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Yang J, Chen R. Radiosensitization Strategies for Hepatocellular Carcinoma: Mechanisms, Therapeutic Advances, and Clinical Perspectives. Crit Rev Oncol Hematol 2025:104773. [PMID: 40412577 DOI: 10.1016/j.critrevonc.2025.104773] [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: 04/19/2025] [Revised: 05/17/2025] [Accepted: 05/19/2025] [Indexed: 05/27/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with treatment efficacy limited by late-stage diagnosis, frequent recurrence, and therapeutic resistance. Radiotherapy is a key local treatment for HCC; however, its efficacy is frequently limited by intrinsic tumor radioresistance. This review discusses strategies to improve the therapeutic response of HCC to radiotherapy. Targeting DNA repair mechanisms can block tumor cells from recovering after radiation-induced damage, whereas modulating cell cycle arrest and programmed cell death pathways (e.g., apoptosis, autophagy) diminishes their survival capacity. Furthermore, remodeling the tumor microenvironment-through hypoxia alleviation, metabolic reprogramming, oxidative stress regulation, and immune activation-may potentiate radiotherapy efficacy. Technological advances, such as stereotactic body radiotherapy and nanomaterial-based approaches, have also improved the precision and effectiveness of radiotherapy. Clinically, combining radiotherapy with systemic therapies (e.g., immune checkpoint inhibitors and antiangiogenic agents) has demonstrated preliminary promise in enhancing treatment outcomes. However, translating preclinical findings into clinical practice remains challenging due to tumor heterogeneity, normal tissue toxicity, and the lack of predictive biomarkers for treatment selection. Future research should focus on integrating molecular profiling with multimodal therapies to enable personalized radiosensitization and bridge the gap between mechanistic insights and clinical outcomes.
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Affiliation(s)
- Jiahui Yang
- Medical School of Southeast University, Nanjing, Jiangsu Province, China
| | - Rong Chen
- Department of Radiation Oncology, Affiliated ZhongDa Hospital, Southeast University, Nanjing, Jiangsu Province, China.
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Li L, Wang X, Jiang M, Li L, Wang D, Li Y. Advancements in a novel model of autophagy and immune network regulation in radioresistance of cancer stem cells. Biomed Pharmacother 2024; 179:117420. [PMID: 39255736 DOI: 10.1016/j.biopha.2024.117420] [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: 06/25/2024] [Revised: 09/01/2024] [Accepted: 09/04/2024] [Indexed: 09/12/2024] Open
Abstract
Radiotherapy, a precise modality for treating malignant tumors, has undergone rapid advancements in primary and clinical research. The mechanisms underlying tumor radioresistance have become significant research. With the introduction and in-depth study of cancer stem cells (CSCs) theory, CSCs have been identified as the primary factor contributing to the development of tumor radioresistance. The "stemness" of CSCs is a biological characteristic of a small subset of cells within tumor tissues, characterized by self-renewal solid ability. This characteristic leads to resistance to radiotherapy, chemotherapy, and targeted therapies, driving tumor recurrence and metastasis. Another study revealed that cellular autophagy plays a pivotal role in maintaining the "stemness" of CSCs. Autophagy is a cellular mechanism that degrades proteins and organelles to generate nutrients and energy in response to stress. This process maintains cellular homeostasis and contributes to CSCs radioresistance. Furthermore, ionizing radiation (IR) facilitates epithelial-to-mesenchymal transition (EMT), vascular regeneration, and other tumor processes by influencing the infiltration of M2-type tumor-associated macrophages (TAMs). IR promotes the activation of the classical immunosuppressive "switch," PD-1/PD-L1, which diminishes T-cell secretion, leading to immune evasion and promoting radioresistance. Interestingly, recent studies have found that the immune pathway PD-1/PD-L1 is closely related to cellular autophagy. However, the interrelationships between immunity, autophagy, and radioresistance of CSCs and the regulatory mechanisms involved remain unclear. Consequently, this paper reviews recent research to summarize these potential connections, aiming to establish a theoretical foundation for future studies and propose a new model for the network regulation of immunity, autophagy, and radioresistance of tumor cells.
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Affiliation(s)
- Leyao Li
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Xin Wang
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Mei Jiang
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Lei Li
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Di Wang
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Yajun Li
- Department of Oncology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China; Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China.
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Ding W, Bao S, Zhao Q, Hao W, Fang K, Xiao Y, Lin X, Zhao Z, Xu X, Cui X, Yang X, Yao L, Jin H, Zhang K, Guo J. Blocking ACSL6 Compromises Autophagy via FLI1-Mediated Downregulation of COLs to Radiosensitize Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403202. [PMID: 39206814 PMCID: PMC11516120 DOI: 10.1002/advs.202403202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/13/2024] [Indexed: 09/04/2024]
Abstract
Lung cancer (LC) is the leading cause of cancer-related mortality worldwide. Radiotherapy is the main component of LC treatment; however, its efficacy is often limited by radioresistance development, resulting in unsatisfactory clinical outcomes. Here, we found that LC radiosensitivity is up-regulated by decreased expression of long-chain acyl-CoA synthase 6 (ACSL6) after irradiation. Deletion of ACSL6 results in significant elevation of Friend leukemia integration 1 transcription factor (FLI1) and a marked decline of collagens (COLs). Blocking of ACSL6 impairs the tumor growth and upregulates FLI1, which reduces the levels of COLs and compromises irradiation-induced autophagy, leading to considerable therapeutic benefits during radiotherapy. Moreover, the direct interaction between ACSL6 and FLI1 and engagement between FLI1 and COLs indicates the involvement of the ACSL6-FLI1-COL axis. Finally, the potently adjusted autophagy flux reduces its otherwise contributive capability in surviving irradiation stress and leads to satisfactory radiosensitization for LC radiotherapy. These results demonstrate that enhanced ACSL6 expression promotes the aggressive performance of irradiated LC through increased FLI1-COL-mediated autophagy flux. Thus, the ACSL6-FLI1-Col-autophagy axis may be targeted to enhance the radiosensitivity of LC and improve the management of LC in radiotherapy.
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Affiliation(s)
- Wen Ding
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Shijun Bao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Qingwei Zhao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Wei Hao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Kai Fang
- Department of Medicine CollegeJiangnan UniversityWuxiJiangsu214000P. R. China
| | - Yanlan Xiao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Xiaoting Lin
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Zhemeng Zhao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Xinyi Xu
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
- College of Basic MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Xinyue Cui
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Xiwen Yang
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Liuhuan Yao
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
| | - Hai Jin
- Department of Cardiothoracic SurgeryChanghai HospitalNaval Medical UniversityShanghai200433P. R. China
| | - Kun Zhang
- Department of Laboratory Medicine and Central LaboratorySichuan Academy of Medical SciencesSichuan Provincial People's HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaNo. 32, West Second Section, First Ring RoadChengduSichuan610072P. R. China
| | - Jiaming Guo
- Department of Radiation MedicineCollege of Naval MedicineNaval Medical UniversityShanghai200433P. R. China
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Zhang L, Xu Y, Cheng Z, Zhao J, Wang M, Sun Y, Mi Z, Yuan Z, Wu Z. The EGR1/miR-139/NRF2 axis orchestrates radiosensitivity of non-small-cell lung cancer via ferroptosis. Cancer Lett 2024; 595:217000. [PMID: 38821254 DOI: 10.1016/j.canlet.2024.217000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/08/2024] [Accepted: 05/25/2024] [Indexed: 06/02/2024]
Abstract
Radiotherapy is one of the predominant treatment modalities for almost all kinds of malignant cancers, including non-small cell lung cancer (NSCLC). Increasing evidence shows that ionizing radiation (IR) induces reactive oxygen species (ROS) leading to lipid peroxidation and subsequently ferroptosis of cancer cells. However, cancer cells evolve multiple mechanisms against ROS biology resulting in resistance to ferroptosis and radiotherapy, of which NRF2 signaling is one of the most studied. In the current research, we identified that microRNA-139 (miR-139) could be a novel radiosensitizer for NSCLC by inhibiting NRF2 signaling. We found that miR-139 possessed great potential as a diagnostic biomarker for NSCLC and multiple other types of cancer. Overexpression of miR-139 increased radiosensitivity of NSCLC cells in vitro and in vivo. MiR-139 directly targeted cJUN and KPNA2 to impair NRF2 signaling resulting in enhanced IR-induced lipid peroxidation and cellular ferroptosis. We proved KPNA2 to be a binding partner of NRF2 that involved in nuclear translocation of NRF2. Moreover, we found that IR induced miR-139 expression through transcriptional factor EGR1. EGR1 bound to the promoter region and transactivated miR-139. Overall, our findings elucidated the effect of EGR1/miR-139/NRF2 in IR-induced ferroptosis of NSCLC cells and provided theoretical support for the potential diagnostic biomarkers and therapeutic targets for the disease.
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Affiliation(s)
- Lu Zhang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yihan Xu
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Zeyuan Cheng
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Jinlin Zhao
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China; Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, China
| | - Meixi Wang
- Department of Public Laboratory, Tianjin Medical University Cancer Institute & Hospital, 300060, Tianjin, China
| | - Yanchen Sun
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Zeyun Mi
- Department of Public Laboratory, Tianjin Medical University Cancer Institute & Hospital, 300060, Tianjin, China; Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, China.
| | - Zhiyong Yuan
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
| | - Zhiqiang Wu
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China; Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, China.
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7
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Zhou L, Shan Y, Li J, Li M, Meng Z, Guo N. Early growth response 1 regulates dual‑specificity protein phosphatase 1 and inhibits cell migration and invasion of tongue squamous cell carcinoma. Oncol Lett 2024; 27:240. [PMID: 38623570 PMCID: PMC11017821 DOI: 10.3892/ol.2024.14373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 04/20/2024] [Indexed: 04/17/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in the head and neck, and among the OSCCs, tongue squamous cell carcinoma (TSCC) is one of the most common types. Although therapy strategies have recently advanced, the prognosis of TSCC has not substantially improved. Metastasis is one of the main causes of patient mortality in TSCC; therefore, it is necessary to elucidate the mechanism by which TSCC metastasis is regulated. In the present study, the early growth response 1 (Egr-1) expression in TSCC was analyzed based on GEO datasets and the effect of Egr-1 in TSCC tumor cell migration and invasion was measured using Transwell assay. By overexpressing dual-specificity protein phosphatase 1 (DUSP1) in cells with Egr-1 knockdown using lentivirus infection, the role of DUSP1 in Egr-1-regulated TSCC cell migration and invasion was determined. By using luciferase and ChIP assays, the mechanism behind how DUSP1 is regulated by Egr-1 was detected. In the present study, it was demonstrated that Egr-1 was downregulated in TSCC and the knockdown of Egr-1 increased TSCC cell migration and invasion. The expression of Egr-1 was also correlated with DUSP1. The overexpression of DUSP1 in Egr-1 knockdown cells, reduced the level of cell migration and invasion. Furthermore, it was demonstrated that knockdown of Egr-1 inhibited the promoter activity of DUSP1 and the site through which Egr-1 regulates DUSP1 transcription was identified. In conclusion, the present study demonstrated that Egr-1 regulates TSCC cell migration and invasion through modulating DUSP1, suggesting the potential of Egr-1 and DUSP1 as therapy targets for TSCC.
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Affiliation(s)
- Longxun Zhou
- Department of Stomatology, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Yuqun Shan
- Clinical Laboratory, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Jun Li
- Precision Biomedical Laboratory, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Min Li
- Precision Biomedical Laboratory, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Zhen Meng
- Biomedical Laboratory, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
| | - Na Guo
- Department of Stomatology, Liaocheng People's Hospital, Medical School of Liaocheng University, Liaocheng, Shandong 252000, P.R. China
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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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Yang Y, Song T, Liu S, Liu Z, Wang X, Li Y, Liu D. Circle-map profiling of extrachromosomal circular DNA as diagnostic biomarkers for lung cancer. PRECISION CLINICAL MEDICINE 2024; 7:pbae006. [PMID: 38616889 PMCID: PMC11015151 DOI: 10.1093/pcmedi/pbae006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 03/11/2024] [Indexed: 04/16/2024] Open
Affiliation(s)
- Yongfeng Yang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tingting Song
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Sha Liu
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhiqiang Liu
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuehui Wang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Li
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dan Liu
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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10
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Pan M, Luo M, Liu L, Chen Y, Cheng Z, Wang K, Huang L, Tang N, Qiu J, Huang A, Xia J. EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL. J Exp Clin Cancer Res 2024; 43:35. [PMID: 38287371 PMCID: PMC10823730 DOI: 10.1186/s13046-024-02957-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 01/14/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. The aim of this study was to identify early growth response 1 (EGR1) as a transcription factor target in HCC and to explore its role and assess the potential of gene therapy utilizing EGR1 for the management of HCC. METHODS In this study, both in vitro and in vivo assays were employed to examine the impact of EGR1 on the growth of HCC. The mouse HCC model and human organoid assay were utilized to assess the potential of EGR1 as a gene therapy for HCC. Additionally, the molecular mechanism underlying the regulation of gene expression and the suppression of HCC growth by EGR1 was investigated. RESULTS The results of our investigation revealed a notable decrease in the expression of EGR1 in HCC. The decrease in EGR1 expression promoted the multiplication of HCC cells and the growth of xenografted tumors. On the other hand, the excessive expression of EGR1 hindered the proliferation of HCC cells and repressed the development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse HCC models and in vitro human hepatoma organoid models, thereby providing additional substantiation for the anti-cancer role of EGR1 in HCC. The mechanistic analysis demonstrated that EGR1 interacted with the promoter region of phosphofructokinase-1, liver type (PFKL), leading to the repression of PFKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the sensitivity of HCC cells and xenografted tumors to sorafenib was found to be increased by EGR1. CONCLUSION Our findings suggest that EGR1 possesses therapeutic potential as a tumor suppressor gene in HCC, and that EGR1 gene therapy may offer benefits for HCC patients.
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Affiliation(s)
- Mingang Pan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Muyu Luo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Lele Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Yunmeng Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Ziyi Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Luyi Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Jianguo Qiu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
| | - Jie Xia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
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Kang D, Hwang HJ, Baek Y, Sung JY, Kim K, Park HJ, Ko YG, Kim YN, Lee JS. TRIM22 induces cellular senescence by targeting PHLPP2 in hepatocellular carcinoma. Cell Death Dis 2024; 15:26. [PMID: 38199981 PMCID: PMC10781680 DOI: 10.1038/s41419-024-06427-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/20/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024]
Abstract
The ubiquitin-proteasome system is a vital protein degradation system that is involved in various cellular processes, such as cell cycle progression, apoptosis, and differentiation. Dysregulation of this system has been implicated in numerous diseases, including cancer, vascular disease, and neurodegenerative disorders. Induction of cellular senescence in hepatocellular carcinoma (HCC) is a potential anticancer strategy, but the precise role of the ubiquitin-proteasome system in cellular senescence remains unclear. In this study, we show that the E3 ubiquitin ligase, TRIM22, plays a critical role in the cellular senescence of HCC cells. TRIM22 expression is transcriptionally upregulated by p53 in HCC cells experiencing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, the SPRY domain of TRIM22 directly associates with the C-terminal domain of PHLPP2, which contains phosphorylation sites that are subject to IKKβ-mediated phosphorylation. The TRIM22-mediated PHLPP2 degradation leads to activation of AKT-p53-p21 signaling, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, the levels of TRIM22 and PHLPP2 show inverse correlations at the mRNA and protein levels. Collectively, our findings reveal that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, suggesting that TRIM22 could potentially serve as a therapeutic target for treating cancer.
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Affiliation(s)
- Donghee Kang
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, 22212, Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, 22212, Korea
| | - Hyun Jung Hwang
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, 22212, Korea
| | - Yurim Baek
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, 22212, Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, 22212, Korea
| | - Jee Young Sung
- Metastasis Branch, Division of Cancer Biology, National Cancer Center, Goyang, 10408, Korea
| | - KyeongJin Kim
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, 22212, Korea
| | - Heon Joo Park
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, 22212, Korea
- Department of Microbiology, College of Medicine, Inha University, Incheon, 22212, Korea
| | - Young-Gyu Ko
- Division of Life Sciences, Korea University, Seoul, 02841, Korea
| | - Yong-Nyun Kim
- Metastasis Branch, Division of Cancer Biology, National Cancer Center, Goyang, 10408, Korea
| | - Jae-Seon Lee
- Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, 22212, Korea.
- Program in Biomedical Science & Engineering, Inha University, Incheon, 22212, Korea.
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, 22212, Korea.
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12
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Zhuang X, Lin X, Xu R, Zhang Z, Zhou B, Deng F. ATG7-mediated autophagy protects human gingival myofibroblasts from irradiation-induced apoptosis. J Oral Pathol Med 2023; 52:996-1003. [PMID: 37876026 DOI: 10.1111/jop.13490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND Apoptosis resistance of myofibroblasts is critical in pathology of irradiation-induced fibrosis and osteoradionecrosis of the jaw (ORNJ). However, molecular mechanism of apoptosis resistance induced by irradiation in oral myofibroblasts remains largely obscure. METHODS Matched ORNJ fibroblasts and normal fibroblasts pairs from gingival were primarily cultured, and myofibroblast markers of α-SMA and FAP were evaluated by qRT-PCR and western blot. CCK8 assay and flow cytometric analysis were performed to investigate the cell viability and apoptosis under irradiation treatment. Autophagy-related protein LC3 and ATG7, and punctate distribution of LC3 localization were further detected. After inhibition of autophagy with inhibitor CQ and 3-MA, as well as transfected ATG7-siRNA, cell viability and apoptosis of ORNJ and normal fibroblasts were further assessed. RESULTS Compared with normal fibroblasts, ORNJ fibroblasts exhibited significantly higher α-SMA and FAP expression, increased cell, viability and decreased apoptosis under irradiation treatment. LC3-II and ATG7 were up-regulated in ORNJ fibroblasts with irradiation stimulation. After inhibition of irradiation-induced autophagic flux with lysosome inhibitor CQ, LC3-II protein was accumulated and punctate distribution of LC3 localization was increased in ORNJ fibroblasts. Moreover, autophagy inhibitor CQ and 3-MA enhanced the irradiation-induced apoptosis but inhibited viability of ORNJ fibroblasts. Silencing ATG7 with siRNA could obviously weaken irradiation-induced LC3-II expression, and promoted irradiation-induced apoptosis of ORNJ fibroblasts. After knockdown of ATG7, finally, p-AKT(Ser473) and p-mTOR(Ser2448) levels of ORNJ fibroblasts were significantly increased under irradiation. CONCLUSION Compared with normal fibroblasts, human gingival myofibroblasts are resistant to irradiation-induced apoptosis via autophagy activation. Silencing ATG7 may evidently inhibit activation of autophagy, and promote apoptosis of gingival myofibroblasts via Akt/mTOR pathway.
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Affiliation(s)
- Xiumei Zhuang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
- Department of Stomatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoxuan Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Ruogu Xu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Zhengchuan Zhang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Bin Zhou
- Department of Stomatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feilong Deng
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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Yang Y, Yang Y, Huang H, Song T, Mao S, Liu D, Zhang L, Li W. PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration. Cell Death Dis 2023; 14:257. [PMID: 37031207 PMCID: PMC10082821 DOI: 10.1038/s41419-023-05755-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 04/10/2023]
Abstract
Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in non-small cell lung cancer (NSCLC). In our research, three surgically matched NSCLC tissue samples, NSCLC cell lines (H1299, A549, and H460), and a normal lung cell line (MRC-5) were used as study objects. High-throughput eccDNA sequencing and bioinformatics analysis were performed to study the distribution pattern and level of eccDNA expression. The upregulated candidate eccDNA-encoding PLCG2 was validated by routine PCR. Plasmid transfection, RNA interference, qRT‒PCR and western blotting experiments were used to verify the expression level of PLCG2. Our results showed that the chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between the NSCLC and normal groups. Nevertheless, there were no significant differences in eccDNAs between NSCLC tissues and matched normal lung tissues. The eccDNA derived from PLCG2 was upregulated in NSCLC cells. TCGA analysis and immunohistochemistry showed that PLCG2 was highly expressed in lung cancer tissues and tended to be associated with poor outcome. We also demonstrated that PLCG2 can promote metastasis through the regulation of mitochondrial respiration. These results suggested that PLCG2 identified by eccDNA sequencing acts as an oncogene and might be a new biomarker for NSCLC diagnosis and prognosis evaluation.
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Affiliation(s)
- Yongfeng Yang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ying Yang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hong Huang
- Institute of Clinical Pathology, Key Laboratory of Transplantation Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tingting Song
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Shengqiang Mao
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Dan Liu
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Li Zhang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Precision Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 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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15
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Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, Salimimoghadam S, Aref AR, Kalbasi A, Rajabi R, Rashidi M, Taheriazam A, Sethi G. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges. Pharmacol Res 2023; 187:106553. [PMID: 36400343 DOI: 10.1016/j.phrs.2022.106553] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- 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
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - 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
| | - Alireza Abbaspour
- Cellular and Molecular Research Center,Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhossein Zabolian
- Resident of department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, 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
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Alireza Kalbasi
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 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.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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16
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Huang CY, Lai ZY, Hsu TJ, Chou FI, Liu HM, Chuang YJ. Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses. J Hepatocell Carcinoma 2022; 9:1385-1401. [PMID: 36600987 PMCID: PMC9807134 DOI: 10.2147/jhc.s383959] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/04/2022] [Indexed: 12/29/2022] Open
Abstract
Introduction For advanced hepatocellular carcinoma (HCC), resistance to conservative treatments remains a challenge. In previous studies, the therapeutic effectiveness and DNA damage responses of boric acid-mediated boron neutron capture therapy (BA-BNCT) in HCC have been demonstrated in animal models and HCC cell line. On the other hand, numerous studies have shown that high linear energy transfer (LET) radiation can overcome tumor resistance. Since BNCT yields a mixture of high and low LET radiation, we aimed to explore whether and how BA-BNCT could eliminate radioresistant HCC cells. Methods Radioresistant human HCC (HepG2-R) cells were established from HepG2 cells via intermittent irradiation. HepG2 and HepG2-R cells were then irradiated with either γ-ray or neutron radiation of BA-BNCT. Colony formation assays were used to assess cell survival and the relative biological effectiveness (RBE). The expression of phosphorylated H2AX (γH2AX) was also examined by immunocytochemistry and Western blot assays to evaluate the extent of DNA double-strand breaks (DSBs). Finally, the expression levels of DNA damage response-associated proteins were determined, followed by cell cycle analysis and caspase-3 activity analysis. Results Our data demonstrated that under the same dose by γ-ray, BNCT effectively eliminated radioresistant HCC by increasing the number of DNA DSBs (p < 0.05) and impeding their repair (p < 0.05), which verified the high RBE of BNCT. We also found that BNCT resulted in delayed homologous recombination (HR) and inhibited the nonhomologous end-joining (NHEJ) pathway during DNA repair. Markedly, BNCT increased cell arrest (p < 0.05) in the G2/M phase by altering G2 checkpoint signaling and increased PUMA-mediated apoptosis (p < 0.05). Conclusion Our data suggest that DNA damage and repair responses could affect the anticancer efficiency of BNCT in radioresistant HepG2-R cells, which highlights the potential of BNCT as a viable treatment option for recurrent HCC.
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Affiliation(s)
- Chu-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Zih-Yin Lai
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Tzu-Jung Hsu
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Fong-In Chou
- Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Hong-Ming Liu
- Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Yung-Jen Chuang
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan,Correspondence: Yung-Jen Chuang, School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, Tel +886-3-5742764, Fax +886-3-5715934, Email
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The Effect of Allograft Inflammatory Factor-1 on Inflammation, Oxidative Stress, and Autophagy via miR-34a/ATG4B Pathway in Diabetic Kidney Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1668000. [PMID: 36345369 PMCID: PMC9637042 DOI: 10.1155/2022/1668000] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/28/2022] [Accepted: 09/12/2022] [Indexed: 11/23/2022]
Abstract
Increasing evidence suggests that disorders of inflammation, oxidative stress, and autophagy contribute to the pathogenesis of diabetic kidney disease (DKD). This study attempted to clarify the effect of allograft inflammatory factor-1 (AIF-1), miR-34a, and ATG4B on inflammation, oxidative stress, and autophagy in DKD both in vitro and in vivo experiments. In vivo, it was found that the levels of AIF-1, miR-34a, oxidative stress, and inflammatory factors were significantly increased in blood and urine samples of DKD patients and mouse models and correlated with the level of urinary protein. In vitro, it was also found that the expressions of AIF-1, miR-34a, ROS, and inflammatory factors were increased, while ATG4B and other autophagy related proteins were decreased in human renal glomerular endothelial cells (HRGECs) cultured with high concentration glucose medium (30 mmol/L). When AIF-1 gene was overexpressed, the levels of miR-34a, ROS, and inflammatory factors were significantly upregulated, and autophagy-related proteins such as ATG4B were downregulated, while downregulation of AIF-1 gene had the opposite effect. In addition, miR-34a inhibited the expression of ATG4B and autophagy-related proteins and increased the levels of ROS and inflammation. Furthermore, the result of luciferase reporter assay suggested that ATG4B was the target gene of miR-34a. When ATG4B gene was overexpressed, the level of autophagy was upregulated, and inflammatory factors were downregulated. Conversely, when ATG4B gene was inhibited, the level of autophagy was downregulated, and inflammatory factors were upregulated. Then, autophagy inducers inhibited the levels of inflammation and ROS, whereas autophagy inhibitors had the opposite function in HRGECs induced by glucose (30 mmol/L). In conclusion, the above data suggested that AIF-1 regulated the levels of inflammation, oxidative stress, and autophagy in HRGECs via miR-34a/ATG4B pathway to contribute to the pathogenesis of diabetic kidney disease.
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18
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Lu Z, Zheng X, Ding C, Zou Z, Liang Y, Zhou Y, Li X. Deciphering the Biological Effects of Radiotherapy in Cancer Cells. Biomolecules 2022; 12:biom12091167. [PMID: 36139006 PMCID: PMC9496570 DOI: 10.3390/biom12091167] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy remains an effective conventional method of treatment for patients with cancer. However, the clinical efficacy of radiotherapy is compromised by the development of radioresistance of the tumor cells during the treatment. Consequently, there is need for a comprehensive understanding of the regulatory mechanisms of tumor cells in response to radiation to improve radiotherapy efficacy. The current study aims to highlight new developments that illustrate various forms of cancer cell death after exposure to radiation. A summary of the cellular pathways and important target proteins that are responsible for tumor radioresistance and metastasis is also provided. Further, the study outlines several mechanistic descriptions of the interaction between ionizing radiation and the host immune system. Therefore, the current review provides a reference for future research studies on the biological effects of new radiotherapy technologies, such as ultra-high-dose-rate (FLASH) radiotherapy, proton therapy, and heavy-ion therapy.
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Affiliation(s)
| | | | | | | | | | - Yan Zhou
- Correspondence: (Y.Z.); (X.L.); Tel.: +86-0816-225-2295 (Y.Z.); +86-0816-220-6272 (X.L.)
| | - Xiaoan Li
- Correspondence: (Y.Z.); (X.L.); Tel.: +86-0816-225-2295 (Y.Z.); +86-0816-220-6272 (X.L.)
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NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP. Int J Mol Sci 2022; 23:ijms23020711. [PMID: 35054896 PMCID: PMC8775719 DOI: 10.3390/ijms23020711] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 02/07/2023] Open
Abstract
A long noncoding RNA (lncRNA), nuclear enriched abundant transcript 1 (NEAT1) variant 1 (NEAT1v1), is involved in the maintenance of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). CSCs are suggested to play important roles in therapeutic resistance. Therefore, we investigated whether NEAT1v1 is involved in the sensitivity to radiation therapy in HCC. Gene knockdown was performed using short hairpin RNAs, and NEAT1v1-overexpressing HCC cell lines were generated by stable transfection with a NEAT1v1-expressing plasmid DNA. Cells were irradiated using an X-ray generator. We found that NEAT1 knockdown enhanced the radiosensitivity of HCC cell lines and concomitantly inhibited autophagy. NEAT1v1 overexpression enhanced autophagy in the irradiated cells and conferred radioresistance. Gamma-aminobutyric acid receptor-associated protein (GABARAP) expression was downregulated by NEAT1 knockdown, whereas it was upregulated in NEAT1v1-overexpressing cells. Moreover, GABARAP was required for NEAT1v1-induced autophagy and radioresistance as its knockdown significantly inhibited autophagy and sensitized the cells to radiation. Since GABARAP is a crucial protein for the autophagosome-lysosome fusion, our results suggest that NEAT1v1 confers radioresistance to HCC by promoting autophagy through GABARAP.
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Xiong YJ, Zhu Y, Liu YL, Zhao YF, Shen X, Zuo WQ, Lin F, Liang ZQ. P300 Participates in Ionizing Radiation-Mediated Activation of Cathepsin L by Mutant p53. J Pharmacol Exp Ther 2021; 378:276-286. [PMID: 34253647 DOI: 10.1124/jpet.121.000639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/28/2021] [Indexed: 11/22/2022] Open
Abstract
Our previous studies have shown that cathepsin L (CTSL) is involved in the ability of tumors to resist ionizing radiation (IR), but the specific mechanisms responsible for this remain unknown. We report here that mutant p53 (mut-p53) is involved in IR-induced transcription of CTSL. We found that irradiation caused activation of CTSL in mut-p53 cell lines, whereas there was almost no activation in p53 wild-type cell lines. Additionally, luciferase reporter gene assay results demonstrated that IR induced the p53 binding region on the CTSL promoter. We further demonstrated that the expression of p300 and early growth response factor-1 (Egr-1) was upregulated in mut-p53 cell lines after IR treatment. Accordingly, the expression of Ac-H3, Ac-H4, AcH3K9 was upregulated after IR treatment in mut-p53 cell lines, whereas histone deacetylase (HDAC) 4 and HDAC6 were reciprocally decreased. Moreover, knockdown of either Egr-1 or p300 abolished the binding of mut-p53 to the promoter of CTSL. Chromatin immunoprecipitation assay results showed that the IR-activated transcription of CTSL was dependent on p300. To further delineate the clinical relevance of interactions between Egr-1/p300, mut-p53, and CTSL, we accessed primary tumor samples to evaluate the relationships between mut-p53, CTSL, and Egr-1/p300 ex vivo. The results support the notion that mut-p53 is correlated with CTSL transcription involving the Egr-1/p300 pathway. Taken together, the results of our study revealed that p300 is an important target in the process of IR-induced transcription of CTSL, which confirms that CTSL participates in mut-p53 gain-of-function. SIGNIFICANCE STATEMENT: Transcriptional activation of cathepsin L by ionizing radiation required the involvement of mutated p53 and Egr-1/p300. Interference with Egr-1 or p300 could inhibit the expression of cathepsin L induced by ionizing radiation. The transcriptional activation of cathepsin L by p300 may be mediated by p53 binding sites on the cathepsin L promoter.
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Affiliation(s)
- Ya-Jie Xiong
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Ying Zhu
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Ya-Li Liu
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Yi-Fan Zhao
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Xiao Shen
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Wen-Qing Zuo
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Fang Lin
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
| | - Zhong-Qin Liang
- Department of Pharmacology, Soochow University, Suzhou, China (Y.X., Y.L., Y.Zha., X.S., Q.Z., F.L., Z.L.), and Department of Pharmacy, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China (Y.Zhu)
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Snail Upregulates Transcription of FN, LEF, COX2, and COL1A1 in Hepatocellular Carcinoma: A General Model Established for Snail to Transactivate Mesenchymal Genes. Cells 2021; 10:cells10092202. [PMID: 34571852 PMCID: PMC8467536 DOI: 10.3390/cells10092202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/14/2021] [Accepted: 08/22/2021] [Indexed: 12/21/2022] Open
Abstract
SNA is one of the essential EMT transcriptional factors capable of suppressing epithelial maker while upregulating mesenchymal markers. However, the mechanisms for SNA to transactivate mesenchymal markers was not well elucidated. Recently, we demonstrated that SNA collaborates with EGR1 and SP1 to directly upregulate MMP9 and ZEB1. Remarkably, a SNA-binding motif (TCACA) upstream of EGR/SP1 overlapping region on promoters was identified. Herein, we examined whether four other mesenchymal markers, lymphoid enhancer-binding factor (LEF), fibronectin (FN), cyclooxygenase 2 (COX2), and collagen type alpha I (COL1A1) are upregulated by SNA in a similar fashion. Expectedly, SNA is essential for expression of these mesenchymal genes. By deletion mapping and site directed mutagenesis coupled with dual luciferase promoter assay, SNA-binding motif and EGR1/SP1 overlapping region are required for TPA-induced transcription of LEF, FN, COX2 and COL1A1. Consistently, TPA induced binding of SNA and EGR1/SP1 on relevant promoter regions of these mesenchymal genes using ChIP and EMSA. Thus far, we found six of the mesenchymal genes are transcriptionally upregulated by SNA in the same fashion. Moreover, comprehensive screening revealed similar sequence architectures on promoter regions of other SNA-upregulated mesenchymal markers, suggesting that a general model for SNA-upregulated mesenchymal genes can be established.
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Ghaznavi H, Shirvaliloo M, Zarebkohan A, Shams Z, Radnia F, Bahmanpour Z, Sargazi S, Saravani R, Shirvalilou S, Shahraki O, Shahraki S, Nazarlou Z, Sheervalilou R. An Updated Review on Implications of Autophagy and Apoptosis in Tumorigenesis: Possible Alterations in Autophagy through Engineered Nanomaterials and Their Importance in Cancer Therapy. Mol Pharmacol 2021; 100:119-143. [PMID: 33990406 DOI: 10.1124/molpharm.121.000234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/19/2021] [Indexed: 12/17/2022] Open
Abstract
Most commonly recognized as a catabolic pathway, autophagy is a perplexing mechanism through which a living cell can free itself of excess cytoplasmic components, i.e., organelles, by means of certain membranous vesicles or lysosomes filled with degrading enzymes. Upon exposure to external insult or internal stimuli, the cell might opt to activate such a pathway, through which it can gain control over the maintenance of intracellular components and thus sustain homeostasis by intercepting the formation of unnecessary structures or eliminating the already present dysfunctional or inutile organelles. Despite such appropriateness, autophagy might also be considered a frailty for the cell, as it has been said to have a rather complicated role in tumorigenesis. A merit in the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. In fact, several investigations on tumorigenesis have reported diminished levels of autophagic activity in tumor cells, which might result in transition to malignancy. On the contrary, autophagy has been suggested to be a seemingly favorable mechanism to progressed malignancies, as it contributes to survival of such cells. Based on the recent literature, this mechanism might also be activated upon the entry of engineered nanomaterials inside a cell, supposedly protecting the host from foreign materials. Accordingly, there is a good chance that therapeutic interventions for modulating autophagy in malignant cells using nanoparticles may sensitize cancerous cells to certain treatment modalities, e.g., radiotherapy. In this review, we will discuss the signaling pathways involved in autophagy and the significance of the mechanism itself in apoptosis and tumorigenesis while shedding light on possible alterations in autophagy through engineered nanomaterials and their potential therapeutic applications in cancer. SIGNIFICANCE STATEMENT: Autophagy has been said to have a complicated role in tumorigenesis. In the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. On the contrary, autophagy has been suggested to be a favorable mechanism to progressed malignancies. This mechanism might be affected upon the entry of nanomaterials inside a cell. Accordingly, therapeutic interventions for modulating autophagy using nanoparticles may sensitize cancerous cells to certain therapies.
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Affiliation(s)
- Habib Ghaznavi
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Milad Shirvaliloo
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Amir Zarebkohan
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Zinat Shams
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Fatemeh Radnia
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Zahra Bahmanpour
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Saman Sargazi
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Ramin Saravani
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Sakine Shirvalilou
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Omolbanin Shahraki
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Sheida Shahraki
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Ziba Nazarlou
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
| | - Roghayeh Sheervalilou
- Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (H.G.), Infectious and Tropical Diseases Research Center, (M.S.), Department of Medical Nanotechnology, School of Advanced Medical Sciences,Tabriz University of Medical Sciences, Tabriz, Iran (A.Z.), Department of Biological Science, Kharazmi University, Tehran, Iran (Z.S.), Department of Medical Biotechnology, Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran (F.R.), Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran (Z.B.), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sar), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (R.S.), Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran (S.Sh), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (O.S), Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran (S.Sha), Material Engineering Department, College of Science Koç University, Istanbul 34450, Turkey (Z.N.), Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (R.Sh)
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Li J, Zhu X, Zhang M, Zhang Y, Ye S, Leng Y, Yang T, Kong L, Zhang H. Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism. J Hepatol 2021; 75:400-413. [PMID: 33746084 DOI: 10.1016/j.jhep.2021.02.035] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/28/2021] [Accepted: 02/18/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cholestatic liver diseases comprise a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury. Regulation of bile acid (BA) synthesis and homeostasis is a promising strategy for the treatment of cholestatic liver disease. Limb expression 1-like protein (LIX1L) plays an important role in post-transcriptional gene regulation, yet its role in cholestatic liver injury remains unclear. METHODS LIX1L expression was studied in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), and 3 murine models of cholestasis (bile duct ligation [BDL], Mdr2 knockout [Mdr2-/-], and cholic acid [CA] feeding). Lix1l knockout mice were employed to investigate the function of LIX1L in cholestatic liver diseases. Chromatin immunoprecipitation assays were performed to determine whether Egr-1 bound to the Lix1l promoter. MiRNA expression profiling was analyzed by microarray. An adeno-associated virus (AAV)-mediated hepatic delivery system was used to identify the function of miR-191-3p in vivo. RESULTS LIX1L expression was increased in the livers of patients with PSC and PBC, and in the 3 murine models, as well as in BA-stimulated primary mouse hepatocytes. BA-induced Lix1l upregulation was dependent on Egr-1, which served as a transcriptional activator. LIX1L deficiency attenuated cholestatic liver injury in BDL and Mdr2-/- mice. MiR-191-3p was the most reduced miRNA in livers of WT-BDL mice, while it was restored in Lix1l-/--BDL mice. MiR-191-3p targets and downregulates Lrh-1, thereby inhibiting Cyp7a1 and Cyp8b1 expression. AAV-mediated hepatic delivery of miR-191-3p significantly attenuated cholestatic liver injury in Mdr2-/- mice. CONCLUSIONS LIX1L deficiency alleviates cholestatic liver injury by inhibiting BA synthesis. LIX1L functions as a nexus linking BA/Egr-1 and miR-191-3p/LRH-1 signaling. LIX1L and miR-191-3p may be promising targets for the treatment of BA-associated hepatobiliary diseases. LAY SUMMARY Bile acid homeostasis can be impaired in cholestatic liver diseases. Our study identified a novel mechanism of positive feedback regulation in cholestasis. LIX1L and miR-191-3p represent potential therapeutic targets for cholestatic liver diseases.
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Affiliation(s)
- Jie Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoyun Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Meihui Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yanqiu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Shengtao Ye
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yingrong Leng
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ting Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep 2021; 48:3695-3717. [PMID: 33893928 DOI: 10.1007/s11033-021-06334-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 04/02/2021] [Indexed: 12/22/2022]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.
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Wang B, Min W, Lin S, Song L, Yang P, Ma Q, Guo J. Saikosaponin-d increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation. Int J Med Sci 2021; 18:1465-1473. [PMID: 33628104 PMCID: PMC7893567 DOI: 10.7150/ijms.53024] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Objective: The aim of this study was to analyze the effects of saikosaponin-d (SSd) on autophagy activity and radiosensitivity of hepatoma cells, and to elucidate its related molecular mechanisms. Methods: The growth of SMMC-7721 and MHCC97L hepatoma cells were detected by clonal formation and survival fraction. Flow cytometry was used to detect the changes of apoptosis of hepatoma cells. The morphological changes of autophagy of hepatoma cells were observed by transmission electron microscopy and were further quantitatively detected by laser confocal microscopy. The expressions of related proteins were detected by Western blotting. Results: SSd can significantly increase the apoptosis of hepatoma cells induced by radiation and inhibit the proliferation of hepatoma cells. The addition of the autophagy inhibitor chloroquine (CQ) or an mTOR agonist (MHY1485), which could reduce the promoting effect of SSd on radiation-induced apoptosis and inhibitory effect on the proliferation of hepatoma cells. Transmission electron microscopy and confocal microscopy results also showed that the number of autophagosomes was significantly higher in the radiation and SSd co-treatment group than in the radiotherapy or SSd alone group; however, the effect of SSd on autophagy in hepatoma cells was decreased after adding MHY1485, siRNA-P53 or AMPK inhibitor (Compound C). Western blot analysis showed that after the addition of SSd, the phosphorylation of mTOR was significantly decreased by radiation, the expression of the autophagy-related proteins LC3-II and Beclin-1 was increased, p62 was decreased, and the expression of cleaved caspase-3 and cleaved PARP was enhanced; this effect of SSd was partially reversed after the addition of MHY1485, siRNA-P53 or Compound C. Conclusions: SSd increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation and providing a possible potential approach for radiosensitization therapy of liver cancer.
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Affiliation(s)
- Baofeng Wang
- Department of Radiation Therapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Weili Min
- Department of Surgical Oncology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Shuai Lin
- Department of Surgical Oncology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Lingqin Song
- Department of Surgical Oncology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Pengtao Yang
- Department of Radiation Therapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jian Guo
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
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26
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Zhou B, Yang C, Yan X, Shi Z, Xiao H, Wei X, Jiang N, Wu Z. LETM1 Knockdown Promotes Autophagy and Apoptosis Through AMP-Activated Protein Kinase Phosphorylation-Mediated Beclin-1/Bcl-2 Complex Dissociation in Hepatocellular Carcinoma. Front Oncol 2021; 10:606790. [PMID: 33552978 PMCID: PMC7859436 DOI: 10.3389/fonc.2020.606790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/04/2020] [Indexed: 12/24/2022] Open
Abstract
Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an inner mitochondrial membrane protein that has been reported to be involved in many primary tumors and may regulate many biological processes. However, the biological role and molecular mechanism of LETM1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that LETM1 was highly expressed in HCC tissues and cell lines and that higher LETM1 expression was associated with a lower overall survival rate in HCC patients. In addition, knockdown of LETM1 inhibited proliferation and enhanced apoptosis and autophagy in the Huh 7 and QGY-7701 liver cancer cell lines. Mechanistically, knockdown of LETM1 dissociated the Beclin-1/Bcl-2 complex through phosphorylation of AMPK and Bcl-2. These results demonstrated that LETM1 is involved in the development of HCC and could be a novel therapeutic target in HCC.
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Affiliation(s)
- Baoyong Zhou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Changhong Yang
- Department of Bioinformatics, Chongqing Medical University, Chongqing, China
| | - Xiong Yan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengrong Shi
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Heng Xiao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xufu Wei
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Jiang
- Department of Pathology, Chongqing Medical University, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Xia F, Liu P, Li M. The regulatory factors and pathological roles of autophagy-related protein 4 in diverse diseases: Recent research advances. Med Res Rev 2020; 41:1644-1675. [PMID: 33314291 DOI: 10.1002/med.21772] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Macroautophagy (autophagy) is an evolutionarily conserved and dynamic degradation/recycling pathway in which portions of the cytoplasm, such as dysfunctional proteins and surplus organelles, are engulfed by double-membrane bound vesicles through a lysosome-dependent process. As the only proteolytic enzyme of the core mammalian autophagy proteins, autophagy-related protein 4 (ATG4) primes newly synthesized pro-light chain 3 (LC3) to form LC3-I that attaches to phosphatidylethanolamine and delipidates LC3-PE to LC3-I for recycling. Besides autophagy, ATG4 has been shown to be involved in regulating various biological and pathological processes. The roles of ATG4 in cancer therapy, a methodology for ATG4 activity detection, and the discovery of chemical modulators have been well-reviewed. However, a comprehensive summary on how ATG4 is regulated by multiple factors and, thereby, how ATG4 influences autophagy or other pathways remains lacking. In this paper, we summarize multiple processes and molecules that regulate the activity of ATG4, such as micro-RNAs, posttranslational modifications, and small molecules. Additionally, we focus on the relationship between ATG4 and diverse diseases, including cancer, neurodegeneration, microbial infection, and other diseases. It provides insight regarding potential ATG4-targeted therapeutic opportunities, which could be beneficial for future studies and human health.
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Affiliation(s)
- Fan Xia
- Department of Pharmacology and Toxicology, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Peiqing Liu
- Department of Pharmacology and Toxicology, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Min Li
- Department of Pharmacology and Toxicology, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
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He Z, Yuan J, Shen F, Zeng F, Qi P, Wang Z, Zhai Z. Atorvastatin Enhances Effects of Radiotherapy on Prostate Cancer Cells and Xenograft Tumor Mice Through Triggering Interaction Between Bcl-2 and MSH2. Med Sci Monit 2020; 26:e923560. [PMID: 32870824 PMCID: PMC7485286 DOI: 10.12659/msm.923560] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/08/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Prostate cancer (PCa) is considered to be the 4th most common cancer in males in the world. This study aimed to explore effects of atorvastatin on colony formation of PCa cells and radio-resistance of xenograft tumor models. MATERIAL AND METHODS PCa cell lines, including PC3, DU145, and Lncap, were treated with irradiation (4 Gy) and/or atorvastatin (6 μg/mL). Cells were divided into tumor cell group, irradiation treatment group (IR group) and irradiation+atorvastatin treatment group (IR-AS group). Xenograft tumor mouse model was established. Plate clone formation assay (multi-target/single-hit model) was conducted to evaluate colony formation. Flow cytometry analysis was employed to detect apoptosis. Interaction between Bcl-2 and MSH2 was evaluated with immuno-fluorescence assay. RESULTS According to the plate colony formation assay and multi-target/single-hit model, IR-treatment significantly suppressed colony formation in PCa cells (including PC3, DU145, and Lncap cells) compared to no-IR treated cells (P<0.05). Atorvastatin remarkably enhanced inhibitive effects of irradiation on colony formation of PCa cells (P<0.05), however, the IR+AS group demonstrated no effects on apoptosis, comparing to IR group (P>0.05). Atorvastatin administration (IR+AS group) significantly reduced tumor size of IR-treated PCa cells-induced xenograft tumor mice (P<0.05). Bcl-2 interacted with MSH2 both in tumor tissues of xenograft tumor mice. CONCLUSIONS Atorvastatin administration inhibited colony formation in PCa cells and enhanced effects of radiotherapy on tumor growth of xenograft tumor mice, which might be associated with interaction between Bcl-2 and MSH2 molecule.
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Affiliation(s)
- Zhenhua He
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Jingmin Yuan
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Fuhui Shen
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Fangang Zeng
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Ping Qi
- Clinical Laboratory, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Zhiping Wang
- Institute of Urology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Zhenxing Zhai
- Institute of Urology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
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Ramesh G, Das S, Bola Sadashiva SR. Berberine, a natural alkaloid sensitizes human hepatocarcinoma to ionizing radiation by blocking autophagy and cell cycle arrest resulting in senescence. J Pharm Pharmacol 2020; 72:1893-1908. [PMID: 32815562 DOI: 10.1111/jphp.13354] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To study the radiosensitizing potential of Berberine and the underlying mechanism in human hepatocarcinoma (HepG2) cells. METHODS HepG2 cells were challenged with X-rays in combination with Berberine treatment and several in vitro assays were performed. Alteration in cell viability was determined by MTT assay. Changes in intracellular ROS levels, mitochondrial membrane potential/mass, intracellular acidic vesicular organelles as well as cell cycle arrest and apoptotic cell death were analysed by flow cytometry. Induction of autophagy was assessed by staining the cells with Monodansylcadaverine/Lysotracker red dyes and immunoblotting for LC3I/II and p62 proteins. Phase-contrast/fluorescence microscopy was employed to study mitotic catastrophe and senescence. Cellular senescence was confirmed by immunoblotting for p21 levels and ELISA for Interleukin-6. KEY FINDINGS X-rays + Berberine had a synergistic effect in reducing cell proliferation accompanied by a robust G2/M arrest. Berberine-mediated radiosensitization was associated with elevated levels of LC3II and p62 suggesting blocked autophagy that was followed by mitotic catastrophe and senescence. Treatment of cells with X-rays + Berberine resulted in increased oxidative stress, hyperpolarized mitochondria with increased mitochondrial mass and reduced ATP levels. CONCLUSIONS The study expands the understanding of the pharmacological properties of Berberine and its applicability as a radiosensitizer towards treating liver cancer.
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Affiliation(s)
- Gautham Ramesh
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shubhankar Das
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Satish Rao Bola Sadashiva
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Lin M, Xiao Y, Jiang X, Zhang J, Guo T, Shi Y. A Combination Therapy of pHRE-Egr1-HSV-TK/Anti-CD133McAb- 131I/MFH Mediated by FePt Nanoparticles for Liver Cancer Stem Cells. JOURNAL OF NANOMATERIALS 2020; 2020:1-15. [DOI: 10.1155/2020/7180613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
It has been evidenced that liver cancer stem cells (LCSCs) are to blame hepatocellular carcinoma (HCC) occurrence, development, metastasis, and recurrence. Using iron-platinum nanoparticles (FePt-NPs) as a carrier and CD133 antigen as a target, a new strategy to targetly kill LCSCs by integrating HSV-TK suicide gene, 131I nuclide irradiation, and magnetic fluid hyperthermia (MFH) together was designed and investigated in the present study. The results showed that FePt-NPs modified with PEI (PEI-FePt-NPs) could bind with DNA, and the best binding ratio was 1 : 40 (mass ratio). Moreover, DNA binding to PEI-FePt-NPs could refrain from Dnase1 enzyme digestion and could release under certain conditions. LCSCs (CD133+ Huh-7 cells) were transfected with pHRE-Egr1-HSV-TK by PEI-FePt-NPs, and the transfection efficiency was 53.65±3.40%. These data showed a good potential of PEI-FePt-NPs as a gene transfer carrier.131I was labeled with anti-CD133McAb in order to facilitate therapy targeting. The combined intervention of pHRE-Egr1-HSV-TK/anti-CD133McAb-131I/MFH mediated by PEI-FePt-NPs could greatly inhibit LCSCs’ growth and induce cell apoptosis in vitro, significantly higher than any of the individual interventions (p<0.05). This study offers a practicable idea for LCSC treatment, and PEI-FePt-NPs may act as novel nonviral gene vectors and a magnetic induction medium.
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Affiliation(s)
- Mei Lin
- Clinical Laboratory, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
| | - Yanhong Xiao
- Imaging Department, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
| | - Xingmao Jiang
- Hubei Key Lab of Novel Reactor & Green Chemical Technology, Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China
| | - Jun Zhang
- Isotopic Laboratory, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
| | - Ting Guo
- Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
| | - Yujuan Shi
- Imaging Department, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
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Jing Z, Ye X, Ma X, Hu X, Yang W, Shi J, Chen G, Gong L. SNGH16 regulates cell autophagy to promote Sorafenib Resistance through suppressing miR-23b-3p via sponging EGR1 in hepatocellular carcinoma. Cancer Med 2020; 9:4324-4338. [PMID: 32324343 PMCID: PMC7300419 DOI: 10.1002/cam4.3020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 02/22/2020] [Accepted: 03/03/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Tumor cells could acquire drug resistance through cell autophagy. This study aimed to explore the role of SNHG16 in sorafenib-resistant HCC cells and its mechanism with miR-23b-3p. METHODS The sorafenib-resistant Hep3B cell model was established. The SNHG16 and miR-23b-3p gene expressions were determined in normal HCC and sorafenib-resistant HCC tissues. Detection of the expression of SNHG16 and miR-23b-3p and its respective correlation with survival rate were performed. Target genes to SNHG16 and miR-23b-3p were predicted, and verified by dual-fluorescent reporter assay. The effects of SNHG16 and miR-23b-3p on SNHG16, miR-23b-3p, EGR1 expression, viability, apoptosis as well as LC3II/LC3 expression in Hep3B and Hep3B/So cells were detected by qRT-PCR, CCK-8, flow cytometry, and western blot. In in vivo studies, the NOD/SCID mice model was established to explore the effects of Hep3B and Hep3B/So cells with inhibited SNHG16 or miR-23b-3p on tumor size, EGR1 expression, and autophagy. RESULTS High SNHG16 expression in HCC-resistant tissues and low miR-23b-3p expression in all HCC tissues were detected, and the two were negatively correlated. Low SNHG16 and high miR-23b-3p were related to a high survival rate of HCC patients. Moreover, SNHG16 overexpression promoted Hep3B/So cell viability and autophagy, suppressed apoptosis by inhibiting miR-23b-3p expression through up-regulating EGR1, however, the effect of si-SNHG16 was opposite. In in vivo studies, miR-23b-3p inhibitor suppressed the high sorafenib sensitivity in Hep3B/So cells caused by SNHG16 silencing through promoting viability, autophagy, and suppressing apoptosis. CONCLUSION SNHG16 promotes Hep3B/So cell viability, autophagy, and inhibits apoptosis to maintain its resistance to sorafenib through regulating the expression of miR-23b-3p via sponging EGR1.
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Affiliation(s)
- Zhao Jing
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China
| | - Xiaoping Ye
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Xiaojie Ma
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Xiangrong Hu
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Junping Shi
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Gongying Chen
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Ling Gong
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
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The pROS of Autophagy in Neuronal Health. J Mol Biol 2020; 432:2546-2559. [PMID: 32006535 PMCID: PMC7232022 DOI: 10.1016/j.jmb.2020.01.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/19/2019] [Accepted: 01/10/2020] [Indexed: 12/15/2022]
Abstract
Autophagy refers to a set of catabolic pathways that together facilitate degradation of superfluous, damaged and toxic cellular components. The most studied type of autophagy, called macroautophagy, involves membrane mobilisation, cargo engulfment and trafficking of the newly formed autophagic vesicle to the recycling organelle, the lysosome. Macroautophagy responds to a variety of intra- and extra-cellular stress conditions including, but not limited to, pathogen intrusion, oxygen or nutrient starvation, proteotoxic and organelle stress, and elevation of reactive oxygen species (ROS). ROS are highly reactive oxygen molecules that can interact with cellular macromolecules (proteins, lipids, nucleic acids) to either modify their activity or, when released in excess, inflict irreversible damage. Although increased ROS release has long been recognised for its involvement in macroautophagy activation, the underlying mechanisms and the wider impact of ROS-mediated macroautophagy stimulation remain incompletely understood. We therefore discuss the growing body of evidence that describes the variety of mechanisms modulated by ROS that trigger cytoprotective detoxification via macroautophagy. We outline the role of ROS in signalling upstream of autophagy initiation, by increased gene expression and post-translational modifications of transcription factors, and in the formation and nucleation of autophagic vesicles by cysteine modification of conserved autophagy proteins including ATG4B, ATG7 and ATG3. Furthermore, we review the effect of ROS on selective forms of macroautophagy, specifically on cargo recognition by autophagy receptor proteins p62 and NBR1 (neighbour of BRCA1) and the recycling of mitochondria (mitophagy), and peroxisomes (pexophagy). Finally, we highlight both, the standalone and mutual contributions of abnormal ROS signalling and macroautophagy to the development and progression of neurodegenerative diseases.
ROS are messengers that modify protein activity by PTMs. ROS-mediated PTMs regulate activity and specificity of autophagy proteins. Increase in autophagy mediates rapid clearance of oxidised cargo and ROS sources. The importance of ROS-mediated autophagy is highlighted in neurodegeneration.
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Qi Y, Yao X, Du X. Midazolam inhibits proliferation and accelerates apoptosis of hepatocellular carcinoma cells by elevating microRNA-124-3p and suppressing PIM-1. IUBMB Life 2019; 72:452-464. [PMID: 31651086 DOI: 10.1002/iub.2171] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 09/05/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Recently, the impact of microRNAs (miRNAs) has been identified in hepatocellular carcinoma (HCC), this study was designed to assess the effects of miR-124-3p and midazolam (MDZ) in HCC with the involvement of PIM-1. METHODS HepG2 human HCC cells were selected for our study, which were treated with different concentrations of MDZ. The gain- and loss-of-function experiments were performed to elucidate the migration, invasion, proliferation, colony formation ability, cell cycle, and apoptosis of HepG2 cells upon treatment of MDZ, miR-124-3p mimics, or miR-124-3p inhibitor. The expression levels of miR-124-3p, PIM-1, Bax, Bcl-2, P21, and Ki-67 in HepG2 cells were assessed by reverse transcription quantitative polymerase chain reaction and western blot analysis. Moreover, HepG2 cell growth in vivo was measured by subcutaneous tumorigenesis in nude mice, and the target relation between miR-124-3p and PIM-1 was evaluated using dual luciferase reporter gene assay. RESULTS We have found that after treated with overexpression of miR-124-3p and MDZ, there exhibited elevated miR-124-3p, declined expression of PIM-1, attenuated migration, invasion, proliferation and colony formation ability, and promoted apoptosis of HepG2 cells. Additionally, it could be observed that the tumor volume and weight were all reduced upon treatment of overexpression of miR-124-3p and MDZ. Meanwhile, the results in the HepG2 cells that treated with down-regulated miR-124-3p were the opposite. Furthermore, PIM-1 was found to be a target gene of miR-124-3p. CONCLUSION Our study found that MDZ could inhibit proliferation and accelerate apoptosis of HCC cells by elevation of miR-124-3p and suppressing PIM-1, which may be an effective method in the treatment of HCC.
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Affiliation(s)
- Yanyan Qi
- Anesthesiology Department, Henan Province People's hospital, Zhengzhou, Henan, People's Republic of China
| | - Xiangyan Yao
- Anesthesiology Department, Henan Province People's hospital, Zhengzhou, Henan, People's Republic of China
| | - Xianhui Du
- Anesthesiology Department, Henan Province People's hospital, Zhengzhou, Henan, People's Republic of China
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Sosthenes MCK, Diniz DG, Roodselaar J, Abadie-Guedes R, de Siqueira Mendes FDCC, Fernandes TN, Bittencourt JC, Diniz CWP, Anthony DC, Guedes RCA. Stereological Analysis of Early Gene Expression Using Egr-1 Immunolabeling After Spreading Depression in the Rat Somatosensory Cortex. Front Neurosci 2019; 13:1020. [PMID: 31607855 PMCID: PMC6774394 DOI: 10.3389/fnins.2019.01020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 09/09/2019] [Indexed: 12/20/2022] Open
Abstract
Early growth response-1 (Egr-1), defined as a zinc finger transcription factor, is an upstream master switch of the inflammatory response, and its expression can be used to investigate the spatial and temporal extent of inflammatory changes in the brain. Cortical spreading depression (CSD) is characterized as a slowly propagating (2-5 mm/min) depolarization wave through neurons and astrocytes in humans that contributes to migraines and possibly to other brain pathologies. In rodents, CSD can be induced experimentally, which involves unilateral depolarization that is associated with microglial and astrocyte responses. The impact of CSD on structures beyond the affected hemisphere has not been explored. Here, we used an optical fractionator method to investigate potential correlations between the number of and period of the eletrophysiologic record of CSD phenomena and Egr-1 expression in ipsilateral and contralateral hemispheres. CSD was elicited by the restricted application of a 2% KCl solution over the left premotor cortex. Electrophysiological events were recorded using a pair of Ag/AgCl agar-Ringer electrodes for 2 or 6 h. An optical fractionator was applied to count the Egr-1 positive cells. We found that CSD increased Egr-1 expression in a time- and event-dependent manner in the ipsilateral/left hemisphere. Although CSD did not cross the midline, multiple CSD inductions were associated with an increased number of Egr-1 positive cells in the contralateral/right hemisphere. Thus, repeated CSD waves may have far reaching effects that are more global than previously considered possible. The mechanism of contralateral expression is unknown, but we speculate that callosal projections from the depolarized hemisphere may be related to this phenomenon.
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Affiliation(s)
- Marcia Consentino Kronka Sosthenes
- Laboratório de Investigações em Neurodegeneração e Infecção, Instituto de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil.,Laboratory of Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, United Kingdom.,Laboratório de Neuroanatomia Química, Departamento de Anatomia, Universidade de São Paulo, São Paulo, Brazil
| | - Daniel Guerreiro Diniz
- Laboratório de Investigações em Neurodegeneração e Infecção, Instituto de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Jay Roodselaar
- Laboratory of Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Ricardo Abadie-Guedes
- Laboratório de Fisiologia da Nutrição Naíde Teodósio, Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brazil
| | - Fabíola de Carvalho Chaves de Siqueira Mendes
- Laboratório de Investigações em Neurodegeneração e Infecção, Instituto de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil.,Curso de Medicina, Centro Universitário do Estado do Pará, Belém, Brazil
| | - Taiany Nogueira Fernandes
- Laboratório de Investigações em Neurodegeneração e Infecção, Instituto de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Jackson Cioni Bittencourt
- Laboratório de Neuroanatomia Química, Departamento de Anatomia, Universidade de São Paulo, São Paulo, Brazil.,Núcleo de Neurociências e Comportamento, Instituto de Psicologia, Universidade de São Paulo, São Paulo, Brazil
| | - Cristovam Wanderley Picanço Diniz
- Laboratório de Investigações em Neurodegeneração e Infecção, Instituto de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Daniel Clive Anthony
- Laboratory of Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Rubem Carlos Araújo Guedes
- Laboratório de Fisiologia da Nutrição Naíde Teodósio, Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brazil
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Song W, Zhang J, Xia Q, Sun M. Down-regulated lncRNA TP73-AS1 reduces radioresistance in hepatocellular carcinoma via the PTEN/Akt signaling pathway. Cell Cycle 2019; 18:3177-3188. [PMID: 31564201 DOI: 10.1080/15384101.2019.1671089] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: Recently, the role of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) has been assessed. Our research was determined to investigate the impacts of lncRNA TP73-AS1 on radioresistance of HCC by modulating PTEN/Akt signaling pathway. Methods: Expression of TP73-AS1 in HCC tissues and cells was detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The HCC cells were conducted with different doses of irradiation, then the survival, colony formation and apoptosis were determined by a series of assays. The HCC cell line with a higher expression of TP73-AS1 was transfected with TP73-AS1-siRNA and X-rayed, the expression of TP73-AS1, cell survival, radiosensitivity, and apoptosis were evaluated. Subcutaneous tumorigenesis in nude mice was adopted to record the size of tumors before and after the radiation. RT-qPCR and Western blot analysis were used to clarify the activation of PTEN/Akt signaling pathway. Results: TP73-AS1 was highly expressed in HCC tissues and cells. With the increasing dose of radiation, the relative proliferation activity and survival fraction (SF) of HCC cells was gradually reduced, while the total apoptosis rate was gradually elevated. TP73-AS1 knockdown promoted radiosensitivity and apoptosis, repressed cell proliferation, making it an inhibitor of tumor in HCC. Moreover, reduced TP73-AS1 was able to decline the phosphorylation of Akt and increase the expression of PTEN in HCC. Down-regulated TP73-AS1 could repress tumorigenesis by promoting radiosensitivity in nude mice with HCC. Conclusion: Our study suggests that lncRNA TP73-AS1 was highly expressed in HCC and participated in radioresistance of HCC via PTEN/Akt signaling pathway. Abbreviations: lncRNAs: long non-coding RNAs; lncRNAs: HCC: hepatocellular carcinoma; RT-qPCR: reverse transcription quantitative polymerase chain reaction; survival fraction: SF; lncRNA TP73-AS1: LncRNA P73 antisense RNA 1T; PTEN: Phosphatase and tensin homologue; Akt: Protein kinase B; P13K: phosphatidylinositol 3-kinase; TNM: tumor, node and metastasis; ACJJ: American Joint Committee on Cancer; FBS: fetal bovine serum; EDTA: ethylene diamine tetraacetic acid; NC: negative control; DMEM: Dulbecco's modified Eagle medium; OD: optical density; PE: Plating efficiency; FITC/PI: fluoresceine isothiocyanate/propidium iodide; PBS: phosphate buffered solution; GAPDH: Glyceraldehyde phosphate dehydrogenase; ANOVA: one-way analysis of variance; LSD-t: least significant difference test.
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Affiliation(s)
- Wei Song
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , Henan , PR China
| | - Jingjing Zhang
- Department of Cardiovascularology, The Zhengzhou Central Hospital Affiliated to Zhengzhou University , Zhengzhou , Henan , PR China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , Henan , PR China
| | - Miaomiao Sun
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , Henan , PR China
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36
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Targeting ATG4 in Cancer Therapy. Cancers (Basel) 2019; 11:cancers11050649. [PMID: 31083460 PMCID: PMC6562779 DOI: 10.3390/cancers11050649] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 12/30/2022] Open
Abstract
Autophagy is a lysosome-mediated degradation pathway that enables the degradation and recycling of cytoplasmic components to sustain metabolic homoeostasis. Recently, autophagy has been reported to have an astonishing number of connections to cancer, as tumor cells require proficient autophagy in response to metabolic and therapeutic stresses to sustain cell proliferation. Autophagy-related gene 4 (ATG4) is essential for autophagy by affecting autophagosome formation through processing full-length microtubule-associated protein 1A/1B-light chain 3 (pro-LC3) and lipidated LC3. An increasing amount of evidence suggests that ATG4B expression is elevated in certain types of cancer, implying that ATG4B is a potential anticancer target. In this review, we address the central roles of ATG4B in the autophagy machinery and in targeted cancer therapy. Specifically, we discuss how pharmacologically inhibiting ATG4B can benefit cancer therapies.
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Abstract
Resistance to therapy is one of the prime causes for treatment failure in cancer and recurrent disease. In recent years, autophagy has emerged as an important cell survival mechanism in response to different stress conditions that are associated with cancer treatment and aging. Autophagy is an evolutionary conserved catabolic process through which damaged cellular contents are degraded after uptake into autophagosomes that subsequently fuse with lysosomes for cargo degradation, thereby alleviating stress. In addition, autophagy serves to maintain cellular homeostasis by enriching nutrient pools. Although autophagy can act as a double-edged sword at the interface of cell survival and cell death, increasing evidence suggest that in the context of cancer therapy-induced stress responses, it predominantly functions as a cell survival mechanism. Here, we provide an up-to-date overview on our current knowledge of the role of pro-survival autophagy in cancer therapy at the preclinical and clinical stages and delineate the molecular mechanisms of autophagy regulation in response to therapy-related stress conditions. A better understanding of the interplay of cancer therapy and autophagy may allow to unveil new targets and avenues for an improved treatment of therapy-resistant tumors in the foreseeable future.
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38
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McGee HM, Carpenter TJ, Ozbek U, Kirkwood KA, Tseng TC, Blacksburg S, Germano IM, Green S, Buckstein M. Analysis of Local Control and Pain Control After Spine Stereotactic Radiosurgery Reveals Inferior Outcomes for Hepatocellular Carcinoma Compared With Other Radioresistant Histologies. Pract Radiat Oncol 2019; 9:89-97. [DOI: 10.1016/j.prro.2018.11.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/18/2018] [Accepted: 11/29/2018] [Indexed: 01/10/2023]
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Wang W, Xiong Y, Ding X, Wang L, Zhao Y, Fei Y, Zhu Y, Shen X, Tan C, Liang Z. Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:61. [PMID: 30732622 PMCID: PMC6367810 DOI: 10.1186/s13046-019-1054-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/23/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Ionizing radiation (IR) is one of the major clinical therapies of cancer, although it increases the epithelial-mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC), unexpectedly. The cellular and molecular mechanisms underlying this role are not completely understood. METHODS We used NSCLC cell lines as well as tumor specimens from 78 patients with NSCLC to evaluate p53, Cathepsin L (CTSL) and EMT phenotypic changes. Xenograft models was also utilized to examine the roles of mutant p53 (mut-p53) and CTSL in regulating IR-induced EMT of NSCLC. RESULTS Expression of CTSL was markedly increased in human NSCLC tissues with mutant p53 (mut-p53), and p53 mutation positively correlated with metastasis of NSCLC patients. In human non-small cell lung cancer cell line, H1299 cells transfected with various p53 lentivirus vectors, mut-p53 could promote the invasion and motility of cells under IR, mainly through the EMT. This EMT process was induced by elevating intranuclear CTSL which was regulated by mut-p53 depending on Early growth response protein-1 (Egr-1) activation. In the subcutaneous tumor xenograft model, IR promoted the EMT of the cancer cells in the presence of mut-p53, owing to increase expression and nuclear transition of its downstream protein CTSL. CONCLUSION Taken together, these data reveal the role of the mut-p53/Egr-1/CTSL axis in regulating the signaling pathway responsible for IR-induced EMT.
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Affiliation(s)
- Wenjuan Wang
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China.,Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Yajie Xiong
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Xinyuan Ding
- Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China.,Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215000, China
| | - Long Wang
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Yifan Zhao
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Yao Fei
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Ying Zhu
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Xiao Shen
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China
| | - Caihong Tan
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China. .,Department of Pharmacy, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, China.
| | - Zhongqin Liang
- Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China.
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Zhang R, Lin XH, Liu HH, Ma M, Chen J, Chen J, Gao DM, Cui JF, Chen RX. Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation. Int J Hyperthermia 2019; 36:253-263. [PMID: 30701994 DOI: 10.1080/02656736.2018.1558459] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Rui Zhang
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Xia-Hui Lin
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Hua-Hua Liu
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Min Ma
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jie Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jun Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Dong-Mei Gao
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Jie-Feng Cui
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
| | - Rong-Xin Chen
- Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute, Shanghai, China
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41
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EGR-mediated control of STIM expression and function. Cell Calcium 2018; 77:58-67. [PMID: 30553973 DOI: 10.1016/j.ceca.2018.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/03/2018] [Accepted: 12/04/2018] [Indexed: 12/22/2022]
Abstract
Ca2+ is a ubiquitous, dynamic and pluripotent second messenger with highly context-dependent roles in complex cellular processes such as differentiation, proliferation, and cell death. These Ca2+ signals are generated by Ca2+-permeable channels located on the plasma membrane (PM) and endoplasmic reticulum (ER) and shaped by PM- and ER-localized pumps and transporters. Differences in the expression of these Ca2+ homeostasis proteins contribute to cell and context-dependent differences in the spatiotemporal organization of Ca2+ signals and, ultimately, cell fate. This review focuses on the Early Growth Response (EGR) family of zinc finger transcription factors and their role in the transcriptional regulation of Stromal Interaction Molecule (STIM1), a critical regulator of Ca2+ entry in both excitable and non-excitable cells.
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42
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Ma L, Yu Y, Qu X. Suppressing serum response factor inhibits invasion in cervical cancer cell lines via regulating Egr‑1 and epithelial-mesenchymal transition. Int J Mol Med 2018; 43:614-620. [PMID: 30365040 DOI: 10.3892/ijmm.2018.3954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 09/27/2018] [Indexed: 11/06/2022] Open
Abstract
Serum response factor (SRF) is a transcription factor that has important roles in tumor progression. However, its role in cervical cancer cell proliferation and invasion remains unclear. The present study revealed that SRF silencing constrained cervical cancer cell proliferation and invasion via controlling early growth response‑1 (Egr‑1). The results demonstrated that SRF was significantly increased in cervical cancer tissues and cell lines, compared with normal. Suppressing SRF, by using a loss‑of‑function experiment, constrained cervical cancer cell proliferation, invasion, and epithelial‑mesenchymal transition. Furthermore, SRF knockdown significantly downregulated Egr‑1 expression in cervical cancer cell lines, and overexpression of Egr‑1 reversed the effect of SRF on cell proliferation, invasion, and epithelial‑mesenchymal transition. Therefore, SRF may control cell proliferation and invasion by regulating Egr‑1 in cervical cancer.
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Affiliation(s)
- Liya Ma
- Clinical Skills Training Center, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China
| | - Ying Yu
- Perinatal Care Division, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, P.R. China
| | - Xiaohui Qu
- Obstetrics and Gynecology, Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712000, P.R. China
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Liang ZG, Lin GX, Yu BB, Su F, Li L, Qu S, Zhu XD. The role of autophagy in the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R. Cancer Manag Res 2018; 10:4125-4134. [PMID: 30323668 PMCID: PMC6174314 DOI: 10.2147/cmar.s176536] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Purpose The present study aimed to study the role of autophagy in the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R. Methods Before being irradiated, CNE-2R cells were treated with the autophagy inhibitor chloroquine diphosphate (CDP) or the autophagy inducer rapamycin (RAPA). Microtubule-associated protein light chain 3 (LC3-II) and p62 were assessed using Western blotting analysis 48 hours after CNE-2R cells were irradiated. The percentage of apoptotic cells was assessed via flow cytometry. CNE-2R cell viability was evaluated using the Cell Counting Kit-8 (CCK8). The radiosensitivity of cells was assessed via clone formation analysis. Results The level of autophagy in CNE-2R cells improved as the radiation dose increased, reaching the maximum at a dose of 10 Gy. Autophagy was most significantly inhibited by 60 µmol/L CDP in CNE-2R cells, but was obviously enhanced by 100 nmol/L RAPA. Compared with the irradiation (IR) alone group, in the IR + CDP group, autophagy was significantly inhibited, viability was low, the rate of radiation-induced apoptosis was increased, and radiosensitivity was upregulated. In contrast, cells of the IR + RAPA group exhibited greater autophagy, higher viability, a lower rate of radiation-induced apoptosis, and downregulated radiosensitivity. Conclusion The autophagy level is negatively correlated with radiosensitivity for the radio-resistant human nasopharyngeal carcinoma cell line CNE-2R.
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Affiliation(s)
- Zhong-Guo Liang
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Guo-Xiang Lin
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Bin-Bin Yu
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Fang Su
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Ling Li
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Song Qu
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
| | - Xiao-Dong Zhu
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Guangxi Medical University, Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China,
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Peeters JGC, Picavet LW, Coenen SGJM, Mauthe M, Vervoort SJ, Mocholi E, de Heus C, Klumperman J, Vastert SJ, Reggiori F, Coffer PJ, Mokry M, van Loosdregt J. Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy. Autophagy 2018; 15:98-112. [PMID: 30153076 PMCID: PMC6287694 DOI: 10.1080/15548627.2018.1509608] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.
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Affiliation(s)
- J G C Peeters
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,b Laboratory of Translational Immunology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - L W Picavet
- b Laboratory of Translational Immunology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - S G J M Coenen
- b Laboratory of Translational Immunology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - M Mauthe
- d Department of Cell Biology , University Medical Center Groningen, University of Groningen , Groningen , The Netherlands
| | - S J Vervoort
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - E Mocholi
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - C de Heus
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,f Department of Cell Biology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - J Klumperman
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,f Department of Cell Biology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - S J Vastert
- b Laboratory of Translational Immunology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - F Reggiori
- d Department of Cell Biology , University Medical Center Groningen, University of Groningen , Groningen , The Netherlands
| | - P J Coffer
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - M Mokry
- c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,g Epigenomics facility , University Medical Center Utrecht , Utrecht , The Netherlands
| | - J van Loosdregt
- a Center for Molecular Medicine , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,b Laboratory of Translational Immunology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,c Division of Pediatrics , Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.,e Regenerative Medicine Center , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
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Hu WQ, Wang W, Fang DL, Yin XF. Identification of Biological Targets of Therapeutic Intervention for Hepatocellular Carcinoma by Integrated Bioinformatical Analysis. Med Sci Monit 2018; 24:3450-3461. [PMID: 29795057 PMCID: PMC5996840 DOI: 10.12659/msm.909290] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/02/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND We screened the potential molecular targets and investigated the molecular mechanisms of hepatocellular carcinoma (HCC). MATERIAL AND METHODS Microarray data of GSE47786, including the 40 μM berberine-treated HepG2 human hepatoma cell line and 0.08% DMSO-treated as control cells samples, was downloaded from the GEO database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed; the protein-protein interaction (PPI) networks were constructed using STRING database and Cytoscape; the genetic alteration, neighboring genes networks, and survival analysis of hub genes were explored by cBio portal; and the expression of mRNA level of hub genes was obtained from the Oncomine databases. RESULTS A total of 56 upregulated and 8 downregulated DEGs were identified. The GO analysis results were significantly enriched in cell-cycle arrest, regulation of transcription, DNA-dependent, protein amino acid phosphorylation, cell cycle, and apoptosis. The KEGG pathway analysis showed that DEGs were enriched in MAPK signaling pathway, ErbB signaling pathway, and p53 signaling pathway. JUN, EGR1, MYC, and CDKN1A were identified as hub genes in PPI networks. The genetic alteration of hub genes was mainly concentrated in amplification. TP53, NDRG1, and MAPK15 were found in neighboring genes networks. Altered genes had worse overall survival and disease-free survival than unaltered genes. The expressions of EGR1, MYC, and CDKN1A were significantly increased, but expression of JUN was not, in the Roessler Liver datasets. CONCLUSIONS We found that JUN, EGR1, MYC, and CDKN1A might be used as diagnostic and therapeutic molecular biomarkers and broaden our understanding of the molecular mechanisms of HCC.
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Inhibition of ATG12-mediated autophagy by miR-214 enhances radiosensitivity in colorectal cancer. Oncogenesis 2018; 7:16. [PMID: 29459645 PMCID: PMC5833763 DOI: 10.1038/s41389-018-0028-8] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 01/04/2018] [Indexed: 12/17/2022] Open
Abstract
Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase patients' response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.
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Wu Y, Li D, Wang Y, Liu X, Zhang Y, Qu W, Chen K, Francisco NM, Feng L, Huang X, Wu M. Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS. Front Immunol 2018; 9:211. [PMID: 29487594 PMCID: PMC5816924 DOI: 10.3389/fimmu.2018.00211] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 01/24/2018] [Indexed: 01/08/2023] Open
Abstract
Beta-defensins 2 and 3 (BD2 and BD3) are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA). Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1) and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS.
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Affiliation(s)
- Yongjian Wu
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Dandan Li
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Yi Wang
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Xi Liu
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuanqing Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Wenting Qu
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Kang Chen
- Division of Clinical Laboratory, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, China
| | - Ngiambudulu M Francisco
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Lianqiang Feng
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Xi Huang
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Minhao Wu
- Program of Pathobiology and Immunology, Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Diseases Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
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Ni Z, Wang X, Zhang T, Li L, Li J. Comprehensive analysis of differential expression profiles reveals potential biomarkers associated with the cell cycle and regulated by p53 in human small cell lung cancer. Exp Ther Med 2018; 15:3273-3282. [PMID: 29545845 PMCID: PMC5841087 DOI: 10.3892/etm.2018.5833] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 01/23/2018] [Indexed: 12/13/2022] Open
Abstract
Small cell lung cancer (SCLC) is the subtype of lung cancer with the highest degree of malignancy and the lowest degree of differentiation. The purpose of this study was to investigate the molecular mechanisms of SCLC using bioinformatics analysis, and to provide new ideas for the early diagnosis and targeted therapy of SCLC. Microarray data were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) in SCLC were compared with the normal lung samples and identified. Gene Ontology (GO) function and pathway analysis of DEGs was performed through the DAVID database. Furthermore, microarray data was analyzed by using the clustering analysis tool GoMiner. Protein-protein interaction (PPI) networks of DEGs were constructed using the STRING online database. Protein expression was determined from the Human Protein Atlas, and SCLC gene expression was determined using Oncomine. In total, 153 DEGs were obtained. Functional enrichment analysis suggested that the majority of DEGs were associated with the cell cycle. CCNB1, CCNB2, MAD2L1 and CDK1 were identified to contribute to the progression of SCLC through combined use of GO, Kyoto Encyclopedia of Genes and Genomes enrichment analysis and a PPI network. mRNA and protein expression were also validated in an integrative database. The present study indicated that the formation of SCLC may be associated with cell cycle regulation. In addition, the four crucial genes CCNB1, CCNB2, MAD2L1 and CDK1, which are downstream of p53, may have important roles in the occurrence and progression of SCLC, and thus may be promising potential biomarkers and therapeutic targets.
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Affiliation(s)
- Zhong Ni
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xiting Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Tianchen Zhang
- Institute of Reproduction and Development, Fudan University, Shanghai 200032, P.R. China.,China National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Shanghai Institute of Planned Parenthood Research (SIPPR), Shanghai 200032, P.R. China
| | - Linlin Li
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jianxue Li
- Department of Stomatology, Lanzhou General Hospital, Lanzhou, Gansu 730050, P.R. China
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Ni Z, He J, Wu Y, Hu C, Dai X, Yan X, Li B, Li X, Xiong H, Li Y, Li S, Xu L, Li Y, Lian J, He F. AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells. Autophagy 2018; 14:685-701. [PMID: 29165041 DOI: 10.1080/15548627.2017.1407887] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Phosphorylation is a major type of post-translational modification, which can influence the cellular physiological function. ATG4B, a key macroautophagy/autophagy-related protein, has a potential effect on the survival of tumor cells. However, the role of ATG4B phosphorylation in cancers is still unknown. In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells. The phosphorylation of ATG4B at Ser34 had little effect on autophagic flux, but promoted the Warburg effect including the increase of L-lactate production and glucose consumption, and the decrease of oxygen consumption in HCC cells. The Ser34 phosphorylation of ATG4B also contributed to the impairment of mitochondrial activity including the inhibition of F1Fo-ATP synthase activity and the elevation of mitochondrial ROS in HCC cells. Moreover, the phosphorylation of ATG4B at Ser34 enhanced its mitochondrial location and the subsequent colocalization with F1Fo-ATP synthase in HCC cells. Furthermore, recombinant human ATG4B protein suppressed the activity of F1Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues in vitro. In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. Our findings reveal a noncanonical working pattern of ATG4B under pathological conditions, which may provide a scientific basis for developing novel strategies for HCC treatment by targeting ATG4B and its Ser34 phosphorylation.
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Affiliation(s)
- Zhenhong Ni
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Jintao He
- b Battalion 17 of Students , College of Preventive Medicine, Third Military Medical University , Chongqing, China
| | - Yaran Wu
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Changjiang Hu
- c Department of Gastroenterology , Xinqiao Hospital, Third Military Medical University , Chongqing , China
| | - Xufang Dai
- d College of Educational Science, Chongqing Normal University , Chongqing , China
| | - Xiaojing Yan
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Bo Li
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Xinzhe Li
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Haojun Xiong
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Yuming Li
- e Department of Hepatobiliary Surgery , Xinqiao Hospital, Third Military Medical University , Chongqing , China
| | - Song Li
- f Center for Pharmacogenetics , Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , PA , USA
| | - Liang Xu
- g Department of Molecular Biosciences and Department of Radiation Oncology , University of Kansas Cancer Center, University of Kansas , Lawrence , KS , USA
| | - Yongsheng Li
- h Institute of Cancer, Xinqiao Hospital, Third Military Medical University , Chongqing , China
| | - Jiqin Lian
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
| | - Fengtian He
- a Department of Biochemistry and Molecular Biology , College of Basic Medical Sciences, Third Military Medical University , Chongqing, China
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HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells. Cancer Lett 2017; 409:81-90. [DOI: 10.1016/j.canlet.2017.08.039] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 08/21/2017] [Accepted: 08/28/2017] [Indexed: 12/19/2022]
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