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Wang H, Zhang W, Sun Y, Xu X, Chen X, Zhao K, Yang Z, Liu H. Nanotherapeutic strategies exploiting biological traits of cancer stem cells. Bioact Mater 2025; 50:61-94. [PMID: 40242505 PMCID: PMC12002948 DOI: 10.1016/j.bioactmat.2025.03.016] [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: 11/30/2024] [Revised: 03/08/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.
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Affiliation(s)
- Hongyu Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Wenjing Zhang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Yun Sun
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xican Xu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xiaoyang Chen
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Kexu Zhao
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Zhao Yang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Huiyu Liu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
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Ozdil B, Avci CB, Calik-Kocaturk D, Gorgulu V, Uysal A, Güler G, Karabay Yavaşoğlu NÜ, Aktug H. Modulating Cancer Stem Cell Characteristics in CD133+ Melanoma Cells through Hif1α, KLF4, and SHH Silencing. ACS OMEGA 2025; 10:16804-16814. [PMID: 40321496 PMCID: PMC12044452 DOI: 10.1021/acsomega.5c00799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 03/19/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
Malignant melanoma is a highly aggressive form of skin cancer, partly driven by a subset of cancer stem cells (CSCs) with remarkable capacities for self-renewal, differentiation, and resistance to therapy. In this study, we examined how silencing three key genes-Hif1α, KLF4, and SHH-affects CSC characteristics. Using small interfering RNA (siRNA)-based approaches, we observed significant changes at both the gene and protein levels, shedding light on how these pathways influence melanoma progression. Our results demonstrated that silencing these genes reduces the stem-like features of CSCs. Notably, Hif1α silencing triggered a marked decrease in hypoxia-related gene expression, while targeting SHH led to a reduction in Gli1, a downstream effector of SHH signaling, highlighting its potential as a therapeutic target. We also observed changes in epigenetic markers such as HDAC9 and EP300, which play crucial roles in maintaining stemness and regulating gene expression. Interestingly, these interventions appeared to reprogram CSCs, pushing them toward a phenotype distinct from both traditional CSCs and non-stem cancer cells (NCSCs). Our findings emphasize the importance of targeting key signaling pathways in melanoma CSCs and underscore the value of mimicking the tumor microenvironment in experimental models. By revealing the dynamic plasticity of melanoma CSCs, this study offers fresh insights into potential therapeutic strategies, particularly using siRNA to modulate pathways associated with tumor progression and stem cell behavior.
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Affiliation(s)
- Berrin Ozdil
- Department
of Histology and Embryology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
- Department
of Physics, Biophysics Laboratory, Izmir
Institute of Technology, Izmir 35430, Turkey
| | - Cigir Biray Avci
- Department
of Medical Biology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | | | - Volkan Gorgulu
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Aysegul Uysal
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Günnur Güler
- Department
of Physics, Biophysics Laboratory, Izmir
Institute of Technology, Izmir 35430, Turkey
| | | | - Huseyin Aktug
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
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Lie Q, Jiang H, Lu X, Chen Z, Liang J, Zhang Y, Chao H. Photo-Activated Ferrocene-Iridium(III) Prodrug Induces Immunogenic Cell Death in Melanoma Stem Cells. J Med Chem 2025; 68:8894-8906. [PMID: 40233007 DOI: 10.1021/acs.jmedchem.5c00533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Cancer stem cells (CSCs) are key contributors to tumor resistance, recurrence, and metastasis. Conventional chemotherapy often fails to target and eradicate CSCs, significantly impairing their therapeutic efficacy. Herein, we design and synthesize a photoactivated ferrocene-iridium(III) complex (Ir-3) to achieve immunotherapy against melanoma cells (including stem cells). In short, Ir-3 effectively targets mitochondria and dissociates under light irradiation to produce a cytotoxic Ir(III) photosensitizer and Fe2+ ions. They can generate reactive oxygen species by the Fenton reaction, robustly induce ferroptosis and autophagy, and eventually trigger immunogenic cell death in melanoma cells (including stem cells). Furthermore, under light exposure, Ir-3 effectively inhibits stem cell-related properties and promotes macrophage-mediated phagocytosis of melanoma stem cells. For in vivo studies, Ir-3 is encapsulated in DSPE-PEG 2000 to form tumor-targeting Ir-3@PEG nanoparticles. After photoactivation, Ir-3@PEG can significantly inhibit primary and distant tumors, effectively inhibit the stemness of melanoma stem cells, and induce innate and adaptive immune responses.
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Affiliation(s)
- Qiaoshan Lie
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Hui Jiang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Xiangwan Lu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Zhuoli Chen
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Jinzhe Liang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Yan Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China
| | - Hui Chao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510006, P. R. China
- MOE Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 400201, P. R. China
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Zhong R, He H, Wang X. Novel neutrophil targeting platforms in treating Glioblastoma: Latest evidence and therapeutic approaches. Int Immunopharmacol 2025; 150:114173. [PMID: 39938169 DOI: 10.1016/j.intimp.2025.114173] [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: 10/08/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Glioblastoma (GBM) is the most aggressive and lethal type of primary brain tumor, characterized by its rapid growth, resistance to conventional therapies, and a highly immunosuppressive tumor microenvironment (TME). Recent studies have highlighted the critical role of neutrophils in the progression of GBM, where they contribute to tumor growth, invasion, and treatment resistance. As a result, neutrophils have emerged as a promising target for therapeutic intervention in GBM. Various strategies are being investigated to specifically target neutrophils within the GBM environment, including using small molecules, antibodies, and nanoparticle-based methods. These approaches aim to regulate neutrophils' recruitment, activation, and functions. This study reviews the latest findings regarding the involvement of neutrophils in GBM, explores potential techniques targeting neutrophils for therapeutic purposes, and discusses current clinical studies and prospects in this rapidly evolving field. By studying the diverse functions of neutrophils in GBM, these innovative therapeutic strategies can help address some of the most significant challenges in treating this malignancy.
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Affiliation(s)
- Rui Zhong
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Hongmei He
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Xiande Wang
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China.
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Muhammad FA, Adhab AH, Mahdi MS, Jain V, Ganesan S, Bhanot D, Naidu KS, Kaur S, Mansoor AS, Radi UK, Abd NS, Kariem M. Unveiling Novel Targets in Lung Tumors for Enhanced Radiotherapy Efficacy: A Comprehensive Review. J Biochem Mol Toxicol 2025; 39:e70180. [PMID: 39987513 DOI: 10.1002/jbt.70180] [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: 10/23/2024] [Revised: 12/06/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
Radiotherapy is a cornerstone of lung cancer management, though its efficacy is frequently undermined by intrinsic and acquired radioresistance. This review examines the complexity of lung tumors, highlighting their potential as a reservoir of novel targets for radiosensitization. Ionizing radiation (IR) primarily exerts its effects through oxidative damage and DNA double-strand breaks (DSBs). Lung cancer cells, however, develop mutations that enhance DNA damage response (DDR) and suppress cell death pathways. Additionally, interactions between tumor cells and tumor microenvironment (TME) components-including immune cells, stromal cells, and molecular mediators such as cytokines, chemokines, and growth factors-contribute to resistance against IR. Understanding these intricate relationships reveals potential targets to improve radiotherapy outcomes. Promising targets include DDR pathways, immunosuppressive cells and molecules, hypoxia, proangiogenic mediators, and other key signaling pathways. This review discusses emerging strategies, such as combining radiotherapy with immunomodulators, hypoxia and proangiogenic inhibitors, DDR-targeting agents, and other innovative approaches. By offering a comprehensive analysis of the lung TME, this review underscores opportunities to enhance radiotherapy effectiveness through targeted radiosensitization strategies.
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Affiliation(s)
| | | | | | - Vicky Jain
- Department of Chemistry, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, India
| | - Deepak Bhanot
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, India
| | - Sharnjeet Kaur
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, India
| | | | - Usama Kadem Radi
- Collage of Pharmacy, National University of Science and Technology, Nasiriyah, Iraq
| | - Nasr Saadoun Abd
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Muthena Kariem
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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Rakoczy K, Szymańska N, Stecko J, Kisiel M, Sleziak J, Gajewska-Naryniecka A, Kulbacka J. The Role of RAC2 and PTTG1 in Cancer Biology. Cells 2025; 14:330. [PMID: 40072059 PMCID: PMC11899714 DOI: 10.3390/cells14050330] [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: 01/22/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Several molecular pathways are likely involved in the regulation of cancer stem cells (CSCs) via Ras-associated C3 botulinum toxin substrate 2, RAC2, and pituitary tumor-transforming gene 1 product, PTTG1, given their roles in cellular signaling, survival, proliferation, and metastasis. RAC2 is a member of the Rho GTPase family and plays a crucial role in actin cytoskeleton dynamics, reactive oxygen species production, and cell migration, contributing to epithelial-mesenchymal transition (EMT), immune evasion, and therapy resistance. PTTG1, also known as human securin, regulates key processes such as cell cycle progression, apoptosis suppression, and EMT, promoting metastasis and enhancing cancer cell survival. This article aims to describe the molecular pathways involved in the proliferation, invasiveness, and drug response of cancer cells through RAC2 and PTTG1, aiming to clarify their respective roles in neoplastic process dependencies. Both proteins are involved in critical signaling pathways, including PI3K/AKT, TGF-β, and NF-κB, which facilitate tumor progression by modulating CSC properties, angiogenesis, and immune response. This review highlights the molecular mechanisms by which RAC2 and PTTG1 influence tumorigenesis and describes their potential and efficacy as prognostic biomarkers and therapeutic targets in managing various neoplasms.
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Affiliation(s)
- Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Natalia Szymańska
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Jakub Stecko
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Michał Kisiel
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Jakub Sleziak
- Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland; (K.R.); (N.S.); (J.S.); (M.K.); (J.S.)
| | - Agnieszka Gajewska-Naryniecka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland;
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland;
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Santariškių g. 5, LT-08406 Vilnius, Lithuania
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Taher MY, Hassouna E, El Hadidi A, El-aassar O, Fathy Bakosh M, Said Shater M. Serum CYFRA 21-1 and CK19-2G2 as Predictive Biomarkers of Response to Transarterial Chemoembolization in Hepatitis C-related Hepatocellular Carcinoma Among Egyptians: A Prospective Study. J Clin Exp Hepatol 2025; 15:102405. [PMID: 39309220 PMCID: PMC11414665 DOI: 10.1016/j.jceh.2024.102405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
Background and aim Cytokeratin 19 (CK19)-positive HCC is a subtype of hepatocellular carcinoma (HCC) with poor biological behavior and resistance to different treatments including transarterial chemoembolization (TACE). The current study aimed to investigate the predictive value of serum CK 19 fragment 21-1 (CYFRA 21-1) and serum CK 19 fragment 2G2 (CK 19-2G2) for TACE response in patients with hepatitis C virus (HCV)-related HCC. Methods This prospective study assessed the pretreatment serum CYFRA 21-1 and CK 19-2G2 levels in 64 patients with HCV-related naïve HCC who underwent TACE to predict 1-year overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, 40 healthy individuals were included as controls. Pretreatment alpha-fetoprotein (AFP) was also measured for comparison. Results After exclusions, 60 patients completed TACE sessions, and the 1-year OS was 52%, and ORR post TACE was 71.8%. HCC patients with elevated levels of CYFRA 21-1, CK 19-2G2, or baseline AFP measuring ≥400 ng/ml have decreased 1-year OS and PFS after TACE. Serum CK19-2G2 was an independent predictor of 1-year OS using multivariate hazard regression analysis. Pretreatment normal serum CYFRA 21-1 levels (P = 0.047), serum AFP measuring <400 ng/ml (P = 0.016), and lower AST (P = 0.002) were independent predictors of ORR to TACE using multivariate logistic regression analysis. The predictive ability of pretreatment elevated serum CYFRA 21-1, AFP measuring ≥400 ng/ml, AFP + CYFRA 21-1, AFP + CK 19-2G2, or AFP + CYFRA 21-1+ CK19-2G2 to predict nonresponse (progressive disease) to TACE (area under the curve = 0.795, 0.690, 0.830, 0.725, and 0.850, respectively). Conclusions This study demonstrated that incorporating the measurement of serum CYFRA 21-1 or CK19-2G2 levels, along with AFP, during the initial diagnosis can aid in predicting poor 1-year OS, PFS, and ORR to TACE in patients with HCV-related HCC.
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Affiliation(s)
- Mohamed Y. Taher
- Hepatobiliary Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, Egypt
| | - Ehab Hassouna
- Hepatobiliary Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, Egypt
| | - Abeer El Hadidi
- Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Egypt
| | - Omar El-aassar
- Diagnostic and Interventional Radiology, Faculty of Medicine, Alexandria University, Egypt
| | - Mohamed Fathy Bakosh
- Hepatobiliary Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, Egypt
| | - Mohamed Said Shater
- Hepatobiliary Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, Egypt
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Famta P, Shah S, Dey B, Kumar KC, Bagasariya D, Vambhurkar G, Pandey G, Sharma A, Srinivasarao DA, Kumar R, Guru SK, Raghuvanshi RS, Srivastava S. Despicable role of epithelial-mesenchymal transition in breast cancer metastasis: Exhibiting de novo restorative regimens. CANCER PATHOGENESIS AND THERAPY 2025; 3:30-47. [PMID: 39872366 PMCID: PMC11764040 DOI: 10.1016/j.cpt.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 01/30/2025]
Abstract
Breast cancer (BC) is the most prevalent cancer in women globally. Anti-cancer advancements have enabled the killing of BC cells through various therapies; however, cancer relapse is still a major limitation and decreases patient survival and quality of life. Epithelial-to-mesenchymal transition (EMT) is responsible for tumor relapse in several cancers. This highly regulated event causes phenotypic, genetic, and epigenetic changes in the tumor microenvironment (TME). This review summarizes the recent advancements regarding EMT using de-differentiation and partial EMT theories. We extensively review the mechanistic pathways, TME components, and various anti-cancer adjuvant and neo-adjuvant therapies responsible for triggering EMT in BC tumors. Information regarding essential clinical studies and trials is also discussed. Furthermore, we also highlight the recent strategies targeting various EMT pathways. This review provides a holistic picture of BC biology, molecular pathways, and recent advances in therapeutic strategies.
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Affiliation(s)
- Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Biswajit Dey
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Kondasingh Charan Kumar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Deepkumar Bagasariya
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Giriraj Pandey
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Anamika Sharma
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Dadi A. Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Santosh Kumar Guru
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | | | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
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Sharafabad BE, Abdoli A, Jamour P, Dilmaghani A. The ability of clostridium novyi-NT spores to induce apoptosis via the mitochondrial pathway in mice with HPV-positive cervical cancer tumors derived from the TC-1 cell line. BMC Complement Med Ther 2024; 24:427. [PMID: 39732669 DOI: 10.1186/s12906-024-04742-5] [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: 10/07/2023] [Accepted: 12/24/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND A precise observation is that the cervix's solid tumors possess hypoxic regions where the oxygen concentration drops below 1.5%. Hypoxia negatively impacts the host's immune system and significantly diminishes the effectiveness of several treatments, including radiotherapy and chemotherapy. Utilizing oncolytic spores of Clostridium novyi-NT to target the hypoxic regions of solid tumors has emerged as a noteworthy treatment strategy. METHODS The transplantation procedure involved injecting TC-1 cells, capable of expressing HPV-16 E6/7 oncoproteins, into the subcutaneous layer of 6-8-week-old female C57/BL6 mice. The TC-1 cell line, was subcutaneously transplanted into 6-8-week-old female C57/BL6 mice. The tumor-bearing mice were randomly divided into 4 groups, and after selecting the control group, they were treated with different methods. Group 1- control without treatment (0.1 ml sterile PBS intratumor) Group 2- received cisplatin intraperitoneally (10 mg/kg) Group 3- received 107Clostridium novyi-NT spores systemically through the tail vein Group 4-tumor mice received 107Clostridium novyi-NT spores intratumorally. 20 days after the start of treatment, the mice were sacrificed and tumor tissues were isolated. In order to clarify the mechanism of the therapeutic effect with spores, the amount of ROS and ceramide was measured by ELISA technique, and the expression level of cytochrome c, cleaved caspase- 3, Bax, Bcl-2, HIF-1α, and VEGF proteins was measured by western blotting. RESULTS Our results clearly showed that the injection of Clostridium novyi-NT spores (either intratumorally or intravenously) causes the regression of mouse cervical tumors. Spore germination induces internal apoptosis in cancer cells by inducing ROS production and increasing total cell ceramide, releasing cytochrome c and damaging mitochondria. Additionally, the results provided clear evidence of a significant decrease in the expression of HIF-1 alpha and VEGF proteins among the tumor groups that received spores, when compared to both the cisplatin-treated group and the control group. CONCLUSIONS The study's outcomes demonstrated that the introduction of Clostridium novyi-NT spores triggered apoptosis in cervical cancer cells (derived from the TC-1 cell line) via the mitochondrial pathway, subsequently resulting in tumor regression in a mouse model.
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Affiliation(s)
- Behrouz Ebadi Sharafabad
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asghar Abdoli
- Department of Hepatitis and HIV, Pasteur Institute of Iran (IPI), Tehran, Iran
| | - Parisa Jamour
- Department of Hepatitis and HIV, Pasteur Institute of Iran (IPI), Tehran, Iran
| | - Azita Dilmaghani
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhao J, Zhang H, Liu Y, Lu G, Wang Z, Mo Q, Wang G, Shen Y, Jiao L. HIF-1α knockdown suppresses breast cancer metastasis via epithelial mesenchymal transition Abrogation. Heliyon 2024; 10:e37900. [PMID: 39386828 PMCID: PMC11462230 DOI: 10.1016/j.heliyon.2024.e37900] [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: 06/24/2024] [Revised: 09/12/2024] [Accepted: 09/12/2024] [Indexed: 10/12/2024] Open
Abstract
Lung metastasis, a leading cause of breast cancer mortality, lacks effective therapeutic options. Hypoxia-inducible factor 1-alpha (HIF-1α) plays important roles in breast cancer progression, but its direct impact on lung metastasis remains unclear. Herein, in this study, we investigated the role of HIF-1α in breast cancer lung metastasis and the potential of targeting it for therapeutic benefit. HIF-1α expression was knocked down in the 4T1 mouse mammary carcinoma cell line using a lentiviral vector. HIF-1α knockdown significantly reduced the migratory ability of 4T1 cells in vitro and lung metastasis in a mouse model. Mechanistically, HIF-1α knockdown decreased the expression of matrix metalloproteinases (MMP-2 and MMP-9) that degrade the extracellular matrix and suppressed the epithelial-to-mesenchymal transition (EMT) by increasing E-cadherin and decreasing vimentin expression. The findings of this study demonstrate that HIF-1α knockdown effectively inhibits lung metastasis of 4T1 cells both in vitro and in vivo by suppressing EMT. These results underscore a promising new approach for managing breast cancer metastasis.
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Affiliation(s)
- Jinjin Zhao
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Haiguang Zhang
- Department of Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Yaqian Liu
- Otorhinolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Guangjian Lu
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Zhaohui Wang
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Qingjiang Mo
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Guoqiang Wang
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
| | - Yanfei Shen
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
- Medical School, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Luyang Jiao
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
- Department of Blood Transfusion, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453100, China
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11
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Shan Q, Yin L, Zhan Q, Yu J, Pan S, Zhuo J, Zhou W, Bao J, Zhang L, Hong J, Xiang J, Que Q, Chen K, Xu S, Wang J, Zhu Y, He B, Wu J, Xie H, Zheng S, Feng T, Ling S, Xu X. The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma. Signal Transduct Target Ther 2024; 9:249. [PMID: 39300073 DOI: 10.1038/s41392-024-01963-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 08/07/2024] [Accepted: 09/01/2024] [Indexed: 09/22/2024] Open
Abstract
Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.
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MESH Headings
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Humans
- Quinolines/pharmacology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Phenylurea Compounds/pharmacology
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Ubiquitin Thiolesterase/genetics
- Ubiquitin Thiolesterase/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/drug effects
- Myosin Heavy Chains/genetics
- Myosin Heavy Chains/metabolism
- Mice
- Cell Line, Tumor
- Animals
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/genetics
- Male
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Affiliation(s)
- Qiaonan Shan
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Lu Yin
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Qifan Zhan
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jiongjie Yu
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Sheng Pan
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Wei Zhou
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jiaqi Bao
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Lincheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Jiachen Hong
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Jianan Xiang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Qingyang Que
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Kangchen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Shengjun Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Jingrui Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Yangbo Zhu
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Bin He
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jingbang Wu
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Haiyang Xie
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | | | - Sunbin Ling
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China.
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China.
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 314408, China.
- Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China.
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12
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Malik S, Sikander M, Wahid M, Dhasmana A, Sarwat M, Khan S, Cobos E, Yallapu MM, Jaggi M, Chauhan SC. Deciphering cellular and molecular mechanism of MUC13 mucin involved in cancer cell plasticity and drug resistance. Cancer Metastasis Rev 2024; 43:981-999. [PMID: 38498072 DOI: 10.1007/s10555-024-10177-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 02/26/2024] [Indexed: 03/19/2024]
Abstract
There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.
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Affiliation(s)
- Shabnam Malik
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohammed Sikander
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohd Wahid
- Unit of Research and Scientific Studies, College of Nursing and Allied Health Sciences, University of Jazan, Jizan, Saudi Arabia
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Noida, India
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Everardo Cobos
- Department of Medicine, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA.
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA.
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13
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Liu N, Zheng Q, Zhang Y, Wang H, Zhang Z, He L, Wei C, Xia H, Liu Y, Wang X. Hypoxia differently regulates the proportion of ALDH hi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β-catenin pathway. Thorac Cancer 2024; 15:1419-1428. [PMID: 38736300 PMCID: PMC11194122 DOI: 10.1111/1759-7714.15328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self-renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non-small cell lung cancer (NSCLC) remains unclear. METHODS The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β-catenin while pcDNA3-β-catenin (S33Y) plasmid enhanced the expression of β-catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real-time PCR. RESULTS We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β-catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β-catenin inhibitor or siRNA knockdown, whereas increased after β-catenin overexpression. Furthermore, hypoxia treatment suppressed E-cadherin expression in H520 cells and enhanced N-cadherin and β-catenin expression, while this effect was completely opposite in A549 cells. CONCLUSION The hypoxia-EMT-β-catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.
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Affiliation(s)
- Ni Liu
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Qi Zheng
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Yuqing Zhang
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Huimin Wang
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
- Department of OncologyYantai Affiliated Hospital of Binzhou Medical UniversityYantaiChina
| | - Zhihui Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Long He
- Department of OncologyThe Third Hospital of JinanJinanChina
| | - Chenxi Wei
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Handai Xia
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Yanguo Liu
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
| | - Xiuwen Wang
- Department of Medical OncologyQilu Hospital of Shandong UniversityJinanChina
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14
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Knopik-Skrocka A, Sempowicz A, Piwocka O. Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies - do we know enough to overcome this? EXCLI JOURNAL 2024; 23:335-355. [PMID: 38655094 PMCID: PMC11036066 DOI: 10.17179/excli2024-6972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/20/2024] [Indexed: 04/26/2024]
Abstract
According to the CSC hypothesis, cancer stem cells are pivotal in initiating, developing, and causing cancer recurrence. Since the identification of CSCs in leukemia, breast cancer, glioblastoma, and colorectal cancer in the 1990s, researchers have actively investigated the origin and biology of CSCs. However, the CSC hypothesis and the role of these cells in tumor development model is still in debate. These cells exhibit distinct surface markers, are capable of self-renewal, demonstrate unrestricted proliferation, and display metabolic adaptation. CSC phenotypic plasticity and the capacity to EMT is strictly connected to the stemness state. CSCs show high resistance to chemotherapy, radiotherapy, and immunotherapy. The plasticity of CSCs is significantly influenced by tumor microenvironment factors, such as hypoxia. Targeting the genetic and epigenetic changes of cancer cells, together with interactions with the tumor microenvironment, presents promising avenues for therapeutic strategies. See also the Graphical abstract(Fig. 1).
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Affiliation(s)
- Agnieszka Knopik-Skrocka
- Department of Cell Biology, Faculty of Biology, Adam Mickiewicz University of Poznań, Poland
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Alicja Sempowicz
- Department of Cell Biology, Faculty of Biology, Adam Mickiewicz University of Poznań, Poland
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznań, Poland
| | - Oliwia Piwocka
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Center, Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznań, Poland
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15
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Abou Khouzam R, Janji B, Thiery J, Zaarour RF, Chamseddine AN, Mayr H, Savagner P, Kieda C, Gad S, Buart S, Lehn JM, Limani P, Chouaib S. Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy. Semin Cancer Biol 2023; 97:104-123. [PMID: 38029865 DOI: 10.1016/j.semcancer.2023.11.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023]
Abstract
In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.
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Affiliation(s)
- Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
| | - Bassam Janji
- Department of Cancer Research, Luxembourg Institute of Health, Tumor Immunotherapy and Microenvironment (TIME) Group, 6A, rue Nicolas-Ernest Barblé, L-1210 Luxembourg city, Luxembourg.
| | - Jerome Thiery
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Rania Faouzi Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
| | - Ali N Chamseddine
- Gastroenterology Department, Cochin University Hospital, Université de Paris, APHP, Paris, France; Ambroise Paré - Hartmann Private Hospital Group, Oncology Unit, Neuilly-sur-Seine, France.
| | - Hemma Mayr
- Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland; Department of Surgery & Transplantation, University and University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland.
| | - Pierre Savagner
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine-National Research Institute, 04-141 Warsaw, Poland; Centre for Molecular Biophysics, UPR 4301 CNRS, 45071 Orleans, France; Centre of Postgraduate Medical Education, 01-004 Warsaw, Poland.
| | - Sophie Gad
- Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres University (PSL), 75014 Paris, France; UMR CNRS 9019, Genome Integrity and Cancers, Gustave Roussy, Paris-Saclay University, 94800 Villejuif, France.
| | - Stéphanie Buart
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Jean-Marie Lehn
- Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, 8 allée Gaspard Monge, Strasbourg, France.
| | - Perparim Limani
- Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland; Department of Surgery & Transplantation, University and University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland.
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates; INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
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16
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Vlcek P, Bob P, Vales K. Revisiting monoamine oxidase inhibitors: A potential dual-action therapy for patients with prostate cancer and comorbid depression? J Psychopharmacol 2023; 37:1157-1160. [PMID: 37300415 DOI: 10.1177/02698811231179808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Affiliation(s)
- Premysl Vlcek
- National Institute of Mental Health, Klecany, Czech Republic
- Department of Psychiatry, First Faculty of Medicine, Prague, Czech Republic
- Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Bob
- Department of Psychiatry, First Faculty of Medicine, Prague, Czech Republic
| | - Karel Vales
- National Institute of Mental Health, Klecany, Czech Republic
- Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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17
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Zaarour RF, Ribeiro M, Azzarone B, Kapoor S, Chouaib S. Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance. Front Oncol 2023; 13:1222575. [PMID: 37886168 PMCID: PMC10598765 DOI: 10.3389/fonc.2023.1222575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
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Affiliation(s)
- RF. Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - M. Ribeiro
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - B. Azzarone
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - S. Kapoor
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - S. Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, Villejuif, France
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18
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Fang J, Lu Y, Zheng J, Jiang X, Shen H, Shang X, Lu Y, Fu P. Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications. Cell Death Dis 2023; 14:586. [PMID: 37666809 PMCID: PMC10477350 DOI: 10.1038/s41419-023-06119-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/19/2023] [Accepted: 08/25/2023] [Indexed: 09/06/2023]
Abstract
The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.
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Affiliation(s)
- Jianwen Fang
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
| | - Yue Lu
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Huzhou University, 313000, Huzhou, China
| | - Jingyan Zheng
- Department of Breast and Thyroid Surgery, Lishui People's Hospital, The Six Affiliated Hospital of Wenzhou Medical University, 323000, Lishui, China
| | - Xiaocong Jiang
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
| | - Haixing Shen
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
- Department of Breast and Thyroid Surgery, Cixi People's Hospital, 315300, Cixi, China
| | - Xi Shang
- Department of Breast and Thyroid Surgery, Taizhou Hospital, Zhejiang University, 318000, Taizhou, China
| | - Yuexin Lu
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
| | - Peifen Fu
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
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19
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Czarnywojtek A, Borowska M, Dyrka K, Van Gool S, Sawicka-Gutaj N, Moskal J, Kościński J, Graczyk P, Hałas T, Lewandowska AM, Czepczyński R, Ruchała M. Glioblastoma Multiforme: The Latest Diagnostics and Treatment Techniques. Pharmacology 2023; 108:423-431. [PMID: 37459849 DOI: 10.1159/000531319] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 05/05/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death. SUMMARY In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM. KEY MESSAGES This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging.
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Affiliation(s)
- Agata Czarnywojtek
- Chair and Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Magdalena Borowska
- Chair and Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland
| | - Kamil Dyrka
- Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Nadia Sawicka-Gutaj
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Jakub Moskal
- Department of Neurosurgery, Poznan University of Medical Sciences, Poznan, Poland
| | - Jeremi Kościński
- Department of Neurosurgery, Poznan University of Medical Sciences, Poznan, Poland
| | - Patryk Graczyk
- Chair and Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland
| | - Tomasz Hałas
- Chair and Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Rafał Czepczyński
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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20
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Khademi R, Malekzadeh H, Bahrami S, Saki N, Khademi R, Villa-Diaz LG. Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology. Cancers (Basel) 2023; 15:3466. [PMID: 37444576 DOI: 10.3390/cancers15133466] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.
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Affiliation(s)
- Rahele Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
| | - Hossein Malekzadeh
- Department of Oral Medicine, Faculty of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Sara Bahrami
- Resident of Restorative Dentistry, Qazvin University of Medical Sciences, Qazvin 3419759811, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Reyhane Khademi
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Laboratory Sciences, School of Para-Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz 6135715794, Iran
| | - Luis G Villa-Diaz
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
- Department of Bioengineering, Oakland University, Rochester, MI 48309, USA
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21
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Takagi T, Fujiwara-Tani R, Mori S, Kishi S, Nishiguchi Y, Sasaki T, Ogata R, Ikemoto A, Sasaki R, Ohmori H, Luo Y, Bhawal UK, Sho M, Kuniyasu H. Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24087506. [PMID: 37108667 PMCID: PMC10139117 DOI: 10.3390/ijms24087506] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl2-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future.
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Grants
- 19K16564 Ministry of Education, Culture, Sports, Science and Technology
- 20K21659 Ministry of Education, Culture, Sports, Science and Technology
- 20K18007 Ministry of Education, Culture, Sports, Science and Technology
- 21K10143 Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Tadataka Takagi
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
- Department of Surgery, Nara Medical University, Kashihara 634-8522, Japan
| | - Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Yukiko Nishiguchi
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Takamitsu Sasaki
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Ayaka Ikemoto
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Rika Sasaki
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Hitoshi Ohmori
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
| | - Yi Luo
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China
| | - Ujjal Kumar Bhawal
- Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Matsudo 271-8587, Japan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, India
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Kashihara 634-8522, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan
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22
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Mao XG, Xue XY, Lv R, Ji A, Shi TY, Chen XY, Jiang XF, Zhang X. CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway. Cell Death Dis 2023; 14:269. [PMID: 37059730 PMCID: PMC10104878 DOI: 10.1038/s41419-023-05788-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/16/2023]
Abstract
Hypoxia contributes to the initiation and progression of glioblastoma by regulating a cohort of genes called hypoxia-regulated genes (HRGs) which form a complex molecular interacting network (HRG-MINW). Transcription factors (TFs) often play central roles for MINW. The key TFs for hypoxia induced reactions were explored using proteomic analysis to identify a set of hypoxia-regulated proteins (HRPs) in GBM cells. Next, systematic TF analysis identified CEBPD as a top TF that regulates the greatest number of HRPs and HRGs. Clinical sample and public database analysis revealed that CEBPD is significantly up-regulated in GBM, high levels of CEBPD predict poor prognosis. In addition, CEBPD is highly expressed in hypoxic condition both in GBM tissue and cell lines. For molecular mechanisms, HIF1α and HIF2α can activate the CEBPD promotor. In vitro and in vivo experiments demonstrated that CEBPD knockdown impaired the invasion and growth capacity of GBM cells, especially in hypoxia condition. Next, proteomic analysis identified that CEBPD target proteins are mainly involved in the EGFR/PI3K pathway and extracellular matrix (ECM) functions. WB assays revealed that CEBPD significantly positively regulated EGFR/PI3K pathway. Chromatin immunoprecipitation (ChIP) qPCR/Seq analysis and Luciferase reporter assay demonstrated that CEBPD binds and activates the promotor of a key ECM protein FN1 (fibronectin). In addition, the interactions of FN1 and its integrin receptors are necessary for CEBPD-induced EGFR/PI3K activation by promoting EGFR phosphorylation. Furthermore, GBM sample analysis in the database corroborated that CEBPD is positively correlated with the pathway activities of EGFR/PI3K and HIF1α, especially in highly hypoxic samples. At last, HRPs are also enriched in ECM proteins, indicating that ECM activities are important components of hypoxia induced responses in GBM. In conclusion, CEPBD plays important regulatory roles in the GBM HRG-MINW as a key TF, which activates the EGFR/PI3K pathway through ECM, especially FN1, mediated EGFR phosphorylation.
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Affiliation(s)
- Xing-Gang Mao
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
| | - Xiao-Yan Xue
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Rui Lv
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
- College of Life Sciences, Northwest University, Xi'an, Shaanxi Province, People's Republic of China
| | - Ang Ji
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Ting-Yu Shi
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Yan Chen
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Fan Jiang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
| | - Xiang Zhang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
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23
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Karami Fath M, Shafieyari S, Ardalani N, Moumivand F, Kaviani Charati H, Zareei M, Mansoori Nia A, Zokaei M, Barati G. Hypoxia-circular RNA crosstalk to promote breast cancer. Pathol Res Pract 2023; 244:154402. [PMID: 36921546 DOI: 10.1016/j.prp.2023.154402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/25/2023] [Accepted: 03/03/2023] [Indexed: 03/07/2023]
Abstract
The expression of hypoxia-inducible factors (HIFs), particularly HIF-1, plays a major role in the adaptation of solid tumors to hypoxic conditions. The activation of the HIF pathway results in an expression of genes involved in the promotion of cell growth, proliferation, vascularization, metastasis, and therapeutic resistance. Circular RNA (CircRNA) is considered as a major regulator of gene expression. CircRNAs could regulate the HIF-1 pathway in cancer cells. In addition, they might be regulated by the HIF-1 pathway to promote cancer progression. Therefore, the crosstalk between hypoxia and circRNA might be involved in the pathogenesis of cancers, including breast cancer. In this review, we discussed the function of HIF-related circRNAs in the progression, angiogenesis, metabolic reprogramming, and stemness maintenance of breast cancer. In addition, the correlation between HIF-related circRNAs and clinical features of breast cancer is reviewed.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Saba Shafieyari
- Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nasim Ardalani
- Faculty of Medicine, Islamic Azad University, Sari Branch, Sari, Iran
| | - Farzane Moumivand
- Faculty of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Mohammad Zareei
- Faculty of Medicine, Islamic Azad University, Sari Branch, Sari, Iran
| | | | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Veterinary Medicine, Beyza Branch, Islamic Azad University, Beyza, Iran
| | - Ghasem Barati
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran; Stem Cell Technology Research Center, Tehran, Iran.
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24
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Karami Fath M, Garousi S, Mottahedi M, Ghasemzadeh N, Salmani K, Olfati F, Beit Saeed M, Sotoudeh S, Barati G. The role of hypoxia-inducible factors in breast cancer stem cell specification. Pathol Res Pract 2023; 243:154349. [PMID: 36791562 DOI: 10.1016/j.prp.2023.154349] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023]
Abstract
Breast tumor is heterogeneous cancer with high morbidity and mortality rates, particularly in developing countries. Despite new efforts to reduce the breast cancer implications, the number of newly diagnosed cases is increasing worldwide. It is believed that cancer stem cells (CSCs) are responsible for the implication of cancers including breast cancer. Although CSCs compose a small population in tumor bulks, they play a crucial role in tumor initiation, progression, metastasis, and chemotherapeutic resistance. These events are mediated by the hypoxia-inducible factor (HIF) pathway which regulates the transcription of genes involved in CSC maintenance and tumorigenesis. In this review, we discussed the mechanisms by which hypoxia- or chemotherapy-induced HIFs promote breast CSC specification.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Setareh Garousi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Mottahedi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Kiana Salmani
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Olfati
- Department of Reproductive Health, Faculty of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
| | - Miad Beit Saeed
- Faculty of Nursing and Midwifery, Abadan Islamic Azad University, Abadan, Iran
| | - Sina Sotoudeh
- Faculty of Nursing and Midwifery, Guilan University of Medical Sciences, Guilan, Iran
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25
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Guo XH, Wu MY, Zhao G, Wu FH, Xu YD, Yin MZ, Xiang L. The locoregional adiponectin and its synergistic antitumor effect with HIF-1α blockade in TSCC. Oral Dis 2023; 29:515-527. [PMID: 34174132 DOI: 10.1111/odi.13948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023]
Abstract
Adiponectin (APN) is a kind of endogenous anti-tumor adipocytokine, which exerts its function by binding to its receptors (AdipoR1 and AdipoR2). However, hyperadiponectinemia is found in some pathophysiological processes without significant protective effect, which indicates the existence of APN resistance. Here, we aimed to investigate the locoregional expression of APN in tongue squamous cell carcinoma (TSCC) tissues, and to explore the potential regulatory mechanism of APN resistance under hypoxia. Consequently, we found that the protein expression of APN and AdipoR1, but not AdipoR2, was upregulated in the early stage of TSCC and after hypoxic treatment ex vivo and in vitro. Knockdown of HIF-1α decreased the level of APN and AdipoR1, and simultaneously, HIF-1α was identified as transcriptor of the APN. Intriguingly, a regenerative feedback of HIF-1α was unexpectedly detected after application of recombinant globular APN (gAPN), which most likely contributed to the APN resistance. Furthermore, HIF-1α blockade combined with gAPN has a prominent synergistic antitumor effect, which suggested an effective amelioration in APN resistance. In all, our study revealed the possible mechanism of APN resistance under hypoxia and provides a promising strategy of bi-target treatment with APN and HIF-1α for TSCC therapy.
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Affiliation(s)
- Xiao-Hong Guo
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Ming-Yu Wu
- Department of Basic Biology, College of Life Sciences, Hubei University, Wuhan, China
| | - Gang Zhao
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Feng-Hua Wu
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Yun-Dan Xu
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Ming-Zhu Yin
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Lei Xiang
- Department of Medical Biology, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
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26
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Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1α/Notch1 signaling pathway. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023:10.1007/s12094-023-03093-w. [PMID: 36757381 DOI: 10.1007/s12094-023-03093-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/17/2023] [Indexed: 02/10/2023]
Abstract
PURPOSE The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated. MATERIALS AND METHODS Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated. RESULTS In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa. CONCLUSION In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.
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27
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Zhao Q, Qi T. The implications and prospect of cuproptosis-related genes and copper transporters in cancer progression. Front Oncol 2023; 13:1117164. [PMID: 36925927 PMCID: PMC10011146 DOI: 10.3389/fonc.2023.1117164] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/17/2023] [Indexed: 03/08/2023] Open
Abstract
Currently, cancer has become one of the major public health problems worldwide. Apoptosis is an important anti-cancer defense mechanism, which is used in the development of targeted drugs. Because cancer cells have endogenous resistance to apoptosis,the clinical efficacy of related drugs is not ideal. Therefore, non-apoptotic regulatory cell death may bring new therapeutic strategies for cancer treatment. Cuproptosis is a novel form of regulatory cell death which is copper-dependent, regulated and distinct from other known cell death regulatory mechanisms. FDX1,LIAS,and DLAT named cuproptosis-related genes play an essential role in regulating cuproptosis. Meanwhile, abnormal accumulation of copper can be observed in various malignant tumors. The correlation has been established between elevated copper levels in serum and tissues and the progression of several cancers. Copper transporters, CTR1 and Copper-transporting ATPases(ATP7A and ATP7B), are mainly involved in regulating the dynamic balance of copper concentration to maintain copper homeostasis. Thus,cuproptosis-related genes and copper transporters will be the focus of cancer research in future. This review elaborated the basic functions of cuproptosis-related genes and copper transporters by retrievalling PubMed. And then we analyzed their potential relationship with cancer aiming to provide theoretical support and reference in cancer progression, diagnosis and treatment for future study.
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Affiliation(s)
- Qianwen Zhao
- Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, China
| | - Tonggang Qi
- Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, China
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Vazifehmand R, Ali DS, Othman Z, Chau DM, Stanslas J, Shafa M, Sekawi Z. The evaluation expression of non-coding RNAs in response to HSV-G47∆ oncolytic virus infection in glioblastoma multiforme cancer stem cells. J Neurovirol 2022; 28:566-582. [PMID: 35951174 DOI: 10.1007/s13365-022-01089-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/11/2022] [Accepted: 07/25/2022] [Indexed: 01/13/2023]
Abstract
Glioblastoma multiforme is the most aggressive astrocytes brain tumor. Glioblastoma cancer stem cells and hypoxia conditions are well-known major obstacles in treatment. Studies have revealed that non-coding RNAs serve a critical role in glioblastoma progression, invasion, and resistance to chemo-radiotherapy. The present study examined the expression levels of microRNAs (in normoxic condition) and long non-coding RNAs (in normoxic and hypoxic conditions) in glioblastoma stem cells treated with the HSV-G47∆. The expression levels of 43 miRNAs and 8 lncRNAs isolated from U251-GBM-CSCs were analyzed using a miRCURY LNA custom PCR array and a quantitative PCR assay, respectively. The data revealed that out of 43 miRNAs that only were checked in normoxic condition, the only 8 miRNAs, including miR-7-1, miR-let-7b, miR-130a, miR-137, miR-200b, miR-221, miR-222, and miR-874, were markedly upregulated. The expression levels of lncRNAs, including LEF1 antisense RNA 1 (LEF1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein coding RNA 470 (LINC00470), tumor suppressor candidate 7 (TUSC7), HOX transcript antisense RNA (HOTAIR), nuclear paraspeckle assembly transcript 1 (NEAT1), and X inactive specific transcript (XIST), were markedly downregulated in the hypoxic microenvironment, and H19-imprinted maternally expressed transcript (H19) was not observed to be dysregulated in this environment. Under normoxic conditions, LEF1-AS1, MALAT1, LINC00470, H19, HOTAIR, NEAT1, and XIST were downregulated and TUSC7 was not targeted by HSV-G47∆. Overall, the present data shows HSVG47Δ treatment deregulates non-coding RNA expression in GBM-CSC tumor microenvironments.
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Affiliation(s)
- Reza Vazifehmand
- Department of Medical Microbiology & Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - Dhuha Saeed Ali
- Halal Products Research Institute, Universiti Putra Malaysia UPM, Serdang, Selangor, 43400, Malaysia
| | - Zulkefley Othman
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - De-Ming Chau
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia UPM, Serdang, Selangor, 43400, Malaysia
| | - Mehdi Shafa
- Cell Therapy process development, Lonza Houston Inc, Houston, TX, USA
| | - Zamberi Sekawi
- Department of Medical Microbiology & Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor Darul Ehsan, 43400, Malaysia.
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Sung CJ, Wang HH, Sun KH, Hsieh CC, Huang R, Sun GH, Tang SJ. Fucoidan from Sargassum hemiphyllum inhibits the stemness of cancer stem cells and epithelial-mesenchymal transitions in bladder cancer cells. Int J Biol Macromol 2022; 221:623-633. [PMID: 36099992 DOI: 10.1016/j.ijbiomac.2022.09.047] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/25/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
A variety of anticancer activities have been established for fucoidan from brown algae, whereas whether cancer stem cells (CSCs) are inhibited by sulfated polysaccharides is unexplored. In this study, fucoidan extracted from Sargassum hemiphyllum was showed heat stable and might tolerate 140 °C treatment. Fucoidan did not exhibit cytotoxicity in 5637 and T24 bladder cancer cells. After fucoidan treatment, the stress fibers were aggregated into thick and abundant underneath the plasma membrane and getting around the cells, and the structure of F-actin showed a remarkable change in the filopodial protrusion in T24 and 5637 cells. Using culture inserts, transwell assays and time lapse recordings showed that fucoidan inhibited cell migration. In the epithelial-mesenchymal transition (EMT), fucoidan downregulated the expression of vimentin, a mesenchymal marker, and upregulated the expression of E-cadherin, an epithelial marker. Additionally, the transcription levels of Snail, Slug, Twist1, Twist2, MMP2 and MMP9 were significantly decreased by fucoidan, indicating EMT suppression. CSCs are implicated in tumor initiation, metastatic spread, drug resistance and tumor recurrence. Our results showed that fucoidan inhibited stemness gene expression and sphere formation in bladder CSCs. For the first time, our findings demonstrated that fucoidan inhibits CSC formation and provides evidence as potential anticancer therapy.
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Affiliation(s)
- Chun-Ju Sung
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 202, Taiwan
| | - Hsiao-Hsien Wang
- Section of Urology, Cheng-Hsin Rehabilitation Medical Center, Taipei 112, Taiwan
| | - Kuang-Hui Sun
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan
| | - Chii-Cheng Hsieh
- Section of Urology, Cheng-Hsin Rehabilitation Medical Center, Taipei 112, Taiwan
| | - Roger Huang
- Taiwan International Algae Fund, National Taiwan Ocean University, Keelung 202, Taiwan
| | - Guang-Huan Sun
- Department of Urology and Surgery, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Shye-Jye Tang
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; Taiwan International Algae Fund, National Taiwan Ocean University, Keelung 202, Taiwan; Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 202, Taiwan.
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30
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Shi J, Guo C, Li Y, Ma J. The long noncoding RNA TINCR promotes self-renewal of human liver cancer stem cells through autophagy activation. Cell Death Dis 2022; 13:961. [PMID: 36385098 PMCID: PMC9668904 DOI: 10.1038/s41419-022-05424-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is an extraordinarily heterogeneous tumor, which holds high recurrence and metastasis rates. Liver cancer stem cells (LCSCs) have been considered to be important influencing factors of these pathological properties, but the underlying mechanisms are poorly understood in HCC. Considerable evidences have shown that autophagy has an important role in cancer stemness. However, it is still unknown whether a long noncoding RNA (lncRNA) TINCR is involved in autophagy and self-renewal maintenance of HCC. In this study, TINCR was found to be highly expressed in HCC tissues and LCSCs. In vitro and in vivo assays for the first time showed that TINCR was required for LCSC self-renewal and tumorigenesis. Moreover, gene ontology analysis revealed the involvement of autophagy in the maintenance of TINCR-regulated stemness. Mechanically, TINCR was associated with polypyrimidine tract binding protein 1 (PTBP1) protein, which further promoted the transcription activity of autophagy related gene ATG5. In conclusion, we demonstrated that TINCR regulated LCSC self-renewal by autophagy activation through PTBP1/ATG5 regulatory pathway, offering a potential new target for HCC therapy.
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Affiliation(s)
- Jing Shi
- grid.459333.bAffiliated Hospital of Qinghai University, Xining, 810001 Qinghai Province China ,grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
| | - Cao Guo
- grid.216417.70000 0001 0379 7164Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Yang Li
- grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
| | - Junli Ma
- grid.452252.60000 0004 8342 692XAffiliated Hospital of Jining Medical University, Jining, 272029 Shandong China
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Piorecka K, Kurjata J, Stanczyk WA. Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art. J Med Chem 2022; 65:11415-11432. [PMID: 36018000 PMCID: PMC9469206 DOI: 10.1021/acs.jmedchem.2c00573] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
![]()
Acriflavine (ACF) has been known for years as an antibacterial
drug. The identification of key oncogenic mechanisms has brought,
in recent years, a significant increase in studies on ACF as a multipurpose
drug that would improve the prognosis for cancer patients. ACF interferes
with the expression of the hypoxia inducible factor, thus acting on
metastatic niches of tumors and significantly enhancing the effects
of other anticancer therapies. It has been recognized as the most
potent HIF-1 inhibitor out of the 336 drugs approved by the FDA. This
work presents up-to-date knowledge about the mechanisms of action
of ACF and its related prodrug systems in the context of anticancer
and SARS-CoV-2 inhibitory properties. It explains the multitask nature
of this drug and suggests mechanisms of ACF’s action on the
coronavirus. Other recent reports on ACF-based systems as potential
antibacterial and antiviral drugs are also described.
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Affiliation(s)
- Kinga Piorecka
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
| | - Jan Kurjata
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
| | - Wlodzimierz A Stanczyk
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,Sienkiewicza 112, 90-363 Lodz, Poland
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Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells. Biomed Pharmacother 2022; 154:113562. [PMID: 35994813 DOI: 10.1016/j.biopha.2022.113562] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/11/2022] [Accepted: 08/14/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Hypoxic microenvironment of colon cancer is associated with HIF-1α upregulation. HIF-1α response elements are responsible for autophagy induction that promotes tumor proliferation. Moreover, HIF-1α induces tumor cell proliferation via maintaining cancer stem cells (CSCs) survival. Siah2 is E3 ubiquitin ligase that indirectly stabilizes HIF-1α. We hypothesized that dual inhibition of Siah2 as well as autophagy could be a promising approach that may inhibit CSCs growth. AIM OF THE WORK This study investigated the possible effect of vitamin K3 as a Siah2 inhibitor and hydroxychloroquine as an autophagy inhibitor in colon cancer management. The effect (if any) of these agents on CSCs growth will be also manipulated. METHODS Colon cancer was induced by dimethylhydrazine. MDA and GSH were selected as oxidative stress markers, Expression of HIF-1α, Caspase-3, VEGF, MMP-9, EpCAM, SCF, and CA19.9 were assayed using immunoassay. The Western blot technique was used to assess LC3Ⅰ, CD44, and CD133 whereas RT-PCR was used to investigate PHD3 and CD44 in colon tissues. Additionally, Ki-67 and Siah2 were detected immunohistochemically. RESULTS vitamin K3 and hydroxychloroquine either alone or in combination downregulated the expression of Siah2 and HIF-1α through upregulating PHD3 in colon tissues. This combination significantly downregulated MDA, Ki-67, VEGF, and MMP-9 expression and upregulated the expression of GSH and caspase-3. LC3Ⅰ was also upregulated. Interestingly, these therapeutic options were correlated with down-regulation of the cancer stem cell marker such as CD44 and EpCAM. CONCLUSION Our results suggested that suppression of both Siah2-PHD3-HIF-1α axis and autophagy retard colon cancer proliferation and dampened CSCs.
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Tang K, Toyozumi T, Murakami K, Sakata H, Kano M, Endo S, Matsumoto Y, Suito H, Takahashi M, Sekino N, Otsuka R, Kinoshita K, Hirasawa S, Hu J, Uesato M, Hayano K, Matsubara H. HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway. Br J Cancer 2022; 127:474-487. [PMID: 35484214 PMCID: PMC9345968 DOI: 10.1038/s41416-022-01825-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/03/2022] [Accepted: 04/07/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-catenin pathway in oesophageal squamous cell carcinoma (ESCC). METHODS The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. CONCLUSIONS HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway.
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Affiliation(s)
- Kang Tang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Haruhito Sakata
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Satoshi Endo
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroshi Suito
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masahiko Takahashi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Nobufumi Sekino
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ryota Otsuka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuya Kinoshita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Soichiro Hirasawa
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Jie Hu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaya Uesato
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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Barshidi A, Karpisheh V, Noukabadi FK, Kiani FK, Mohammadi M, Afsharimanesh N, Ebrahimi F, Kiaie SH, Navashenaq JG, Hojjat-Farsangi M, Zolbanin NM, Mahmoodpoor A, Hassannia H, Nami S, Jalali P, Jafari R, Jadidi-Niaragh F. Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model. Pharm Res 2022; 39:1851-1866. [PMID: 35715669 DOI: 10.1007/s11095-022-03297-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/18/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.
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Affiliation(s)
- Asal Barshidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Karpisheh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Fariba Karoon Kiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Mohammadi
- Department of Cell and Molecular Biology, School of Advanced Sciences, Islamic Azad University, Tehran Medical Branch, Tehran, , Iran
| | - Negin Afsharimanesh
- Department of Microbiology, Faculty of Basic Sciences, Hamedan Branch, Islamic Azad University, Hamedan, Iran
| | - Farbod Ebrahimi
- Nanoparticle Process Technology, Faculty of Engineering, University of Duisburg-Essen, Duisburg, Germany
| | - Seyed Hossein Kiaie
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Naime Majidi Zolbanin
- Experimental and Applied Pharmaceutical Sciences Research Center,, Urmia University of Medical Sciences, Urmia, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, , Urmia University of Medical Sciences, Urmia, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, School of Medicine, Imam Reza Medical Research & Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Hassannia
- Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sanam Nami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pooya Jalali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Jafari
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Kim I, Choi S, Yoo S, Lee M, Kim IS. Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14143321. [PMID: 35884382 PMCID: PMC9320406 DOI: 10.3390/cancers14143321] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/30/2022] [Accepted: 07/05/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Cancers have regions of low oxygen concentration where hypoxia-related signaling pathways are activated. The hypoxic tumor microenvironment has been widely accepted as a hallmark of cancer and shown to be a critical factor in the crosstalk between cancer and stromal cells. Fibroblasts are one of the most abundant cellular components in the tumor stroma and are also significantly affected by oxygen deprivation. In this case, we discuss the molecular and cellular mechanisms that regulate fibroblasts under hypoxic conditions and their effect on cancer development and progression. Unraveling these regulatory mechanisms could be exploited in developing potential fibroblast-specific therapeutics for cancer. Abstract Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment. CAFs are highly sensitive to hypoxia and participates in the crosstalk with cancer cells. Hypoxic CAFs modulate several mechanisms that induce cancer malignancy, such as extracellular matrix (ECM) remodeling, immune evasion, metabolic reprogramming, angiogenesis, metastasis, and drug resistance. Key signaling molecules regulating CAFs in hypoxia include transforming growth factor (TGF-β) and hypoxia-inducible factors (HIFs). In this article, we summarize the mechanisms underlying the hypoxic regulation of CAFs and how hypoxic CAFs affect cancer development and progression. We also discuss the potential therapeutic strategies focused on targeting CAFs in the hypoxic tumor microenvironment.
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Affiliation(s)
- Iljin Kim
- Department of Pharmacology and Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, Korea; (S.C.); (S.Y.)
- Correspondence: (I.K.); (I.-S.K.)
| | - Sanga Choi
- Department of Pharmacology and Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, Korea; (S.C.); (S.Y.)
| | - Seongkyeong Yoo
- Department of Pharmacology and Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, Korea; (S.C.); (S.Y.)
| | - Mingyu Lee
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - In-San Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute Science and Technology, Seoul 02792, Korea
- Correspondence: (I.K.); (I.-S.K.)
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Yamada T, Toyoda T, Matsushita K, Akane H, Morikawa T, Cho YM, Ogawa K. Persistent γ-H2AX formation and expression of stem cell markers in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats. Toxicol Sci 2022; 189:51-61. [PMID: 35771629 DOI: 10.1093/toxsci/kfac064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We investigated γ-H2AX formation, a biomarker of DNA damage, and expression of stem cell markers (SCMs), including cytokeratin 14, aldehyde dehydrogenase 1A1 (ALDH1A1), and CD44, in the development of rat bladder tumors induced by short-term administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Histopathological examination showed that diffuse simple hyperplasia of the bladder urothelium induced by BBN recovered to the normal-appearing urothelium after withdrawal, whereas focal proliferative lesions were newly developed and subsequently progressed to benign papilloma and carcinoma. Immunohistochemical analysis revealed that BBN-induced γ-H2AX formation and ALDH1A1 and CD44 expression persisted at higher levels in the normal-appearing urothelium than those in the control group for long periods after withdrawal. Since persistent chronic inflammation was observed even after withdrawal, targeted gene expression analysis of inflammation-related factors revealed 101 genes, including Stat3 and Myc, that showed persistent high expression. Pathway analysis suggested that Stat3 and/or Myc activation may be associated with SCM expression. We focused on hepatocyte growth factor (Hgf), one of the genes predicted in relation to Stat3/Myc, and confirmed that HGF-positive cells increased by BBN persisted in the normal-appearing urothelium after withdrawal and colocalized with γ-H2AX and SCMs. These results suggested that the long-term persistence of γ-H2AX formation and SCM expression, which occurred during the early stages of bladder tumorigenesis, is not a transient response to exposure and might contribute to bladder tumorigenesis. Although further studies are needed, BBN-induced rat bladder tumors may originate from focal hyperplasia arising from SCM-positive cells via activation of the STAT3/MYC pathway after DNA damage involving γ-H2AX formation.
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Affiliation(s)
- Takanori Yamada
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan.,Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Takeshi Toyoda
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Kohei Matsushita
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Hirotoshi Akane
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Tomomi Morikawa
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Young-Man Cho
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Kumiko Ogawa
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
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Giuli MV, Mancusi A, Giuliani E, Screpanti I, Checquolo S. Notch signaling in female cancers: a multifaceted node to overcome drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:805-836. [PMID: 35582386 PMCID: PMC8992449 DOI: 10.20517/cdr.2021.53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022]
Abstract
Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.
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Affiliation(s)
- Maria V Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Angelica Mancusi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Eugenia Giuliani
- Scientific Direction, San Gallicano Dermatological Institute IRCCS, Rome 00144, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina 04100, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy
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Zhang J, Du C, Zhang L, Wang Y, Zhang Y, Li J. LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex. Cell Cycle 2022; 21:1034-1047. [PMID: 35188449 PMCID: PMC9037445 DOI: 10.1080/15384101.2022.2040283] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.
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Affiliation(s)
- Jianhua Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Chuang Du
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Linfeng Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Yan Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Yingying Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Jingruo Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Henan, China,CONTACT Jingruo Li Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, Henan Province450000, People’s Republic of China
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Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer. Biomolecules 2022; 12:biom12030418. [PMID: 35327609 PMCID: PMC8946555 DOI: 10.3390/biom12030418] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/05/2022] [Accepted: 03/06/2022] [Indexed: 12/17/2022] Open
Abstract
The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.
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40
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Wang B, Liu L, Wu J, Mao X, Fang Z, Chen Y, Li W. Construction and Verification of a Combined Hypoxia and Immune Index for Clear Cell Renal Cell Carcinoma. Front Genet 2022; 13:711142. [PMID: 35222525 PMCID: PMC8863964 DOI: 10.3389/fgene.2022.711142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive malignancies in humans. Hypoxia-related genes are now recognized as a reflection of poor prognosis in cancer patients with cancer. Meanwhile, immune-related genes play an important role in the occurrence and progression of ccRCC. Nevertheless, reliable prognostic indicators based on hypoxia and immune status have not been well established in ccRCC. The aims of this study were to develop a new gene signature model using bioinformatics and open databases and to validate its prognostic value in ccRCC. The data used for the model structure can be accessed from The Cancer Genome Atlas database. Univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were used to identify the hypoxia- and immune-related genes associated with prognostic risk, which were used to develop a characteristic model of prognostic risk. Kaplan-Meier and receiver-operating characteristic curve analyses were performed as well as independent prognostic factor analyses and correlation analyses of clinical characteristics in both the training and validation cohorts. In addition, differences in tumor immune cell infiltrates were compared between the high and low risk groups. Overall, 30 hypoxia- and immune-related genes were identified, and five hypoxia- and immune-related genes (EPO, PLAUR, TEK, TGFA, TGFB1) were ultimately selected. Survival analysis showed that the high-risk score on the hypoxia- and immune-related gene signature was significantly associated with adverse survival outcomes. Furthermore, clinical ccRCC samples from our medical center were used to validate the differential expression of the five genes in tumor tissue compared to normal tissue through quantitative real-time polymerase chain reaction (qRT-PCR). However, more clinical trials are needed to confirm these results, and future experimental studies must verify the potential mechanism behind the predictive value of the hypoxia- and immune-related gene signature.
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Affiliation(s)
- Bin Wang
- Department of Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lixiao Liu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinting Wu
- Department of Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaolu Mao
- Department of Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhen Fang
- Department of Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yingyu Chen
- Department of Neurosurgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wenfeng Li
- Department of Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wenfeng Li,
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Kheshti AMS, Hajizadeh F, Barshidi A, Rashidi B, Ebrahimi F, Bahmanpour S, Karpisheh V, Noukabadi FK, Kiani FK, Hassannia H, Atyabi F, Kiaie SH, Kashanchi F, Navashenaq JG, Mohammadi H, Bagherifar R, Jafari R, Zolbanin NM, Jadidi-Niaragh F. Combination Cancer Immunotherapy with Dendritic Cell Vaccine and Nanoparticles Loaded with Interleukin-15 and Anti-beta-catenin siRNA Significantly Inhibits Cancer Growth and Induces Anti-Tumor Immune Response. Pharm Res 2022; 39:353-367. [PMID: 35166995 DOI: 10.1007/s11095-022-03169-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE The invention and application of new immunotherapeutic methods can compensate for the inefficiency of conventional cancer treatment approaches, partly due to the inhibitory microenvironment of the tumor. In this study, we tried to inhibit the growth of cancer cells and induce anti-tumor immune responses by silencing the expression of the β-catenin in the tumor microenvironment and transmitting interleukin (IL)-15 cytokine to provide optimal conditions for the dendritic cell (DC) vaccine. METHODS For this purpose, we used folic acid (FA)-conjugated SPION-carboxymethyl dextran (CMD) chitosan (C) nanoparticles (NPs) to deliver anti-β-catenin siRNA and IL-15 to cancer cells. RESULTS The results showed that the codelivery of β-catenin siRNA and IL-15 significantly reduced the growth of cancer cells and increased the immune response. The treatment also considerably stimulated the performance of the DC vaccine in triggering anti-tumor immunity, which inhibited tumor development and increased survival in mice in two different cancer models. CONCLUSIONS These findings suggest that the use of new nanocarriers such as SPION-C-CMD-FA could be an effective way to use as a novel combination therapy consisting of β-catenin siRNA, IL-15, and DC vaccine to treat cancer.
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MESH Headings
- Animals
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/chemistry
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/immunology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Drug Carriers
- Drug Compounding
- Female
- Gene Expression Regulation, Neoplastic
- Interleukin-15/administration & dosage
- Interleukin-15/chemistry
- Lymphocytes, Tumor-Infiltrating/immunology
- Magnetic Iron Oxide Nanoparticles
- Melanoma, Experimental/genetics
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Melanoma, Experimental/therapy
- Mice, Inbred BALB C
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- RNAi Therapeutics
- Skin Neoplasms/genetics
- Skin Neoplasms/immunology
- Skin Neoplasms/pathology
- Skin Neoplasms/therapy
- Tumor Burden/drug effects
- Tumor Microenvironment
- beta Catenin/genetics
- Mice
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Affiliation(s)
| | - Farnaz Hajizadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asal Barshidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bentolhoda Rashidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farbod Ebrahimi
- Nanoparticle Process Technology, Faculty of Engineering, University of Duisburg-Essen, Duisburg, Germany
| | - Simin Bahmanpour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Karpisheh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Fariba Karoon Kiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Hassannia
- Immunogenetic Research Center, Faculty of Medicine and Amol Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Atyabi
- Nanotechnology Research Centre, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Kiaie
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, Iran
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, Virginia, USA
| | | | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Rafieh Bagherifar
- Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, Iran
| | - Reza Jafari
- Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Hematology, Immune Cell Therapy, and Stem Cell Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Naime Majidi Zolbanin
- Hematology, Immune Cell Therapy, and Stem Cell Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
- Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran.
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ray SK, Mukherjee S. Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets. Curr Drug Targets 2022; 23:471-485. [PMID: 35021970 DOI: 10.2174/1389450123666220111114649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 11/22/2022]
Abstract
Cancer is now also reflected as a disease of the tumor microenvironment, primarily supposed to be a decontrolled genetic and cellular expression disease. Over the past two decades, significant and rapid progress has been made in recognizing the dynamics of the tumor's microenvironment and its contribution to influencing the response to various anti-cancer therapies and drugs. Modulations in the tumor microenvironment and immune checkpoint blockade are interesting in cancer immunotherapy and drug targets. Simultaneously, the immunotherapeutic strategy can be done by modulating the immune regulatory pathway; however, the tumor microenvironment plays an essential role in suppressing the antitumor's immunity by its substantial heterogeneity. Hypoxia inducible factor (HIF) is a significant contributor to solid tumor heterogeneity and a key stressor in the tumor microenvironment to drive adaptations to prevent immune surveillance. Checkpoint inhibitors here halt the ability of cancer cells to stop the immune system from activating, and in turn, amplify your body's immune system to help destroy cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways and important drugs involved are Ipilimumab and Nivolumab, mainly along with other drugs in this group. Targeting the hypoxic tumor microenvironment may provide a novel immunotherapy strategy, break down traditional cancer therapy resistance, and build the framework for personalized precision medicine and cancer drug targets. We hope that this knowledge can provide insight into the therapeutic potential of targeting Hypoxia and help to develop novel combination approaches of cancer drugs to increase the effectiveness of existing cancer therapies, including immunotherapy.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya pradesh-462020. India
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Wang P, Gong S, Liao B, Pan J, Wang J, Zou D, Zhao L, Xiong S, Deng Y, Yan Q, Wu N. HIF1α/HIF2α induces glioma cell dedifferentiation into cancer stem cells through Sox2 under hypoxic conditions. J Cancer 2022; 13:1-14. [PMID: 34976166 PMCID: PMC8692689 DOI: 10.7150/jca.54402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 11/04/2021] [Indexed: 11/25/2022] Open
Abstract
Objective: Our previous study showed that glioma stem-like cells could be induced to undergo dedifferentiation under hypoxic conditions, but the mechanism requires further study. HIF1α and HIF2α are the main molecules involved in the response to hypoxia, and Sox2, as a retroelement, plays an important role in the formation of induced pluripotent stem cells, especially in hypoxic microenvironments. Therefore, we performed a series of experiments to verify whether HIF1α, HIF2α and Sox2 regulated glioma cell dedifferentiation under hypoxic conditions. Materials and methods: Sphere formation by single glioma cells was observed, and CD133 and CD15 expression was compared between the normoxic and hypoxic groups. HIF1α, HIF2α, and Sox2 expression was detected using the CGGA database, and the correlation among HIF1α, HIF2α and Sox2 levels was analyzed. We knocked out HIF1α, HIF2α and Sox2 in glioma cells and cultured them under hypoxic conditions to detect CD133 and CD15 expression. The above cells were implanted into mouse brains to analyze tumor volume and survival time. Results: New spheres were formed from single glioma cells in 1% O2, but no spheres were formed in 21% O2. The cells cultured in 1% O2 highly expressed CD133 and CD15 and had a lower apoptosis rate. The CGGA database showed HIF1α and HIF2α expression in glioma. Knocking out HIF1α or HIF2α led to a decrease in CD133 and CD15 expression and inhibited sphere formation under hypoxic conditions. Moreover, tumor volume and weight decreased after HIF1α or HIF2α knockout with the same temozolomide treatment. Sox2 was also highly expressed in glioma, and there was a positive correlation between the HIF1α/HIF2α and Sox2 expression levels. Sox2 was expressed at lower levels after HIF1α or HIF2α was knocked out. Then, Sox2 was knocked out, and we found that CD133 and CD15 expression was decreased. Moreover, a lower sphere formation rate, higher apoptosis rate, lower tumor formation rate and longer survival time after temozolomide treatment were detected in the Sox2 knockout cells. Conclusion: In a hypoxic microenvironment, the HIF1α/HIF2α-Sox2 network induced the formation of glioma stem cells through the dedifferentiation of differentiated glioma cells, thus promoting glioma cell chemoresistance. This study demonstrates that both HIF1α and HIF2α, as genes upstream of Sox2, regulate the malignant progression of glioma through dedifferentiation.
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Affiliation(s)
- Pan Wang
- Chongqing Medical University, Chongqing 400016, China.,Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Sheng Gong
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Bin Liao
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Jinyu Pan
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Junwei Wang
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Dewei Zou
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Lu Zhao
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Shuanglong Xiong
- Department of Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China Correspondence: Dr. Nan Wu, mailing address: No. 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, P. R. China. Tel. and E-mail:
| | - Yangmin Deng
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Qian Yan
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
| | - Nan Wu
- Chongqing Medical University, Chongqing 400016, China.,Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China
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TARBP2 Suppresses Ubiquitin-Proteasomal Degradation of HIF-1α in Breast Cancer. Int J Mol Sci 2021; 23:ijms23010208. [PMID: 35008634 PMCID: PMC8745112 DOI: 10.3390/ijms23010208] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/23/2022] Open
Abstract
TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination–proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer.
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45
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Danielpour D, Corum S, Welford SM, Shankar E. Hypoxia represses early responses of prostate and renal cancer cells to YM155 independent of HIF-1α and HIF-2α. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 3:100076. [PMID: 35005610 PMCID: PMC8717246 DOI: 10.1016/j.crphar.2021.100076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 01/16/2023] Open
Abstract
The imidazolium compound Sepantronium Bromide (YM155) successfully promotes tumor regression in various pre-clinical models but has shown modest responses in human clinical trials. We provide evidence to support that the hypoxic milieu of tumors may limit the clinical usefulness of YM155. Hypoxia (1% O2) strongly (>16-fold) represses the cytotoxic activity of YM155 on prostate and renal cancer cells in vitro. Hypoxia also represses all early signaling responses associated with YM155, including activation of AMPK and retinoblastoma protein (Rb), inactivation of the mechanistic target of rapamycin complex 1 (mTORC1), inhibition of phospho-ribosomal protein S6 (rS6), and suppression of the expression of Cyclin Ds, Mcl-1 and Survivin. Cells pre-incubated with hypoxia for 24 h are desensitized to YM155 even when they are treated with YM155 under atmospheric oxygen conditions, supporting that cells at least temporarily retain hypoxia-induced resistance to YM155. We tested the role of hypoxia-inducible factor (HIF)-1α and HIF-2α in the hypoxia-induced resistance to YM155 by comparing responses of YM155 in VHL-proficient versus VHL-deficient RCC4 and 786-O renal cancer cells and silencing HIF expression in PC-3 prostate cancer cells. Those studies suggested that hypoxia-induced resistance to YM155 occurs independent of HIF-1α and HIF-2α. Moreover, the hypoxia mimetics deferoxamine and dimethyloxalylglycine, which robustly induce HIF-1α levels in PC-3 cells under atmospheric oxygen, did not diminish their early cellular responses to YM155. Collectively, our data support that hypoxia induces resistance of cells to YM155 through a HIF-1α and HIF-2α-independent mechanism. We hypothesize that a hypothetical hypoxia-inducer factor (HIF-X) represses early signaling responses to YM155.
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Affiliation(s)
- David Danielpour
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Urology, University Hospitals of Cleveland, Cleveland, OH, 44106, USA
| | - Sarah Corum
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Scott M. Welford
- Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Radiation Oncology, University of Miami, FL, 33136, USA
| | - Eswar Shankar
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH, 44106, USA
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Gu W, Hua Z, Li Z, Cai Z, Wang W, Guo K, Yuan F, Gao F, Chen H. Palladium cubes with Pt shell deposition for localized surface plasmon resonance enhanced photodynamic and photothermal therapy of hypoxic tumors. Biomater Sci 2021; 10:216-226. [PMID: 34843611 DOI: 10.1039/d1bm01406d] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Multifunctional phototherapy nanoagents for imaging-guided synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) are highly desirable in the field of solid tumor therapy. Nevertheless, the tumor microenvironment (TME) inherently associated with hypoxia significantly hampers the photodynamic effect of these multifunctional nanoagents. Herein, Pd nanocubes coated with an ultrathin Pt shell were prepared and further conjugated with fluorescein labeled and thiol functionalized polyethylene glycol (FITC-PEG-SH) (denoted as Pd@Pt-PEG). The deposition of a Pt shell on Pd nanocubes not only enhances the photothermal performance, exhibiting excellent hyperthermia outcomes and impressive photothermal (PT) imaging quality, but also leads to the formation of singlet oxygen (1O2) induced by plasmonic excitation. In the meantime, the catalytic activity of the Pt layer is enhanced by electronic coupling and the plasmonic effect, which induces the decomposition of endogenous overexpressed hydrogen peroxide (H2O2) in tumors to generate O2 for conquering TME and augmenting 1O2 generation for efficacious tumor cell apoptosis. The modification of FITC-PEG-SH improves the biocompatibility and provides outstanding fluorescence (FL) imaging properties. Upon NIR laser irradiation, Pd@Pt-PEG allows in situ O2 generation and dual-mode imaging-guided synergistic PTT/PDT that effectively kills hypoxic tumor cells, which makes it a promising nanotherapeutic agent for enhanced tumor therapy.
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Affiliation(s)
- Wenxiang Gu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China. .,Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
| | - Zhiyuan Hua
- Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
| | - Zheng Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China. .,Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
| | - Zhiheng Cai
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China.
| | - Wandong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China.
| | - Kaijin Guo
- Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
| | - Feng Yuan
- Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
| | - Fenglei Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China.
| | - Hongliang Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu 221002, People's Republic of China. .,Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Jiangsu 221002, People's Republic of China
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Fathi M, Bahmanpour S, Barshidi A, Rasouli H, Karoon Kiani F, Mahmoud Salehi Khesht A, Izadi S, Rashidi B, Kermanpour S, Mokhtarian R, Karpisheh V, Hassannia H, Mohammadi H, Jalili A, Jadidi-Niaragh F. Simultaneous blockade of TIGIT and HIF-1α induces synergistic anti-tumor effect and decreases the growth and development of cancer cells. Int Immunopharmacol 2021; 101:108288. [PMID: 34710844 DOI: 10.1016/j.intimp.2021.108288] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/11/2021] [Accepted: 10/18/2021] [Indexed: 01/19/2023]
Abstract
PURPOSE T-cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint that is overexpressed on both immune cells and some cancer cells. TIGIT can alter the anti-tumor responses inside the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a significant role in the TME and involves suppressing the anti-tumor responses. Under hypoxic conditions, HIF-1α can enhance the expression of different immune checkpoints. Accordingly, hypoxic TME and TIGIT overexpression cause cancer development. Thus, we decided to inhibit tumor cell expansion by inhibiting TIGIT and HIF-1α molecules and discovering the relationship between TIGIT and HIF-1α. METHODS In this research, we utilized superparamagnetic iron oxide-based NPs (SPIONs) combined with chitosan lactate (CL) and folic acid (FA) nanoparticles (NPs) loaded with TIGIT-siRNA and HIF-1α- siRNA for suppressing TIGIT and HIF-1α in tumor cells and evaluated the consequences of this treatment strategy on tumor growth, apoptosis, and metastasis. RESULTS The results showed that cancer cells treated with TIGIT and HIF-1α siRNA-loaded SPIONs-CL-FA NPs, strongly suppressed the TIGIT and HIF-1α expression, colony formation ability, angiogenesis, and the growth rate of cancer cells. CONCLUSIONS Present data suggest the combination treatment of TIGIT and HIF-1α as a novel treatment strategy against colorectal and breast cancer, but more researches are required to realize the complete role of TIGIT and HIF-1α inside the TME.
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Affiliation(s)
- Mehrdad Fathi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran; Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Simin Bahmanpour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asal Barshidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Rasouli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Karoon Kiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sepideh Izadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bentolhoda Rashidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shiva Kermanpour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roya Mokhtarian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Karpisheh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Hassannia
- Immunogenetic Research Center, Faculty of Medicine and Amol Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ali Jalili
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Liu H, Wan J, Feng Q, Li J, Liu J, Cui S. Long non-coding RNA SOS1-IT1 promotes endometrial cancer progression by regulating hypoxia signaling pathway. J Cell Commun Signal 2021; 16:253-270. [PMID: 34637090 DOI: 10.1007/s12079-021-00651-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/03/2021] [Indexed: 12/18/2022] Open
Abstract
Endometrial cancer (EC) is one of the most common types of gynecological cancer. Hypoxia is an important clinical feature and regulates various tumor processes. However, the prognostic value of hypoxia-related lncRNA in EC remains to be further elucidated. Here, we aimed to characterize the molecular features of EC by the development of a classification system based on the expression profile of hypoxia-related lncRNA. Based on univariate Cox regression analysis, we identified 17 hypoxia-related lncRNAs significantly associated with overall survival. Next, the least absolute shrinkage and selection operator Cox regression model was utilized to construct a multigene signature in the TCGA EC cohort. The risk score was confirmed as an independent predictor for overall survival in multivariate Cox regression analysis and receiver operating characteristic (ROC) curve analysis. Besides, the survival time of EC patients in different risk group was significantly correlated to clinicopathologic factors, such as age, stage and grade. Furthermore, hypoxia-related lncRNA associated with the high-risk group were involved in various aspects of the malignant progression of EC via Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and Gene Set Enrichment Analysis. Moreover, the risk score was closely correlated to immunotherapy response, microsatellite instability and tumor mutation burden. Finally, we select one hypoxia-related lncRNA SOS1-IT1 to validate its role in hypoxia and EC progression. Interestingly, we found SOS1-IT1 was overexpressed in tumor tissues, and closely correlated with clinicopathological parameters of EC. The expression level of SOS1-IT1 was significantly increased under hypoxia condition. Additionally, the important hypoxia regulatory factor HIF-1α can directly bind SOS1-IT1 promoter region, and affect its expression level. In summary, this study established a new EC classification based on the hypoxia-related lncRNA signature, thereby provide a novel sight to understand the potential mechanism of human EC development.
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Affiliation(s)
- Hongyang Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Junhu Wan
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Quanling Feng
- Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jingyu Li
- Department of Neurology, Yuzhou People's Hospital, Yuzhou, 461670, Henan, China
| | - Jun Liu
- Department of General Surgery, Shangqiu Medical College, Zhecheng People's Hospital, Shangqiu, 476000, Henan, China
| | - Shihong Cui
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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49
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Du P, Luo K, Li G, Zhu J, Xiao Q, Li Y, Zhang X. Long non-coding RNA VCAN-AS1 promotes the malignant behaviors of breast cancer by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. Bioengineered 2021; 12:5028-5044. [PMID: 34365889 PMCID: PMC8806652 DOI: 10.1080/21655979.2021.1960774] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
An accumulating number of studies have found that long noncoding RNAs (lncRNAs) participate in breast cancer (BC) development. LncRNA VCAN-AS1, a novel lncRNA, has been confirmed to regulate the progression of gastric cancer, while its role in BC is elusive. Here, our results illustrate that VCAN-AS1 is overexpressed in BC tissues and cells, while miR-106a-5p was downregulated and negatively correlated with VCAN-AS1. In addition, high VCAN-AS1 expression and low miR-106a-5p expression were closely correlated with poor overall survival in BC patients. Functional experiments confirmed that VCAN-AS1 overexpression notably accelerated BC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) and enhanced tumor cell growth while also suppressing cell apoptosis. However, overexpression of miR-106a-5p had the opposite effects. In addition, rescue experiments confirmed that overexpression of VCAN-AS1 inhibited the tumor-suppressive effects mediated by miR-106a-5p. Mechanistically, through bioinformatics analysis, we found that VCAN-AS1 functions as a competitive endogenous RNA (ceRNA) of miR-106a-5p, which targets the 3ʹ untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3). Further experiments indicated that miR-106a-5p downregulated the STAT3/hypoxia-inducible factor-1alpha (HIF-1α) pathway, while activating the STAT3 pathway reversed miR-106a-5p-mediated antitumor effects. Collectively, our data suggest that VCAN-AS1 is upregulated in breast cancer and promotes its progression by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. This study provides a new target for BC therapy.
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Affiliation(s)
- Peng Du
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kaifeng Luo
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Guoyong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jisheng Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingjian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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50
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Wozny AS, Gauthier A, Alphonse G, Malésys C, Varoclier V, Beuve M, Brichart-Vernos D, Magné N, Vial N, Ardail D, Nakajima T, Rodriguez-Lafrasse C. Involvement of HIF-1α in the Detection, Signaling, and Repair of DNA Double-Strand Breaks after Photon and Carbon-Ion Irradiation. Cancers (Basel) 2021; 13:cancers13153833. [PMID: 34359734 PMCID: PMC8345054 DOI: 10.3390/cancers13153833] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/22/2021] [Accepted: 07/26/2021] [Indexed: 01/31/2023] Open
Abstract
Simple Summary Hypoxia-Inducible Factor 1α (HIF-1α), the main regulator of the oxygen homeostasis, promotes cancer cell survival through proliferation, angiogenesis, metastasis and radioresistance. Previously, our group demonstrated that silencing HIF-1α under hypoxia leads to a substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and carbon-ions, probably resulting from an accumulation of deleterious complex DNA damage. In this study, we aimed at determining the potential role of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, under hypoxia, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). Silencing HIF-1α under hypoxia led us to demonstrate the involvement of this transcriptional regulator in DSB repair in non-CSCS and CSC, thus highlighting its targeting together with radiation as a promising therapeutic strategy against radioresistant tumor cells in hypoxic niches. Abstract Hypoxia-Inducible Factor 1α (HIF-1α), which promotes cancer cell survival, is the main regulator of oxygen homeostasis. Hypoxia combined with photon and carbon ion irradiation (C-ions) stabilizes HIF-1α. Silencing HIF-1α under hypoxia leads to substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and C-ions. Thus, this study aimed to clarify a potential involvement of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). After confirming the nucleoshuttling of HIF-1α in response to both exposure under hypoxia, we showed that silencing HIF-1α in non-CSCs and CSCs decreased the initiation of the DSB detection (P-ATM), and increased the residual phosphorylated H2AX (γH2AX) foci. While HIF-1α silencing did not modulate 53BP1 expression, P-DNA-PKcs (NHEJ-c) and RAD51 (HR) signals decreased. Altogether, our experiments demonstrate the involvement of HIF-1α in the detection and signaling of DSBs, but also in the main repair pathways (NHEJ-c and HR), without favoring one of them. Combining HIF-1α silencing with both types of radiation could therefore present a potential therapeutic benefit of targeting CSCs mostly present in tumor hypoxic niches.
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Affiliation(s)
- Anne-Sophie Wozny
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
| | - Arnaud Gauthier
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
| | - Gersende Alphonse
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
| | - Céline Malésys
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
| | - Virginie Varoclier
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
| | - Michael Beuve
- Univ Lyon, Lyon 1 University, UMR CNRS5822/IP2I, 69100 Villeurbanne, France;
| | - Delphine Brichart-Vernos
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
| | - Nicolas Magné
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Radiotherapy, Institute of Cancerology Lucien Neuwirth, 42270 Saint-Priest-en-Jarez, France
| | - Nicolas Vial
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Radiotherapy, Institute of Cancerology Lucien Neuwirth, 42270 Saint-Priest-en-Jarez, France
| | - Dominique Ardail
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
| | - Tetsuo Nakajima
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan;
| | - Claire Rodriguez-Lafrasse
- Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France; (A.-S.W.); (A.G.); (G.A.); (C.M.); (V.V.); (D.B.-V.); (N.M.); (N.V.); (D.A.)
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
- Correspondence: ; Tel.: +33-426-235-965
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