOI: 10.1093/carcin/bgab019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/03/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy-related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.
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Affiliation(s)
- Hongwei Chu
- Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.,CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Changqing Wu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China.,Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Qun Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Rui Sun
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Kuo Yang
- BNRIST/Department of Automation, Tsinghua University, Beijing, China
| | - Baofeng Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Yang Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China.,Innovative Research Center for Integrated Cancer Omics, the Second Hospital Affiliated to China Medical University, Shenyang, China
| | - Zhen Liang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Shijun Zhong
- School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Lihua Zhang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Yukui Zhang
- Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.,CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
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29
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Petriv N, Neubert L, Vatashchuk M, Timrott K, Suo H, Hochnadel I, Huber R, Petzold C, Hrushchenko A, Yatsenko AS, Shcherbata HR, Wedemeyer H, Lichtinghagen R, Falfushynska H, Lushchak V, Manns MP, Bantel H, Semchyshyn H, Yevsa T. Increase of α-dicarbonyls in liver and receptor for advanced glycation end products on immune cells are linked to nonalcoholic fatty liver disease and liver cancer. Oncoimmunology 2021; 10:1874159. [PMID: 33628620 PMCID: PMC7889131 DOI: 10.1080/2162402x.2021.1874159] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a very poor prognosis and constantly growing incidence. Among other primary risks of HCC, metabolic disorders and obesity have been extensively investigated over recent decades. The latter can promote nonalcoholic fatty liver disease (NAFLD) leading to the inflammatory form of nonalcoholic steatohepatitis (NASH), that, in turn, promotes HCC. Molecular determinants of this pathogenic progression, however, remain largely undefined. In this study, we have focussed on the investigation of α-dicarbonyl compounds (α-dC), highly reactive and tightly associated with overweight-induced metabolic disorders, and studied their potential role in NAFLD and progression toward HCC using murine models. NAFLD was induced using high-fat diet (HFD). Autochthonous HCC was induced using transposon-based stable intrahepatic overexpression of oncogenic NRASG12V in mice lacking p19Arf tumor suppressor. Our study demonstrates that the HFD regimen and HCC resulted in strong upregulation of α-dC in the liver, heart, and muscles. In addition, an increase in α-dC was confirmed in sera of NAFLD and NASH patients. Furthermore, higher expression of the receptor for advanced glycation products (RAGE) was detected exclusively on immune cells and not on stroma cells in livers of mice with liver cancer progression. Our work confirms astable interplay of liver inflammation, carbonyl stress mediated by α-dC, and upregulated RAGE expression on CD8+ Tand natural killer (NK) cells in situ in NAFLD and HCC, as key factors/determinants in liver disease progression. The obtained findings underline the role of α-dC and RAGE+CD8+ Tand RAGE+ NK cells as biomarkers and candidates for a local therapeutic intervention in NAFLD and malignant liver disease.
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Affiliation(s)
- Nataliia Petriv
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Lavinia Neubert
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Myroslava Vatashchuk
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Kai Timrott
- Department of General-, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Inga Hochnadel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - René Huber
- Department of Clinical Chemistry, Hannover Medical School, Hannover, Germany
| | | | - Anastasiia Hrushchenko
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Andriy S Yatsenko
- Gene Expression and Signaling Group, Institute of Cell Biochemistry, Hannover Medical School, Germany
| | - Halyna R Shcherbata
- Gene Expression and Signaling Group, Institute of Cell Biochemistry, Hannover Medical School, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ralf Lichtinghagen
- Department of Clinical Chemistry, Hannover Medical School, Hannover, Germany
| | - Halina Falfushynska
- Department of Biochemistry, Ternopil Volodymyr Hnatiuk National Pedagogical University, Ternopil, Ukraine
| | - Volodymyr Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Halyna Semchyshyn
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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30
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RAGE Signaling in Melanoma Tumors. Int J Mol Sci 2020; 21:ijms21238989. [PMID: 33256110 PMCID: PMC7730603 DOI: 10.3390/ijms21238989] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/22/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022] Open
Abstract
Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.
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31
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The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression. Cell Death Dis 2020; 11:961. [PMID: 33168816 PMCID: PMC7652828 DOI: 10.1038/s41419-020-03158-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 12/16/2022]
Abstract
Accumulating data indicate caspase-1 (CASP1), one of the inflammatory caspases, promotes hepatocellular carcinoma (HCC) progression in tumor proliferation, invasion, EMT phenotype and sorafenib resistance. However, the molecular basis of regulating caspase-1 expression and caspase-1/IL1B (interleukin-1β) pathway in HCC remains unclear. Here, we demonstrated the novel interplay between caspase-1/IL1B activation and cluster differentiation 44 standard isoform (CD44s) in HCC. In this study, we observed that CD44s is responsible for caspase-1/IL1B activation both in HCC tissues and five HCC cell lines. In normoxia conditions, CD44s knockdown repressed the activation of caspase-1/IL1B via stimulating AMPK-mediated autophagy. Moreover, our data suggested that p62-induced autophagic degradation of caspase-1 accounted for caspase-1/IL1B inactivation in CD44s deficient cells. Administration of recombinant human IL1B could rescue impaired proliferation, invasion, and EMT phenotype in CD44s deficient HCC cells. Lastly, hypoxia-mediated caspase-1/IL1B overexpression could be abolished by CD44s downregulation through decreasing HIF1A and enhancing autophagic activity. Overall, targeting CD44s is a novel inhibitory mechanism of caspase-1/IL1B expression, both in normoxia and hypoxia conditions.
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32
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Waghela BN, Vaidya FU, Ranjan K, Chhipa AS, Tiwari BS, Pathak C. AGE-RAGE synergy influences programmed cell death signaling to promote cancer. Mol Cell Biochem 2020; 476:585-598. [PMID: 33025314 DOI: 10.1007/s11010-020-03928-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022]
Abstract
Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reaction between the free reducing sugars and proteins, lipids, or nucleic acids. AGEs are predominantly synthesized during chronic hyperglycemic conditions or aging. AGEs interact with their receptor RAGE and activate various sets of genes and proteins of the signal transduction pathway. Accumulation of AGEs and upregulated expression of RAGE is associated with various pathological conditions including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. The role of AGE-RAGE signaling has been demonstrated in the progression of various types of cancer and other pathological disorders. The expression of RAGE increases manifold during cancer progression. The activation of AGE-RAGE signaling also perturbs the cellular redox balance and modulates various cell death pathways. The programmed cell death signaling often altered during the progression of malignancies. The cellular reprogramming of AGE-RAGE signaling with cell death machinery during tumorigenesis is interesting to understand the complex signaling mechanism of cancer cells. The present review focus on multiple molecular paradigms relevant to cell death particularly Apoptosis, Autophagy, and Necroptosis that are considerably influenced by the AGE-RAGE signaling in the cancer cells. Furthermore, the review also attempts to shed light on the provenience of AGE-RAGE signaling on oxidative stress and consequences of cell survival mechanism of cancer cells.
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Affiliation(s)
- Bhargav N Waghela
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Foram U Vaidya
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Kishu Ranjan
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, 06519, USA
| | - Abu Sufiyan Chhipa
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Budhi Sagar Tiwari
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Chandramani Pathak
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India.
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33
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Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
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Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
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34
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Abstract
Receptor for advanced glycation end products (RAGE) is an immunoglobulin-like receptor present on cell surface. RAGE binds to an array of structurally diverse ligands, acts as a pattern recognition receptor (PRR) and is expressed on cells of different origin performing different functions. RAGE ligation leads to the initiation of a cascade of signaling events and is implicated in diseases, such as inflammation, cancer, diabetes, vascular dysfunctions, retinopathy, and neurodegenerative diseases. Because of the significant involvement of RAGE in the progression of numerous diseases, RAGE signaling has been targeted through use of inhibitors and anti-RAGE antibodies as a treatment strategy and therapy. Here in this review, we have summarized the physical and physiological aspects of RAGE biology in mammalian system and the importance of targeting this molecule in the treatment of various RAGE mediated pathologies. Highlights Receptor for advanced glycation end products (RAGE) is a member of immunoglobulin superfamily of receptors and involved in many pathophysiological conditions. RAGE ligation with its ligands leads to initiation of distinct signaling cascades and activation of numerous transcription factors. Targeting RAGE signaling through inhibitors and anti-RAGE antibodies can be promising treatment strategy.
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Affiliation(s)
- Nitish Jangde
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India.,Manipal Academy of Higher Education, Manipal, India
| | - Rashmi Ray
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India
| | - Vivek Rai
- Laboratory of Vascular Immunology, Institute of Life Sciences, Bhubaneswar, India
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Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis. Sci Rep 2020; 10:13582. [PMID: 32788720 PMCID: PMC7423894 DOI: 10.1038/s41598-020-70137-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 07/24/2020] [Indexed: 02/07/2023] Open
Abstract
In many human cancers, including hepatocellular carcinoma (HCC), high density of infiltrating tumor-associated macrophages (TAM) is associated with poor prognosis. Most TAMs express a M2 phenotype subsequently supporting tumor growth. How tumor cells polarize these TAMs to a pro-tumor M2 phenotype is still poorly understood. Our previous studies have revealed that a Toll-like receptor 2 (TLR2)-dependent autophagy triggered by hepatoma-derived factors down-regulates NF-κB p65 and drives M2 macrophage differentiation. However, the underlying mechanisms and potential hepatoma-derived TLR2 ligands are not clear. Here, we provide evidence to reveal that NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation is crucial for HCC-induced autophagy, NF-κB p65 down-regulation and M2 phenotype polarization in primary macrophages. This NOX2-generated ROS production in abolished in TLR2-deficient macrophages. HCC-derived or recombinant high-mobility group box 1 (HMGB1) is able to trigger this TLR2-mediated M2 macrophage polarization. Blockage of HMGB1 and ROS by inhibitors, ethyl pyruvate and N-acetylcysteine amide, respectively, significantly reduces both M2 macrophage accumulation and liver nodule formation in HCC-bearing mice. Our findings uncover a HMGB1/TLR2/NOX2/autophagy axis to trigger M2 macrophage polarization in HCC that can be considered as a novel therapeutic target for treating HCC.
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Bachmann M, Lamprecht L, Gonther S, Pfeilschifter J, Mühl H. A murine cellular model of necroinflammation displays RAGE-dependent cytokine induction that connects to hepatoma cell injury. J Cell Mol Med 2020; 24:10356-10366. [PMID: 32697038 PMCID: PMC7521286 DOI: 10.1111/jcmm.15649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/28/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.
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Affiliation(s)
- Malte Bachmann
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Laura Lamprecht
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Sina Gonther
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Josef Pfeilschifter
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Heiko Mühl
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
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Yuan J, Li Y, Liao J, Liu M, Zhu L, Liao K. MicroRNA-7 inhibits hepatocellular carcinoma cell invasion and metastasis by regulating Atg5-mediated autophagy. Transl Cancer Res 2020; 9:3965-3972. [PMID: 35117763 PMCID: PMC8797968 DOI: 10.21037/tcr-20-1930] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/04/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, with a low 5-year survival rate (5-9%). The abnormal expression of miRNA in liver cancer cells may play an important role in the pathophysiology of liver cancer. The ability of tumor invasion and metastasis is an important indicator to evaluate the degree of malignancy of HCC. Autophagy may affect the ability of tumor cells to invade and metastasize. Autophagy-related genes and proteins (Atg) are the core and key to regulating autophagy. The purpose of this study was to investigate the effect of microRNA-7 (miR-7) on targeting autophagy-related protein Atg5 to inhibit the effect of autophagy on the invasion and metastasis ability of liver cancer cells. METHODS The content of miR-7 and Atg5 in normal liver tissue and HCC tissues was detected by quantitative real-time polymerase chain (qRT-PCR). SMMC-7721 hepatoma cells were cultured in vitro, a starvation environment was simulated to activate autophagy, and transfection of cells was carried out by using miR-7 mimic, inhibitor, and autophagic inhibitor 3-MA. The RFP-GFP-LC3 double-labeled adenovirus infected hepatoma cells, and autophagy was detected by fluorescence microscopy. Western blot was used to detect the expression of LC3, Atg5, and the epithelial-mesenchymal transition (EMT)-related proteins (N-cadherin, vimentin, and snail). Transwell and plate cloning were used to detect the proliferation, invasion, and metastasis of hepatocarcinoma cells. RESULTS Expression of miR-7 (16.72±4.71, P<0.05) in HCC tissues was low, but the expression of Atg5 (13.70±2.80, P<0.05)was high. MiR-7 and Atg5 were highly negatively correlated in hepatoma tissues (r=-0.97). With the overexpression of hepatoma cells, the expression of Atg5 (0.49±0.07, F=395.26) and LC3II (0.51±0.06, F=23.58) was increased (P<0.05), and the autophagy was enhanced. As a result, the proliferation of hepatocarcinoma cells was decreased (t=3.22, P<0.05), the expression of EMT-related protein [N-cadherin (0.37±0.04), vimentin (0.60±0.07), snail (0.54±0.07)] was decreased (P<0.05), and hepatoma cell invasion and metastasis were decreased (n=6, F=162.28, P<0.05). CONCLUSIONS MiR-7 can inhibit the invasion and metastasis of hepatoma cells by targeting Atg5 to regulate autophagy.
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Affiliation(s)
- Jinling Yuan
- Department of Clinical Laboratory of the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Yingjia Li
- Department of Clinical Laboratory of the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Jinfeng Liao
- Department of Clinical Laboratory of the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Minji Liu
- Department of Gastroenterology, Zhuzhou Central Hospital of Hunan Province, Zhuzhou 412007, China
| | - Lili Zhu
- Department of Electrocardiogram of the Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Kai Liao
- Changsha Blood Center of Hunan Province, Changsha 410001, China
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Fan G, Wei X, Xu X. Is the era of sorafenib over? A review of the literature. Ther Adv Med Oncol 2020; 12:1758835920927602. [PMID: 32518599 PMCID: PMC7252361 DOI: 10.1177/1758835920927602] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 04/27/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most severe diseases worldwide. For the different stages of HCC, there are different clinical treatment strategies, such as surgical therapy for the early stage, and transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) for intermediate-stage disease. Systemic treatment, which uses mainly targeted drugs, is the standard therapy against advanced HCC. Sorafenib is an important first-line therapy for advanced HCC. As a classically effective drug, sorafenib can increase overall survival markedly. However, it still has room for improvement because of the heterogeneity of HCC and acquired resistance. Scientists have reported the acquired sorafenib resistance is associated with the anomalous expression of certain genes, most of which are also related with HCC onset and development. Combining sorafenib with inhibitors targeting these genes may be an effective treatment. Combined treatment may not only overcome drug resistance, but also inhibit the expression of carcinoma-related genes. This review focuses on the current status of sorafenib in advanced HCC, summarizes the inhibitors that can combine with sorafenib in the treatment against HCC, and provides the rationale for clinical trials of sorafenib in combination with other inhibitors in HCC. The era of sorafenib in the treatment of HCC is far from over, as long as we find better methods of medication.
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Affiliation(s)
- Guanghan Fan
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, 79 QingChun Road, Hangzhou, 310003, China
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Hua X, Zhang H, Jia J, Chen S, Sun Y, Zhu X. Roles of S100 family members in drug resistance in tumors: Status and prospects. Biomed Pharmacother 2020; 127:110156. [PMID: 32335300 DOI: 10.1016/j.biopha.2020.110156] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy and targeted therapy can significantly improve survival rates in cancer, but multiple drug resistance (MDR) limits the efficacy of these approaches. Understanding the molecular mechanisms underlying MDR is crucial for improving drug efficacy and clinical outcomes of patients with cancer. S100 proteins belong to a family of calcium-binding proteins and have various functions in tumor development. Increasing evidence demonstrates that the dysregulation of various S100 proteins contributes to the development of drug resistance in tumors, providing a basis for the development of predictive and prognostic biomarkers in cancer. Therefore, a combination of biological inhibitors or sensitizers of dysregulated S100 proteins could enhance therapeutic responses. In this review, we provide a detailed overview of the mechanisms by which S100 family members influence resistance of tumors to cancer treatment, with a focus on the development of effective strategies for overcoming MDR.
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Affiliation(s)
- Xin Hua
- Southeast University Medical College, Nanjing, 210009, China.
| | - Hongming Zhang
- Department of Respiratory Medicine, Yancheng Third People's Hospital, Southeast University Medical College, Yancheng, 224000, China.
| | - Jinfang Jia
- Southeast University Medical College, Nanjing, 210009, China.
| | - Shanshan Chen
- Southeast University Medical College, Nanjing, 210009, China.
| | - Yue Sun
- Southeast University Medical College, Nanjing, 210009, China.
| | - Xiaoli Zhu
- Southeast University Medical College, Nanjing, 210009, China; Department of Respiratory Medicine, Zhongda Hospital of Southeast University Medical College, Nanjing, 210009, China.
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40
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Tang F, Gao R, Jeevan-Raj B, Wyss CB, Kalathur RKR, Piscuoglio S, Ng CKY, Hindupur SK, Nuciforo S, Dazert E, Bock T, Song S, Buechel D, Morini MF, Hergovich A, Matthias P, Lim DS, Terracciano LM, Heim MH, Hall MN, Christofori G. LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nat Commun 2019; 10:5755. [PMID: 31848340 PMCID: PMC6917744 DOI: 10.1038/s41467-019-13591-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 11/14/2019] [Indexed: 12/27/2022] Open
Abstract
Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.
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Affiliation(s)
- Fengyuan Tang
- Department of Biomedicine, University of Basel, Basel, Switzerland.
| | - Ruize Gao
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Beena Jeevan-Raj
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Christof B Wyss
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | | | - Charlotte K Y Ng
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | | | - Sandro Nuciforo
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Eva Dazert
- Biozentrum, University of Basel, Basel, Switzerland
| | - Thomas Bock
- Biozentrum, University of Basel, Basel, Switzerland
| | - Shuang Song
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - David Buechel
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marco F Morini
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Patrick Matthias
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Dae-Sik Lim
- Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | | | - Markus H Heim
- Department of Biomedicine, University of Basel, Basel, Switzerland
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Wang N, Yang B, Muhetaer G, Wang S, Zheng Y, Lu J, Li M, Zhang F, Situ H, Lin Y, Wang Z. XIAOPI formula promotes breast cancer chemosensitivity via inhibiting CXCL1/HMGB1-mediated autophagy. Biomed Pharmacother 2019; 120:109519. [PMID: 31629951 DOI: 10.1016/j.biopha.2019.109519] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/28/2019] [Accepted: 10/01/2019] [Indexed: 02/06/2023] Open
Abstract
XIAOPI formula is a national approved drug prescribed to patients with high breast cancer risk. Previously we demonstrated that XIAOPI formula could inhibit breast cancer metastasis via suppressing CXCL1 expression, and postulated that "autophagy in cancer" might be one of its most core anti-cancer mechanisms. However, whether XIAOPI formula could be simultaneously applied with chemodrugs and their synergistic mechanisms are still remained unknown. In the present study, XIAOPI formula at non-cytotoxic doses could synergistically enhance the chemosensitivity of breast cancer cells MDA-MB-231 and MCF-7. We found that rapamycin-induced autophagy could reduce the chemosensitivity of breast cancer cells to XIAOPI formula, and the autophagy suppression and chemosensitizing activity of this formula was CXCL1-dependent. The evidence came from that XIAOPI formula was associated with a lower expression of CXCL1 combined with either rapamycin or taxol alone. Besides, the inhibitory effect of XIAOPI formula on the LC3-II and ABCG2 signals was weakened following CXCL1 over-expression, whereas P62 upregulation induced by XIAOPI formula was re-declined. A high throughput - qPCR (HT-qPCR) assay identified HMGB1 as the main autophagic target of XIAOPI formula in chemosensitizing breast cancer. and furhter validation suggested XIAOPI formula exerted chemosensitivity mainly via CXCL1/HMGB1 autophagic axis. Finally, we generated both mice and zebrafish xenotransplantation models bearing MDA-MB-231 breast cancer cells, and found that XIAOPI formula safely enhanced in vivo taxol chemosensitivity on breast cancer. Taken together, XIAOPI formula is a potential adjuvant drug via inhibiting CXCL1/HMGB1-mediated autophagy for breast cancer treatment with good safety.
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Affiliation(s)
- Neng Wang
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Bowen Yang
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Gulizeba Muhetaer
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Shengqi Wang
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yifeng Zheng
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jiahong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | - Fengxue Zhang
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Honglin Situ
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Yi Lin
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
| | - Zhiyu Wang
- Research Center of Integrative Medicine, School of basic medical sciences, Guangzhou University of Chinese Medicine; Integrative Research Laboratory of Breast Cancer, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510006, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong.
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Fu C, Liu P, Li P, Liu W, Huang X, Liang Y. FSP1 promotes the biofunctions of adventitial fibroblast through the crosstalk among RAGE, JAK2/STAT3 and Wnt3a/β-catenin signalling pathways. J Cell Mol Med 2019; 23:7246-7260. [PMID: 31454154 PMCID: PMC6815850 DOI: 10.1111/jcmm.14518] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 05/27/2019] [Accepted: 06/04/2019] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence indicates that fibroblast‐specific protein 1 (FSP1) provides vital effects in cell biofunctions. However, whether FSP1 influences the adventitial fibroblast (AF) and vascular remodelling remains unclear. Therefore, we investigated the potential role and action mechanism of FSP1‐mediated AF bioactivity. AFs were cultured and stimulated with FSP1 and siRNA‐FSP1 in vitro. Viability assays demonstrated that siRNA‐FSP1 counteracted AFs proliferative, migratory and adherent abilities enhanced with FSP1. Flow cytometry revealed that FSP1 increased AFs number in S phase and decreased cellular apoptosis. Contrarily, siRNA‐FSP1 displayed the contrary results. RT‐PCR, Western blotting and immunocytochemistry showed that FSP1 synchronously up‐regulated the expression of molecules in RAGE, JAK2/STAT3 and Wnt3a/β‐catenin pathways and induced a proinflammatory cytokine profile characterized by high levels of MCP‐1, ICAM‐1 and VCAM‐1. Conversely, FSP1 knockdown reduced the expression of these molecules and cytokines. The increased number of autophagosomes in FSP1‐stimulated group and fewer autophagic corpuscles in siRNA‐FSP1 group was observed by transmission electron microscope (TEM). Autophagy‐related proteins (LC3B, beclin‐1 and Apg7) were higher in FSP1 group than those in other groups. Conversely, the expression of p62 protein was shown an opposite trend of variation. Therefore, these pathways can promote AFs bioactivity, facilitate autophagy and induce the expression of the proinflammatory cytokines. Contrarily, siRNA‐FSP1 intercepts the crosstalk of these pathways, suppresses AF functions, restrains autophagy and attenuates the expression of the inflammatory factors. Our findings indicate that crosstalk among RAGE, STAT3/JAK2 and Wnt3a/β‐catenin signalling pathways may account for the mechanism of AF functions with the stimulation of FSP1.
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Affiliation(s)
- Caihua Fu
- Department of Cardiology, Jinan Central Hospital Affiliated Shandong University, Jinan, China
| | - Ping Liu
- Department of Cardiology, The Second Hospital of Shandong University, Jinan, China
| | - Peilun Li
- Department of Cardiology, Linyi People's Hospital, Linyi, China
| | - Wenhui Liu
- Department of Cardiology, The Second Hospital of Shandong University, Jinan, China
| | - Xianwei Huang
- Department of Emergency, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yansheng Liang
- Department of Cardiology, The Second Hospital of Shandong University, Jinan, China
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Lin PH, Chang CC, Wu KH, Shih CK, Chiang W, Chen HY, Shih YH, Wang KL, Hong YH, Shieh TM, Hsia SM. Dietary Glycotoxins, Advanced Glycation End Products, Inhibit Cell Proliferation and Progesterone Secretion in Ovarian Granulosa Cells and Mimic PCOS-like Symptoms. Biomolecules 2019; 9:biom9080327. [PMID: 31370285 PMCID: PMC6723748 DOI: 10.3390/biom9080327] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/24/2019] [Accepted: 07/29/2019] [Indexed: 12/17/2022] Open
Abstract
Women with polycystic ovary syndrome (PCOS) have been reported to have an elevated serum advanced glycation end product (AGE) level. However, the effect of AGEs on the pathophysiological ovarian granulosa cells of PCOS is still unclear. In this study, five indented BSA-derived AGE products were used to evaluate their effect on the function of human granulosa cells. We found that the proliferation of both primary human ovarian granulosa (hGC) cells and human granulosa-like tumor (KGN) cells were inhibited by treatment with these five AGE products. The progesterone secretion level was also reduced in both hGC and KGN cells by treatment with these AGE products through downregulation of LH receptor/cAMP regulatory activity. The granulosa cell layer and serum progesterone level were reduced in rats by treatment with MG-BSA; moreover, an increased number of follicle cysts and an irregular estrous cycle were observed. MG-BSA treatment had a similar effect on the phenotypes of the DHEA-induced PCOS model. Additionally, the insulin resistance and hepatic lesions seen in the DHEA-induced PCOS model were observed in the MG-BSA treatment group. Taken together, we found that AGEs exert a toxic effect on ovarian granulosa cells, ovarian morphology, and the estrous cycle that mimics the DHEA-induced PCOS phenotypes.
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Affiliation(s)
- Po-Han Lin
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Chao Chang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Kun-Hsuan Wu
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Chun-Kuang Shih
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Wenchang Chiang
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Hsin-Yuan Chen
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Yin-Hwa Shih
- Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan
| | - Kei-Lee Wang
- Department of Nursing, Ching Kuo Institute of Management and Health, Keelung 20301, Taiwan
| | - Yong-Han Hong
- Department of Nutrition, I-Shou University, Kaohsiung 84001, Taiwan
| | - Tzong-Ming Shieh
- School of Dentistry, College of Dentistry, China Medical University, Taichung 40402, Taiwan
| | - Shih-Min Hsia
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan.
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan.
- School of Food and Safety, Taipei Medical University, Taipei 11031, Taiwan.
- Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan.
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Functional variants of autophagy-related genes are associated with the development of hepatocellular carcinoma. Life Sci 2019; 235:116675. [PMID: 31340167 DOI: 10.1016/j.lfs.2019.116675] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/19/2019] [Accepted: 07/20/2019] [Indexed: 12/14/2022]
Abstract
AIMS Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and accounts for substantial morbidity and mortality. Autophagy plays an essential role in the development and progression of HCC. This study aims to evaluate whether genetic variants in autophagy-related genes (ATGs) affect the development of HCC. MATERIALS AND METHODS We conducted a case-control study with 986 HCC cases and 1000 healthy controls to analyze 14 functional variants of five ATGs (ATG3, ATG5, ATG10, ATG12 and ATG16L1) among a Chinese population. KEY FINDINGS We found ATG5 rs17067724 (G vs A: OR = 0.80; 95% CI = 0.65-0.98; P = 0.031), ATG10 rs1864183 (G vs A: OR = 1.29; 95% CI = 1.07-1.57; P = 0.009), ATG10 rs10514231 (C vs T: OR = 1.41; 95% CI = 1.15-1.73; P = 0.001), ATG12 rs26537 (C vs T: OR = 1.16; 95% CI = 1.02-1.33; P = 0.030), and ATG16L1 rs4663402 (T vs A: OR = 1.28; 95% CI = 1.01-1.63; P = 0.044) were significantly associated with HCC risk. Specifically, ATG10 rs10514231 kept significant association even adjusted for Bonferroni correction (P = 0.001 × 14 = 0.014). Bioinformatics analyses showed that allele C of ATG10 rs10514231 was significantly correlated with higher expression of ATG10 gene in both HCC tissues and normal liver tissues. Dual-luciferase reporter assay presented that cell lines transfected with vectors containing the risk allele C of rs10514231 showed higher relative luciferase activity compared to that containing the allele T. SIGNIFICANCE These results suggested that ATG10 rs10514231 might contribute to an allele-specific effect on the expression of host gene ATG10 and explain a fraction of HCC genetic susceptibility. Our study would benefit the construction of early warning model, early prevention, screening, even therapeutic target of HCC.
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Wei F, Zong S, Zhou J, Fan M, Wang Y, Cheng X, Liu H. [Tumor-associated macrophages attenuate apoptosis-inducing effect of sorafenib in hepatoma cells by increasing autophagy]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:264-270. [PMID: 31068299 DOI: 10.12122/j.issn.1673-4254.2019.03.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To explore the molecular mechanism of sorafenib resistance in hepatoma cells and identify for new targets to reverse drug resistance. METHODS THP-1 cells were induced into M2 tumor-associated macrophages (M2-TAMs) in vitro and identified by immunofluorescence. SMMC-7721 cells were co-cultured with M2-TAMs with or without sorafenib treatment. CCK-8 assay was used to observe the inhibitory effect of sorafenib on the cell proliferation. Annexin V/PI double staining and protein immunoblotting were used to assess the effect of sorafenib on the proliferation, apoptosis and the expressions of apoptosis-related proteins and autophagy-related protein in SMMC-7721 cells co-cultured with M2-TAMs in the presence or absence of the autophagy inhibitor chloroquine (CQ). RESULTS The IC50 of sorafenib at 48 h was 2.25 μmol/L in SMMC-7721 cells cultured alone, and increased to 4.72 μmol/L in the cells co-cultured with M2-TAMs. Compared with the cells cultured alone, the co-cultured SMMC-7721 cells showed significantly reduced apoptosis rate in response to sorafenib (P < 0.01) and significantly increased expression of Bcl-2 and Bcl-2/Bax ratio (P < 0.05) with also increased LC3-II/LC3-I ratio (P < 0.001) and lowered expression of p62 (P < 0.05), suggesting a significantly enhanced level of autophagy. CQ treatment significantly inhibited the proliferation of the co-cultured SMMC-7721 cells (P < 0.05), increased the cell apoptosis (P < 0.05) and reduced the Bcl-2/Bax ratio (P < 0.01). CONCLUSIONS M2-TAMs can attenuate the inhibitory effect of sorafenib on the proliferation of hepatoma cells by increasing the level of autophagy, suggesting a new strategy for reversing sorafenib resistance induced by the tumor microenvironment by inhibiting autophagy.
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Affiliation(s)
- Fang Wei
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Shiye Zong
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Jing Zhou
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Min Fan
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Ying Wang
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Xiu Cheng
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
| | - Hao Liu
- College of Pharmacy, Bengbu Medical College, Bengbu 233003, China
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46
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Takaki A, Kawano S, Uchida D, Takahara M, Hiraoka S, Okada H. Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis. Cancers (Basel) 2019; 11:cancers11020213. [PMID: 30781816 PMCID: PMC6406746 DOI: 10.3390/cancers11020213] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/03/2019] [Accepted: 02/11/2019] [Indexed: 01/17/2023] Open
Abstract
Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as “cancer-eliminating agents” or as products to improve one’s health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.
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Affiliation(s)
- Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Seiji Kawano
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Daisuke Uchida
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
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Mei X, Wang H, Zhang H, Liu C, Guo Z, Wang Y, Yuan Y, Zhao Z, Li D, Tang P. Blockade of receptor for advanced glycation end products promotes oligodendrocyte autophagy in spinal cord injury. Neurosci Lett 2019; 698:198-203. [PMID: 30660637 DOI: 10.1016/j.neulet.2019.01.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 01/14/2019] [Accepted: 01/16/2019] [Indexed: 12/19/2022]
Abstract
Receptor for advanced glycation end product (RAGE) is involved in neuronal inflammation, cell cycle and differentiation. However, the role of RAGE in autophagy in the process of spinal cord injury (SCI) is yet unknown. The present study investigated the effect of RAGE blockade on autophagy in SCI. A rat Allen SCI model was established and the animals were micro-injected with rabbit RAGE neutralizing antibody or rabbit polyclonal Ig G immediately after the injury. The oligodendrocytes(OLs) marker, 2', 3'-cyclic nucleotide 3'-phosphodiesterase(CNPase) and autophagy-related marker microtubule associated protein light chain 3B(LC3B) were evaluated by Western blot. Furthermore, myelin basic protein (MBP) and LC3B double staining were observed in the SCI via immunofluorescence. The results showed that RAGE blockade reduced the expression of CNPase, promoted LC3B-II/I and p62 expression after SCI. In addition, the MBP/LC3B double positive oligodendrocytes-expressing LC3B was up-regulated by RAGE blockade. Moreover, RAGE blockade attenuated the neuronal survival at ventral horn after SCI. The present study revealed the role of RAGE in maintaining oligodendrocyte autophagy to promote neuronal regeneration post-SCI.
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Affiliation(s)
- Xifan Mei
- Department of Orthopedic, Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Hongyu Wang
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Hua Zhang
- Jinzhou Medical University, Jinzhou City, 121000, PR China
| | - Chang Liu
- Department of Endocrinology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Zhanpeng Guo
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Yansong Wang
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Yajiang Yuan
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Ziming Zhao
- Department of Stomatology, Second Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Dingding Li
- Department of Orthopedic, the First People's Hospital of Longquanyi District, Chengdu City, PR China
| | - Peifu Tang
- Department of Orthopedic, Chinese PLA General Hospital, Beijing, 100853, PR China.
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Abstract
Autophagy is an important process of cellular degradation and has been proven to contribute to tumorigenesis. High-mobility group box 1 (HMGB1) is an abundant nonhistone protein that has been widely reported to play a central role in the induction of autophagy. In nucleus, HMGB1 upregulates the expression of HSP27 to induce autophagy. In cytoplasm, the Beclin-1/PI3K-III complex can be activated by HMGB1 to promote autophagy. Extracellular HMGB1 binds to the receptor for advanced glycation end products to induce autophagy. Recent studies have shown that HMGB1-induced autophagy exerts multiple functions in various cancers like proliferation. Moreover, inhibition of HMGB1-induced autophagy can reverse chemoresistance, which is regulated by noncoding RNAs such as microRNAs and lncRNAs. Here, we provide a brief introduction to HMGB1 and HMGB1-induced autophagy in cancer. We also discuss the challenges associated with performing further investigations on this issue. HMGB1-induced autophagy exerts significant functions in cancer and has potential utility for new strategy to reverse drug resistance.
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Affiliation(s)
- Tianwei Xu
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China,
| | - Lihua Jiang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China,
| | - Zhaoxia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China,
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Huang F, Wang BR, Wang YG. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol 2018; 24:4643-4651. [PMID: 30416312 PMCID: PMC6224467 DOI: 10.3748/wjg.v24.i41.4643] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/04/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a “self-degradative” process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.
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Affiliation(s)
- Fang Huang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Bing-Rong Wang
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
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Dai J, Huang Q, Niu K, Wang B, Li Y, Dai C, Chen Z, Tao K, Dai J. Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma. Cancer Med 2018; 7:5691-5703. [PMID: 30311444 PMCID: PMC6247041 DOI: 10.1002/cam4.1826] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 09/04/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.
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Affiliation(s)
- Jimin Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China.,The Cadet Team 6 (Regiment 6) of School of Basic Medicine, Air Force Medical University, Xi'an, China
| | - Qichao Huang
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Air Force Medical University, Xi'an, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Yijie Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Chen Dai
- Department of Orthopedics, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Zhinan Chen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Medical University, Xi'an, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Jingyao Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China.,Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Medical University, Xi'an, China
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