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Huang S, Zhu J, Yu L, Huang Y, Hu Y. Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities. Mol Cancer 2025; 24:133. [PMID: 40320550 PMCID: PMC12051345 DOI: 10.1186/s12943-025-02336-4] [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: 02/20/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
A growing body of research suggests a bidirectional interaction between cancer and the nervous system. Neural cells exert their effects on tumors by secreting neurotransmitters and cell adhesion molecules, which interact with specific receptors on tumor cells to modulate their behavior. Conversely, tumor-secreted factors, particularly including inflammatory factors, can alter neural activity and increase neuronal excitability, potentially contributing to neurological manifestations such as epilepsy. The immune system also serves as a crucial intermediary in the indirect communication between cancer and the nervous system. These insights have opened promising avenues for novel therapeutic strategies targeting both tumors and their associated neurological complications. In this review, we have synthesized the key biological mechanisms underlying cancer-nervous system interactions that have emerged over the past decade. We outline the molecular and cellular pathways mediating this cross-talk and explore the clinical implications of targeting the nervous system to suppress tumor growth and metastasis, mitigate neurological complications arising from cancer progression, and modulate the immune response through neural regulation in the context of cancer therapy.
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Affiliation(s)
- Sirui Huang
- School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Jing Zhu
- School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Linglu Yu
- School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Yan Huang
- Department of Ultrasound, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.
| | - Yue Hu
- School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
- Department of Neurology, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Jiangsu, Nanjing, 210001, China.
- Shen Chun-Ti Nation-Famous Experts Studio for Traditional Chinese Medicine Inheritance, Changzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, 213003, Changzhou, China.
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Wang R, Dong X, Zhang X, Liao J, Cui W, Li W. Exploring viral mimicry combined with epigenetics and tumor immunity: new perspectives in cancer therapy. Int J Biol Sci 2025; 21:958-973. [PMID: 39897033 PMCID: PMC11781167 DOI: 10.7150/ijbs.103877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/20/2024] [Indexed: 02/04/2025] Open
Abstract
Viral mimicry refers to an active antiviral response triggered by the activation of endogenous retroviruses (ERVs), usually manifested by the formation of double-stranded RNA (dsRNA) and activation of the cellular interferon response, which activates the immune system and produces anti-tumor effects. Epigenetic studies have shown that epigenetic modifications (e.g. DNA methylation, histone modifications, etc.) play a crucial role in tumorigenesis, progression, and treatment resistance. Particularly, alterations in DNA methylation may be closely associated with the suppression of ERVs expression, and treatment by demethylation may restore ERVs activity and thus strengthen the tumor immune response. Therefore, we propose that viral mimicry can induce immune responses in the tumor microenvironment by activating the expression of ERVs, and that epigenetic alterations may play a key regulatory role in this process. In this paper, we review the intersection of viral mimicry, epigenetics and tumor immunotherapy, and explore the possible interactions and synergistic effects among the three, aiming to provide a new theoretical basis and potential strategies for cancer immunotherapy.
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Affiliation(s)
- Ruirui Wang
- Department of Radiology, The Third Xiangya Hospital of Central South University. Tongzipo Road 138, Changsha, Hunan, People's Republic of China
| | - Xin Dong
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiongjian Zhang
- Department of Radiology, The Third Xiangya Hospital of Central South University. Tongzipo Road 138, Changsha, Hunan, People's Republic of China
| | - Jinzhuang Liao
- Department of Radiology, The Third Xiangya Hospital of Central South University. Tongzipo Road 138, Changsha, Hunan, People's Republic of China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Li
- Department of Radiology, The Third Xiangya Hospital of Central South University. Tongzipo Road 138, Changsha, Hunan, People's Republic of China
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Li Y, Wu S, Huang J, Zhao L. Integrated miRNA-seq and functional analyses reveal the regulatory role of sha-miR-92a_L + 2R + 4 via targeting vegfaa in rainbow trout (Oncorhynchus mykiss) responding to acute hypoxia and reoxygenation stress. BMC Genomics 2024; 25:1163. [PMID: 39623322 PMCID: PMC11610304 DOI: 10.1186/s12864-024-11019-1] [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: 01/08/2024] [Accepted: 11/08/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Hypoxia negatively affects the behavior, growth, reproduction and survival of fish, causing serious economic losses to aquaculture. Rainbow trout (Oncorhynchus mykiss), an important economic fish worldwide, belongs to a hypoxia-sensitive fish species, however, little is known about the regulatory mechanism of microRNAs (miRNAs) under hypoxia stress. RESULTS Rainbow trout were subjected to hypoxia stress for 3 h (H3h_L), 12 h (H12h_L), 24 h (H24h_L) and 3 h reoxygenation (R3h_L) to systemically evaluate the changes of miRNA expression profiles in liver, and functions of sha-miR-92a_L + 2R + 4 were investigated. We found 17, 144, 57 and 55 differentially expressed (DE) miRNAs in the H3h_L vs. control (N_L), H12h_L vs. N_L, H24h_L vs. N_L and R3h_L vs. N_L comparisons, respectively. Enrichment analysis revealed that the targets of DE miRNAs were significantly enriched in HIF signaling pathway, VEGF signaling pathway, FoxO signaling pathway and glycolysis/gluconeogenesis. Through miRNA-mRNA interaction and weighted gene co-expression network analysis (WGCNA), five key DE miRNAs (sha-miR-92a_L + 2R + 4, ssa-miR-128-3p, ssa-miR-101b-3p_R + 1, ola-miR-199a-5p_R + 2 and tni-miR-199_1ss18CG) were identified, which can target at least two hypoxia-responsive genes, such as vegfaa, ho, glut1a and junb. Functional analysis found that sha-miR-92a_L + 2R + 4 directly regulated vegfaa expression by targeting its 3'-UTR, overexpression of sha-miR-92a_L + 2R + 4 significantly decreased vegfaa expression in rainbow trout liver cells, while opposite results were obtained after transfection of sha-miR-92a_L + 2R + 4 inhibitor. Furthermore, overexpressed sha-miR-92a_L + 2R + 4 promoted rainbow trout liver cell proliferation and inhibited apoptosis. CONCLUSION This study deepens our understanding of the crucial roles of miRNAs under hypoxia stress in rainbow trout. These results can contribute to devise strategies for improving rainbow trout survival rate and aquaculture production during hypoxia stress and help speeding up the selective breeding of hypoxia-tolerant rainbow trout.
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Affiliation(s)
- Yongjuan Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
- College of Science, Gansu Agricultural University, Lanzhou, 730070, China
| | - Shenji Wu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jinqiang Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China.
| | - Lu Zhao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
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4
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He J, Yu Y, Liu W, Li Z, Qi Z, Weng S, Guo C, He J. Molecular mechanism of infectious spleen and kidney necrosis virus in manipulating the hypoxia-inducible factor pathway to augment virus replication. Virulence 2024; 15:2349027. [PMID: 38680083 PMCID: PMC11085990 DOI: 10.1080/21505594.2024.2349027] [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: 01/08/2024] [Accepted: 03/28/2024] [Indexed: 05/01/2024] Open
Abstract
Infectious spleen and kidney necrosis virus (ISKNV), a member of the genus Megalocytivirus in the family Iridoviridae, can infect over 50 fish species and cause significant economic losses in Asia. Our previous study showed that hypoxia triggers the hypoxia-inducible factor pathway (HIF-pathway), leading to increased replication of ISKNV through promoting the upregulation of viral hypoxic response genes like orf077r. This study delved into the molecular mechanism of how ISKNV manipulates the HIF-pathway to enhance its replication. In vitro and in vivo experiments confirmed that ISKNV infection activated the HIF-pathway, which in turn promoted ISKNV replication. These findings suggest that ISKNV actively manipulates the HIF-pathway. Co-immunoprecipitation experiments revealed that the ISKNV-encoded protein VP077R interacts with the Von Hippel-Lindau (VHL) protein at the HIF-binding region, competitively inhibiting the interaction of HIF-1α with VHL. This prevents HIF degradation and activates the HIF-pathway. Furthermore, VP077R interacts with factor-inhibiting HIF (FIH), recruiting FIH and S-phase kinase-associated protein 1 (Skp1) to form an FIH - VP077R - Skp1 complex. This complex promotes FIH protein degradation via ubiquitination, further activating the HIF-pathway. These findings indicated that ISKNV takes over the HIF-pathway by releasing two "brakes" on this pathway (VHL and FIH) via VP077R, facilitating virus replication. We speculate that hypoxia initiates a positive feedback loop between ISKNV VP077R and the HIF pathway, leading to the outbreak of ISKNV disease. This work offers valuable insights into the complex interactions between the environment, host, and virus.
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Affiliation(s)
- Jian He
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Yang Yu
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Wenhui Liu
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Zhimin Li
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Zhang Qi
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Shaoping Weng
- Guangdong Province Key Laboratory of Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China
| | - Changjun Guo
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Province Key Laboratory of Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China
| | - Jianguo He
- State Key Laboratory for Biocontrol/Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Guangdong Provincial Observation and Research Station for Marine Ranching of the Lingdingyang Bay, School of Marine Sciences, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Province Key Laboratory of Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, PR China
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Bou-Gharios J, Noël G, Burckel H. The neglected burden of chronic hypoxia on the resistance of glioblastoma multiforme to first-line therapies. BMC Biol 2024; 22:278. [PMID: 39609830 PMCID: PMC11603919 DOI: 10.1186/s12915-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/21/2024] [Indexed: 11/30/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.
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Affiliation(s)
- Jolie Bou-Gharios
- Institut de Cancérologie Strasbourg Europe (ICANS), Radiobiology Laboratory, 3 Rue de La Porte de L'Hôpital, Strasbourg, 67000, France
- Laboratory of Engineering, Informatics and Imaging (ICube), UMR 7357, Integrative Multimodal Imaging in Healthcare (IMIS), University of Strasbourg, 4 Rue Kirschleger, Strasbourg, 67000, France
| | - Georges Noël
- Institut de Cancérologie Strasbourg Europe (ICANS), Radiobiology Laboratory, 3 Rue de La Porte de L'Hôpital, Strasbourg, 67000, France
- Laboratory of Engineering, Informatics and Imaging (ICube), UMR 7357, Integrative Multimodal Imaging in Healthcare (IMIS), University of Strasbourg, 4 Rue Kirschleger, Strasbourg, 67000, France
- Institut de Cancérologie Strasbourg Europe (ICANS), Department of Radiation Oncology, UNICANCER, 17 Rue Albert Calmette, Strasbourg, 67200, France
| | - Hélène Burckel
- Institut de Cancérologie Strasbourg Europe (ICANS), Radiobiology Laboratory, 3 Rue de La Porte de L'Hôpital, Strasbourg, 67000, France.
- Laboratory of Engineering, Informatics and Imaging (ICube), UMR 7357, Integrative Multimodal Imaging in Healthcare (IMIS), University of Strasbourg, 4 Rue Kirschleger, Strasbourg, 67000, France.
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Konigorski S, Janke J, Patone G, Bergmann MM, Lippert C, Hübner N, Kaaks R, Boeing H, Pischon T. Identification of novel genes whose expression in adipose tissue affects body fat mass and distribution: an RNA-Seq and Mendelian Randomization study. Eur J Hum Genet 2024; 32:1127-1135. [PMID: 35953519 PMCID: PMC11369295 DOI: 10.1038/s41431-022-01161-3] [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: 02/09/2022] [Revised: 06/26/2022] [Accepted: 07/19/2022] [Indexed: 10/15/2022] Open
Abstract
Many studies have shown that abdominal adiposity is more strongly related to health risks than peripheral adiposity. However, the underlying pathways are still poorly understood. In this cross-sectional study using data from RNA-sequencing experiments and whole-body MRI scans of 200 participants in the EPIC-Potsdam cohort, our aim was to identify novel genes whose gene expression in subcutaneous adipose tissue has an effect on body fat mass (BFM) and body fat distribution (BFD). The analysis identified 625 genes associated with adiposity, of which 531 encode a known protein and 487 are novel candidate genes for obesity. Enrichment analyses indicated that BFM-associated genes were characterized by their higher than expected involvement in cellular, regulatory and immune system processes, and BFD-associated genes by their involvement in cellular, metabolic, and regulatory processes. Mendelian Randomization analyses suggested that the gene expression of 69 genes was causally related to BFM and BFD. Six genes were replicated in UK Biobank. In this study, we identified novel genes for BFM and BFD that are BFM- and BFD-specific, involved in different molecular processes, and whose up-/downregulated gene expression may causally contribute to obesity.
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Affiliation(s)
- Stefan Konigorski
- Digital Health & Machine Learning Research Group, Hasso Plattner Institute for Digital Engineering, University of Potsdam, Potsdam, Germany.
- Molecular Epidemiology Research Group, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Jürgen Janke
- Molecular Epidemiology Research Group, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Giannino Patone
- Genetics and Genomics of Cardiovascular Diseases Research Group, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Manuela M Bergmann
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Christoph Lippert
- Digital Health & Machine Learning Research Group, Hasso Plattner Institute for Digital Engineering, University of Potsdam, Potsdam, Germany
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Norbert Hübner
- Genetics and Genomics of Cardiovascular Diseases Research Group, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- DZHK (German Center for Cardiovascular Research) partner site Berlin, Berlin, Germany
- Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Rudolf Kaaks
- Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heiner Boeing
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Tobias Pischon
- Molecular Epidemiology Research Group, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
- DZHK (German Center for Cardiovascular Research) partner site Berlin, Berlin, Germany.
- Charité Universitätsmedizin Berlin, Berlin, Germany.
- MDC Biobank, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany.
- BIH Biobank, Berlin Institute of Health, Berlin, Germany.
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Begagić E, Bečulić H, Džidić-Krivić A, Kadić Vukas S, Hadžić S, Mekić-Abazović A, Šegalo S, Papić E, Muchai Echengi E, Pugonja R, Kasapović T, Kavgić D, Nuhović A, Juković-Bihorac F, Đuričić S, Pojskić M. Understanding the Significance of Hypoxia-Inducible Factors (HIFs) in Glioblastoma: A Systematic Review. Cancers (Basel) 2024; 16:2089. [PMID: 38893207 PMCID: PMC11171068 DOI: 10.3390/cancers16112089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/25/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND The study aims to investigate the role of hypoxia-inducible factors (HIFs) in the development, progression, and therapeutic potential of glioblastomas. METHODOLOGY The study, following PRISMA guidelines, systematically examined hypoxia and HIFs in glioblastoma using MEDLINE (PubMed), Web of Science, and Scopus. A total of 104 relevant studies underwent data extraction. RESULTS Among the 104 studies, global contributions were diverse, with China leading at 23.1%. The most productive year was 2019, accounting for 11.5%. Hypoxia-inducible factor 1 alpha (HIF1α) was frequently studied, followed by hypoxia-inducible factor 2 alpha (HIF2α), osteopontin, and cavolin-1. Commonly associated factors and pathways include glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) receptors, vascular endothelial growth factor (VEGF), phosphoinositide 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway, and reactive oxygen species (ROS). HIF expression correlates with various glioblastoma hallmarks, including progression, survival, neovascularization, glucose metabolism, migration, and invasion. CONCLUSION Overcoming challenges such as treatment resistance and the absence of biomarkers is critical for the effective integration of HIF-related therapies into the treatment of glioblastoma with the aim of optimizing patient outcomes.
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Affiliation(s)
- Emir Begagić
- Department of General Medicine, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Hakija Bečulić
- Department of Neurosurgery, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina;
- Department of Anatomy, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Amina Džidić-Krivić
- Department of Neurology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina (S.K.V.)
| | - Samra Kadić Vukas
- Department of Neurology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina (S.K.V.)
| | - Semir Hadžić
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Alma Mekić-Abazović
- Department of Oncology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Sabina Šegalo
- Department of Laboratory Technologies, Faculty of Health Studies, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; (S.Š.); (E.P.)
| | - Emsel Papić
- Department of Laboratory Technologies, Faculty of Health Studies, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; (S.Š.); (E.P.)
| | - Emmanuel Muchai Echengi
- College of Health Sciences, School of Medicine, Kenyatta University, Nairobi 43844-00100, Kenya
| | - Ragib Pugonja
- Department of Anatomy, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina
| | - Tarik Kasapović
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Dalila Kavgić
- Department of Physiology, Faculty of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina
| | - Adem Nuhović
- Department of General Medicine, School of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina;
| | - Fatima Juković-Bihorac
- Department of Pathology, Cantonal Hospital Zenica, 72000 Zenica, Bosnia and Herzegovina
- Department of Pathology, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina;
| | - Slaviša Đuričić
- Department of Pathology, School of Medicine, University of Zenica, 72000 Zenica, Bosnia and Herzegovina;
| | - Mirza Pojskić
- Department of Neurosurgery, University Hospital Marburg, 35033 Marburg, Germany
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Ren X, Deng D, Xiang S, Feng J. Promoter hypomethylated PDZK1 acts as a tumorigenic gene in glioma by interacting with AKT1. Aging (Albany NY) 2024; 16:7174-7187. [PMID: 38669103 PMCID: PMC11087087 DOI: 10.18632/aging.205750] [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: 11/15/2023] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
Glioma is the most frequently diagnosed primary brain tumor and typically has a poor prognosis because of malignant proliferation and invasion. It is urgent to elucidate the mechanisms driving glioma tumorigenesis and develop novel treatments to address this deadly disease. Here, we first revealed that PDZK1 is expressed at high levels in gliomas. Promoter hypomethylation may cause high expression of PDZK1 in glioma. Knockdown of PDZK1 inhibits glioma cell proliferation and invasion in vitro. Mechanistically, further investigations revealed that the loss of PDZK1 expression by siRNA inhibited the activation of the AKT/mTOR signaling pathway, leading to cell cycle arrest and apoptosis. Clinically, high expression of PDZK1 predicts a poorer prognosis for glioma patients than low expression of PDZK1. Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.
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Affiliation(s)
- Xing Ren
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Dan Deng
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Shasha Xiang
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
| | - Jianbo Feng
- Clinical Laboratory Medicine Center, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, P.R. China
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, P.R. China
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Chakraborty S, Nandi P, Mishra J, Niharika, Roy A, Manna S, Baral T, Mishra P, Mishra PK, Patra SK. Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation. Cancer Lett 2024; 587:216779. [PMID: 38458592 DOI: 10.1016/j.canlet.2024.216779] [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: 01/13/2024] [Revised: 02/19/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024]
Abstract
Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers.
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Affiliation(s)
- Subhajit Chakraborty
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Piyasa Nandi
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Jagdish Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Tirthankar Baral
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Prahallad Mishra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India
| | - Pradyumna Kumar Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bypass Road, Bhauri, Bhopal, 462 030, MP, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India.
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10
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Qin Y, Xiong S, Ren J, Sethi G. Autophagy machinery in glioblastoma: The prospect of cell death crosstalk and drug resistance with bioinformatics analysis. Cancer Lett 2024; 580:216482. [PMID: 37977349 DOI: 10.1016/j.canlet.2023.216482] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/01/2023] [Accepted: 11/03/2023] [Indexed: 11/19/2023]
Abstract
Brain tumors are common malignancies with high mortality and morbidity in which glioblastoma (GB) is a grade IV astrocytoma with heterogeneous nature. The conventional therapeutics for the GB mainly include surgery and chemotherapy, however their efficacy has been compromised due to the aggressiveness of tumor cells. The dysregulation of cell death mechanisms, especially autophagy has been reported as a factor causing difficulties in cancer therapy. As a mechanism contributing to cell homeostasis, the autophagy process is hijacked by tumor cells for the purpose of aggravating cancer progression and drug resistance. The autophagy function is context-dependent and its role can be lethal or protective in cancer. The aim of the current paper is to highlight the role of autophagy in the regulation of GB progression. The cytotoxic function of autophagy can promote apoptosis and ferroptosis in GB cells and vice versa. Autophagy dysregulation can cause drug resistance and radioresistance in GB. Moreover, stemness can be regulated by autophagy and overall growth as well as metastasis are affected by autophagy. The various interventions including administration of synthetic/natural products and nanoplatforms can target autophagy. Therefore, autophagy can act as a promising target in GB therapy.
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Affiliation(s)
- Yi Qin
- Department of Lab, Chifeng Cancer Hospital (The 2nd Afflicted Hospital of Chifeng University), Chifeng University, Chifeng City, Inner Mongolia Autonomous Region, 024000, China.
| | - Shengjun Xiong
- Department of Cardiology, Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology, Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, 16 Medical Drive, Singapore, 117600, Singapore.
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11
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Pan Y, Fu Y, Baird PN, Guymer RH, Das T, Iwata T. Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration. Prog Retin Eye Res 2023; 97:101159. [PMID: 36581531 DOI: 10.1016/j.preteyeres.2022.101159] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022]
Abstract
Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.
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Affiliation(s)
- Yang Pan
- Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1, Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan
| | - Yingbin Fu
- Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza, NC506, Houston, TX, 77030, USA
| | - Paul N Baird
- Department of Surgery, (Ophthalmology), Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia
| | - Robyn H Guymer
- Department of Surgery, (Ophthalmology), Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, East Melbourne, Victoria, 3002, Australia
| | - Taraprasad Das
- Anant Bajaj Retina Institute-Srimati Kanuri Santhamma Centre for Vitreoretinal Diseases, Kallam Anji Reddy Campus, L. V. Prasad Eye Institute, Hyderabad, 500034, India
| | - Takeshi Iwata
- Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1, Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan.
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12
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Jiang Y, Song S, Liu J, Zhang L, Guo X, Lu J, Li L, Yang C, Fu Q, Zeng B. Epigenetic regulation of programmed cell death in hypoxia-induced pulmonary arterial hypertension. Front Immunol 2023; 14:1206452. [PMID: 37753070 PMCID: PMC10518698 DOI: 10.3389/fimmu.2023.1206452] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 07/28/2023] [Indexed: 09/28/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a severe progressive disease that may cause early right ventricular failure and eventual cardiac failure. The pathogenesis of PAH involves endothelial dysfunction, aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs), and vascular fibrosis. Hypoxia has been shown to induce elevated secretion of vascular endothelial growth factor (VEGF), leading to the development of hypoxic PAH. However, the molecular mechanisms underlying hypoxic PAH remain incompletely understood. Programmed cell death (PCD) is a natural cell death and regulated by certain genes. Emerging evidence suggests that apoptotic resistance contributes to the development of PAH. Moreover, several novel types of PCD, such as autophagy, pyroptosis, and ferroptosis, have been reported to be involved in the development of PAH. Additionally, multiple diverse epigenetic mechanisms including RNA methylation, DNA methylation, histone modification, and the non-coding RNA molecule-mediated processes have been strongly linked to the development of PAH. These epigenetic modifications affect the expression of genes, which produce important changes in cellular biological processes, including PCD. Consequently, a better understanding of the PCD processes and epigenetic modification involved in PAH will provide novel, specific therapeutic strategies for diagnosis and treatment. In this review, we aim to discuss recent advances in epigenetic mechanisms and elucidate the role of epigenetic modifications in regulating PCD in hypoxia-induced PAH.
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Affiliation(s)
- Yuan Jiang
- College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China
| | - Shasha Song
- College of Pharmacy, Shenzhen Technology University, Shenzhen, China
| | - Jingxin Liu
- College of Pharmacy, Shenzhen Technology University, Shenzhen, China
| | - Liyuan Zhang
- Shanghai Baoxing Biological Equipment Engineering Co., Ltd, Shanghai, China
| | - Xiaofei Guo
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Jiayao Lu
- College of Pharmacy, Shenzhen Technology University, Shenzhen, China
| | - Lie Li
- Shenzhen Reyson Biotechnology Co., Ltd, Shenzhen, China
- Nanjing Evertop Electronics Ltd., Nanjing, China
| | - Chao Yang
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Qiang Fu
- College of Pharmacy, Shenzhen Technology University, Shenzhen, China
| | - Bin Zeng
- College of Pharmacy, Shenzhen Technology University, Shenzhen, China
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13
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Zhang Y, Sun Y, Hu Y, Zheng S, Shao H, Lin L, Pan Y, Li C. Porphyromonas gingivalis msRNA P.G_45033 induces amyloid-β production by enhancing glycolysis and histone lactylation in macrophages. Int Immunopharmacol 2023; 121:110468. [PMID: 37320870 DOI: 10.1016/j.intimp.2023.110468] [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: 03/10/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND High expression of amyloid-β (Aβ) in periodontal tissue could contribute to exacerbating the development of both periodontitis and Alzheimer's disease (AD). Porphyromonas gingivalis (P. gingivalis) as a periodontal pathogen expresses msRNAs, which can regulate gene transcription in host cells. OBJECTIVE The aim of this study is to reveal the mechanism of msRNA P.G_45033, a high copy msRNA in P. gingivalis, inducing Aβ expression in macrophages, and provide a new insight to explain the development of periodontitis, and also to explain the role of periodontal infection on AD. METHODS The levels of glucose consumption, pyruvate and lactate productions in macrophages after transfection with msRNA P.G_45033 were detected. Miranda, TargetScan, and RNAhybrid databases were used to predict the target gene of msRNA P.G_45033, and GO analysis was conducted to describe the functions of the overlapping ones. RT2 glucose-metabolism PCR Array was used to verify the relationship between msRNA P.G_45033 and the expression of genes related to glucose metabolism. The levels of histone Kla were detected using western blotting. The levels of Aβ in the macrophages and the culture medium were detected by immunofluorescence and ELISA, respectively. RESULTS The levels of glucose consumption, pyruvate and lactate productions were increased after transfection of msRNA P.G_45033 in macrophages. GO analysis revealed that target genes were enriched in the metabolic process. RT2 glucose-metabolism PCR Array showed the expression of genes associated with glycolysis. The results of western blotting showed that the level of histone Kla was increased in macrophages. The results of immunofluorescence and ELISA showed that Aβ levels in macrophages and culture medium were increased after transfection. CONCLUSION The present study revealed that msRNA P.G_45033 can induce Aβ production by enhancing glycolysis and histone Kla in macrophages.
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Affiliation(s)
- Yonghuan Zhang
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Yangyang Sun
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Ying Hu
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Shaowen Zheng
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Haigang Shao
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Li Lin
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China
| | - Yaping Pan
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China.
| | - Chen Li
- Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China; Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning, China.
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14
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Xu X, Peng Q, Jiang X, Tan S, Yang Y, Yang W, Han Y, Chen Y, Oyang L, Lin J, Xia L, Peng M, Wu N, Tang Y, Li J, Liao Q, Zhou Y. Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential. Exp Mol Med 2023; 55:1357-1370. [PMID: 37394582 PMCID: PMC10394076 DOI: 10.1038/s12276-023-01020-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 03/15/2023] [Accepted: 03/24/2023] [Indexed: 07/04/2023] Open
Abstract
Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.
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Affiliation(s)
- Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- University of South China, Hengyang, 421001, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yiqing Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Wenjuan Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yuyu Chen
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jinyun Li
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
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15
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Advanced Bioinformatics Analysis and Genetic Technologies for Targeting Autophagy in Glioblastoma Multiforme. Cells 2023; 12:cells12060897. [PMID: 36980238 PMCID: PMC10047676 DOI: 10.3390/cells12060897] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
As the most malignant primary brain tumor in adults, a diagnosis of glioblastoma multiforme (GBM) continues to carry a poor prognosis. GBM is characterized by cytoprotective homeostatic processes such as the activation of autophagy, capability to confer therapeutic resistance, evasion of apoptosis, and survival strategy even in the hypoxic and nutrient-deprived tumor microenvironment. The current gold standard of therapy, which involves radiotherapy and concomitant and adjuvant chemotherapy with temozolomide (TMZ), has been a game-changer for patients with GBM, relatively improving both overall survival (OS) and progression-free survival (PFS); however, TMZ is now well-known to upregulate undesirable cytoprotective autophagy, limiting its therapeutic efficacy for induction of apoptosis in GBM cells. The identification of targets utilizing bioinformatics-driven approaches, advancement of modern molecular biology technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)—CRISPR-associated protein (Cas9) or CRISPR-Cas9 genome editing, and usage of microRNA (miRNA)-mediated regulation of gene expression led to the selection of many novel targets for new therapeutic development and the creation of promising combination therapies. This review explores the current state of advanced bioinformatics analysis and genetic technologies and their utilization for synergistic combination with TMZ in the context of inhibition of autophagy for controlling the growth of GBM.
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16
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Cheng Y, Wang C, Wang H, Zhang Z, Yang X, Dong Y, Ma L, Luo J. Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy. BMC Med 2022; 20:411. [PMID: 36303207 PMCID: PMC9615197 DOI: 10.1186/s12916-022-02614-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. METHODS Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). RESULTS PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. CONCLUSIONS Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.
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Affiliation(s)
- Yibin Cheng
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China
| | - Caixia Wang
- Key Laboratory for the Synthesis and Application of Organic Functional Molecules, College of Chemistry and Chemical Engineering, Hubei University, Wuhan, 430062, P. R. China
| | - Huihui Wang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China
| | - Zhiwei Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China
| | - Xiaopeng Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China
| | - Yanming Dong
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China
| | - Lixin Ma
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China.
| | - Jingwen Luo
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan, 430062, P. R. China.
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17
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Guo W, Ma S, Zhang Y, Liu H, Li Y, Xu JT, Yang B, Guan F. Genome-wide methylomic analyses identify prognostic epigenetic signature in lower grade glioma. J Cell Mol Med 2021; 26:449-461. [PMID: 34894053 PMCID: PMC8743658 DOI: 10.1111/jcmm.17101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/19/2022] Open
Abstract
Glioma is the most malignant and aggressive type of brain tumour with high heterogeneity and mortality. Although some clinicopathological factors have been identified as prognostic biomarkers, the individual variants and risk stratification in patients with lower grade glioma (LGG) have not been fully elucidated. The primary aim of this study was to identify an efficient DNA methylation combination biomarker for risk stratification and prognosis in LGG. We conducted a retrospective cohort study by analysing whole genome DNA methylation data of 646 patients with LGG from the TCGA and GEO database. Cox proportional hazard analysis was carried out to screen and construct biomarker model that predicted overall survival (OS). The Kaplan‐Meier survival curves and time‐dependent ROC were constructed to prove the efficiency of the signature. Then, another independent cohort was used to further validate the finding. A two‐CpG site DNA methylation signature was identified by multivariate Cox proportional hazard analysis. Further analysis indicated that the signature was an independent survival predictor from other clinical factors and exhibited higher predictive accuracy compared with known biomarkers. This signature was significantly correlated with immune‐checkpoint blockade, immunotherapy‐related signatures and ferroptosis regulator genes. The expression pattern and functional analysis showed that these two genes corresponding with two methylation sites contained in the model were correlated with immune infiltration level, and involved in MAPK and Rap1 signalling pathway. The signature may contribute to improve the risk stratification of patients and provide a more accurate assessment for precision medicine in the clinic.
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Affiliation(s)
- Wenna Guo
- School of Life Sciences, Zhengzhou University, Zhengzhou, China.,School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ya Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Ji-Tian Xu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Bo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
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18
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Feng J, Ren X, Fu H, Li D, Chen X, Zu X, Liu Q, Wu M. LRRC4 mediates the formation of circular RNA CD44 to inhibitGBM cell proliferation. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:473-487. [PMID: 34631278 PMCID: PMC8479294 DOI: 10.1016/j.omtn.2021.08.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 08/20/2021] [Indexed: 11/19/2022]
Abstract
Mounting evidence reveals that dysregulation of circular RNAs (circRNAs) is involved in the development of glioblastoma. Leucine-rich repeat-containing 4 (LRRC4) has been shown to suppress tumors in glioblastoma. However, whether LRRC4 can regulate the formation of circRNA is not yet understood. In this study, LRRC4 was found to interact with SAM68. LRRC4 promoted the generation of circCD44 by inhibiting the binding between SAM68 and CD44 pre-mRNA. Moreover, downregulated expression of circCD44 was found in glioblastoma multiforme (GBM) tissues and GBM primary cells. Re-expression of circCD44 significantly suppressed the proliferation, colony formation, and invasion of GBM cells and inhibited tumor growth in vivo. Mechanistically, circCD44 could regulate the expression of SMAD6 via sponging miR-326 and miR-330-5p involved in the progression of GBM. Thus, the LRRC4/SAM68/circCD44/miR-326/miR-330-5p/SMAD6 signaling axis could be a potential target for GBM treatment.
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Affiliation(s)
- Jianbo Feng
- Cancer Research Institute, First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Xing Ren
- Cancer Research Institute, First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Haijuan Fu
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Di Li
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Xiguang Chen
- Cancer Research Institute, First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xuyu Zu
- Cancer Research Institute, First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Qing Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- Corresponding author: Qing Liu, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
| | - Minghua Wu
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
- Corresponding author: Minghua Wu, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
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19
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Pandey A, Yadav P, Shukla S. Unfolding the role of autophagy in the cancer metabolism. Biochem Biophys Rep 2021; 28:101158. [PMID: 34754952 PMCID: PMC8564564 DOI: 10.1016/j.bbrep.2021.101158] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/28/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Autophagy is considered an indispensable process that scavenges toxins, recycles complex macromolecules, and sustains the essential cellular functions. In addition to its housekeeping role, autophagy plays a substantial role in many pathophysiological processes such as cancer. Certainly, it adapts cancer cells to thrive in the stress conditions such as hypoxia and starvation. Cancer cells indeed have also evolved by exploiting the autophagy process to fulfill energy requirements through the production of metabolic fuel sources and fundamentally altered metabolic pathways. Occasionally autophagy as a foe impedes tumorigenesis and promotes cell death. The complex role of autophagy in cancer makes it a potent therapeutic target and has been actively tested in clinical trials. Moreover, the versatility of autophagy has opened new avenues of effective combinatorial therapeutic strategies. Thereby, it is imperative to comprehend the specificity of autophagy in cancer-metabolism. This review summarizes the recent research and conceptual framework on the regulation of autophagy by various metabolic pathways, enzymes, and their cross-talk in the cancer milieu, including the implementation of altered metabolism and autophagy in clinically approved and experimental therapeutics.
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Affiliation(s)
- Anchala Pandey
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, 462066, Madhya Pradesh, India
| | - Pooja Yadav
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, 462066, Madhya Pradesh, India
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, 462066, Madhya Pradesh, India
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20
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Liu W, Mahdessian H, Helgadottir H, Zhou X, Thutkawkorapin J, Jiao X, Wolk A, Lindblom A. Colorectal cancer risk susceptibility loci in a Swedish population. Mol Carcinog 2021; 61:288-300. [PMID: 34758156 DOI: 10.1002/mc.23366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/12/2022]
Abstract
To search for colorectal cancer (CRC) risk loci, Swedish samples were used for a genome-wide haplotype analysis. A logistic regression model was employed in 2663 CRC cases and 1642 controls in the discovery analysis. Three analyses were done, on all, familial-, and nonfamilial CRC samples and only results with odds ratio (OR) > 1 were analyzed. single nucleotide polymorphism (SNP) analysis did not generate any statistically significant results. Haplotype analysis suggested novel loci, on chromosome 2q36.1 (OR = 1.71, p value = 5.6924 × 10-8 ) in all CRC samples, chromosome 1q43 (OR = 4.04 p value = 3.24 × 10-8 ) in familial CRC samples, and two hits in nonfamilial CRC samples, chromosomes 2q36.1 (OR = 1.71 p value = 5.69 × 10-8 ) and 3p24.3 (OR = 1.62 p value = 6.21 × 10-9 ). Moreover, one locus on chromosome 20q13.33 was suggested in analyses of all samples, and five more novel loci were suggested on chromosomes 10q25.3, 15q,22.31, 17p11.2, 1p34.2, and 3q24. The haplotypes from the analysis of all samples were replicated in a second study of CRC cases and controls from the same part of Sweden. In summary, using haplotype analysis in Swedish CRC samples, the best hits were novel loci and the locus on chromosomes 2q36.1 and 20q13.33 suggested in the analysis of all samples were confirmed in a second cohort. The ORs were often higher than ORs from published genome-wide association study (GWAS). The study suggested it was possible that a risk locus could involve more than one gene, and that haplotypes could give information on the gene or genes possibly involved in the risk at specific locus.
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Affiliation(s)
- Wen Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Hovsep Mahdessian
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Hafdis Helgadottir
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Xingwu Zhou
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | | | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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21
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Wang Q, Wu H, Hu J, Fu H, Qu Y, Yang Y, Cai KQ, Efimov A, Wu M, Yen T, Wang Y, Yang ZJ. Nestin Is Required for Spindle Assembly and Cell-Cycle Progression in Glioblastoma Cells. Mol Cancer Res 2021; 19:1651-1665. [PMID: 34158391 PMCID: PMC8492506 DOI: 10.1158/1541-7786.mcr-20-0994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/06/2021] [Accepted: 06/14/2021] [Indexed: 11/16/2022]
Abstract
Nestin, a class IV intermediate filament protein, is generally considered as a putative marker of neural stem and progenitor cells in the central nervous system. Glioma is a common type of adult brain tumors, and glioblastoma (GBM) represents the most aggressive form of glioma. Here, we report that Nestin expression is significantly upregulated in human GBM, compared with other types of glioma. Nestin knockdown or deletion in U251 cells and tumor cells from GBM patients derived xenografts resulted in G2-M arrest, finally leading to apoptosis in tumor cells. Using proximity-dependent biotin identification method, we identified βII-tubulin as an interacting protein of Nestin in U251 cells. Nestin stabilized βII-tubulin in U251 cells through physical interaction. Knockdown of Nestin or βII-tubulin disrupted spindle morphology in tumor cells. Our studies further revealed that Nestin deficiency in U251 cells and GBM PDX cells repressed tumor growth upon transplantation. Finally, we found that Nestin deficiency sensitized GBM cells to microtubule-destabilizing drugs such as vinblastine and vincristine. Our studies demonstrate the essential functions and underlying mechanisms of Nestin in the growth and drug response of GBM cells. IMPLICATIONS: Through interaction with βII-tubulin, Nestin facilitates cell-cycle progression and spindle assembly of tumor cells in glioblastoma.
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Affiliation(s)
- Qinglin Wang
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Hao Wu
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Jian Hu
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
| | - Haijuan Fu
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yanghui Qu
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yijun Yang
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
| | - Kathy Q Cai
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
| | - Andrey Efimov
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
| | - Minghua Wu
- Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Tim Yen
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania
| | - Yuan Wang
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Zeng-Jie Yang
- Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
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22
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Li Y, Yang G, Yang C, Tang P, Chen J, Zhang J, Liu J, Ouyang L. Targeting Autophagy-Related Epigenetic Regulators for Cancer Drug Discovery. J Med Chem 2021; 64:11798-11815. [PMID: 34378389 DOI: 10.1021/acs.jmedchem.1c00579] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Existing evidence has demonstrated that epigenetic modifications (including DNA methylation, histone modifications, and microRNAs), which are associated with the occurrence and development of tumors, can directly or indirectly regulate autophagy. In particular, nuclear events induced by several epigenetic regulators can regulate the autophagic process and expression levels of tumor-associated genes, thereby promoting tumor progression. Tumor-associated microRNAs, including oncogenic and tumor-suppressive microRNAs, are of great significance to autophagy during tumor progression. Targeting autophagy with emerging epigenetic drugs is expected to be a promising therapeutic strategy for human tumors. From this perspective, we aim to summarize the role of epigenetic modification in the autophagic process and the underlying molecular mechanisms of tumorigenesis. Furthermore, the regulatory efficacy of epigenetic drugs on the autophagic process in tumors is also summarized. This perspective may provide a theoretical basis for the combined treatment of epigenetic drugs/autophagy mediators in tumors.
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Affiliation(s)
- Yang Li
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Gaoxia Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Chengcan Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Pan Tang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Juncheng Chen
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jifa Zhang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
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23
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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24
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Yu S, Cai L, Liu C, Gu R, Cai L, Zhuo L. Identification of prognostic alternative splicing events related to the immune microenvironment of hepatocellular carcinoma. Mol Med 2021; 27:36. [PMID: 33832428 PMCID: PMC8034091 DOI: 10.1186/s10020-021-00294-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/17/2021] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, and its 5-year survival rate is less than 20%, despite various treatments being available. Increasing evidence indicates that alternative splicing (AS) plays a nonnegligible role in the formation and development of the tumor microenvironment (TME). However, the comprehensive analysis of the impact on prognostic AS events on immune-related perspectives in HCC is lacking but urgently needed. Methods The transcriptional data and clinical information of HCC patients were downloaded from TCGA (The Cancer Genome Atlas) database for calculating immune and stromal scores by ESTIMATE algorithm. We then divided patients into high/low score groups and explored their prognostic significance using Kaplan–Meier curves. Based on stromal and immune scores, differentially expressed AS events (DEASs) were screened and evaluated with functional enrichment analysis. Additionally, a risk score model was established by applying univariate and multivariate Cox regression analyses. Finally, gene set variation analysis (GSVA) was adopted to explore differences in biological behaviors between the high- and low-risk subgroups. Results A total of 370 HCC patients with complete and qualified corresponding data were included in the subsequent analysis. According to the results of ESTIMATE analysis, we observed that the high immune/stromal score group had a longer survival probability, which was significantly correlated with prognosis in HCC patients. In addition, 467 stromal/immune score-related DEASs were identified, and enrichment analysis revealed that DEASs were significantly enriched in pathways related to HCC tumorigenesis and the immune microenvironment. More importantly, the final prognostic signature containing 16 DEASs showed powerful predictive ability. Finally, GSVA demonstrated that activation of carcinogenic pathways and immune-related pathways in the high-risk group may lead to poor prognosis. Conclusions Collectively, these outcomes revealed prognostic AS events related to carcinogenesis and the immune microenvironment, which may yield new directions for HCC immunotherapy. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00294-3.
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Affiliation(s)
- Shanshan Yu
- Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Luya Cai
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Chuan Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Ruihong Gu
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Lingyi Cai
- Department of Hematology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Leying Zhuo
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Southern White Elephant Town, Ouhai, Wenzhou, Zhejiang, 325000, People's Republic of China.
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25
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Crake RLI, Burgess ER, Royds JA, Phillips E, Vissers MCM, Dachs GU. The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response. Front Oncol 2021; 11:619300. [PMID: 33842321 PMCID: PMC8027507 DOI: 10.3389/fonc.2021.619300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/25/2021] [Indexed: 12/30/2022] Open
Abstract
Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
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Affiliation(s)
- Rebekah L. I. Crake
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Eleanor R. Burgess
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Janice A. Royds
- Department of Pathology, University of Otago, Dunedin, New Zealand
| | - Elisabeth Phillips
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Margreet C. M. Vissers
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Gabi U. Dachs
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
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26
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Gao Y, Fu Y, Wang J, Zheng X, Zhou J, Ma J. EBV as a high infection risk factor promotes RASSF10 methylation and induces cell proliferation in EBV-associated gastric cancer. Biochem Biophys Res Commun 2021; 547:1-8. [PMID: 33588233 DOI: 10.1016/j.bbrc.2021.02.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus (EBV) is the first identified human tumor-related DNA virus, and has a high infection among people worldwide. Recent studies have showed that nearly 10% of gastric cancers have shown EBV infection and this kind of gastric cancer has been identified as a new subtype: EBV associated Gastric cancer (EBVaGC). Furthermore, it has been reported that tumor related genes in the EBVaGC showed frequent methylation modifications compared to those in the EBV negative gastric cancer (EBVnGC). To fully understand the role of EBV in EBVaGC, we analyzed and found that 16.67% of gastric carcinoma samples showed positive EBER1 signals. Mechanically, EBV-encoded Latent membrane protein 1 (LMP1) inhibited the expression of RASSF10, and promoted tumorigenesis by recruiting DNMT1 and inducing the DNA methylation of RASSF10. Altogether, it allows us a better understanding of the possible mechanism of EBV-induced gene hypermethylation in gastric cancer genome. Targeting EBV-induced DNA methylation is a potential therapeutic modality of EBVaGC.
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Affiliation(s)
- Yingxue Gao
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China
| | - Yuxin Fu
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China
| | - Jia Wang
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, NHC Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, Hunan, China
| | - Xiang Zheng
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, NHC Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, Hunan, China
| | - Jianhua Zhou
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China.
| | - Jian Ma
- Xiangya Hospital, Department of Pathology, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, 410008, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, NHC Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, Hunan, China.
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27
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Giwa A, Fatai A, Gamieldien J, Christoffels A, Bendou H. Identification of novel prognostic markers of survival time in high-risk neuroblastoma using gene expression profiles. Oncotarget 2020; 11:4293-4305. [PMID: 33245713 PMCID: PMC7679032 DOI: 10.18632/oncotarget.27808] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022] Open
Abstract
Neuroblastoma is the most common extracranial solid tumor in childhood. Patients in high-risk group often have poor outcomes with low survival rates despite several treatment options. This study aimed to identify a genetic signature from gene expression profiles that can serve as prognostic indicators of survival time in patients of high-risk neuroblastoma, and that could be potential therapeutic targets. RNA-seq count data was downloaded from UCSC Xena browser and samples grouped into Short Survival (SS) and Long Survival (LS) groups. Differential gene expression (DGE) analysis, enrichment analyses, regulatory network analysis and machine learning (ML) prediction of survival group were performed. Forty differentially expressed genes (DEGs) were identified including genes involved in molecular function activities essential for tumor proliferation. DEGs used as features for prediction of survival groups included EVX2, NHLH2, PRSS12, POU6F2, HOXD10, MAPK15, RTL1, LGR5, CYP17A1, OR10AB1P, MYH14, LRRTM3, GRIN3A, HS3ST5, CRYAB and NXPH3. An accuracy score of 82% was obtained by the ML classification models. SMIM28 was revealed to possibly have a role in tumor proliferation and aggressiveness. Our results indicate that these DEGs can serve as prognostic indicators of survival in high-risk neuroblastoma patients and will assist clinicians in making better therapeutic and patient management decisions.
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Affiliation(s)
- Abdulazeez Giwa
- SAMRC Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa
| | - Azeez Fatai
- Department of Biochemistry, Lagos State University, Lagos, Nigeria
| | - Junaid Gamieldien
- SAMRC Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa
| | - Alan Christoffels
- SAMRC Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa
| | - Hocine Bendou
- SAMRC Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa
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Bhol CS, Panigrahi DP, Praharaj PP, Mahapatra KK, Patra S, Mishra SR, Behera BP, Bhutia SK. Epigenetic modifications of autophagy in cancer and cancer therapeutics. Semin Cancer Biol 2020; 66:22-33. [DOI: 10.1016/j.semcancer.2019.05.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 05/09/2019] [Accepted: 05/30/2019] [Indexed: 12/30/2022]
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Abstract
Purpose of review This review focuses on the development and progression of glioblastoma through the brain and glioma microenvironment. Specifically we highlight how the tumor microenvironment contributes to the hallmarks of cancer in hopes of offering novel therapeutic options and tools to target this microenvironment. Recent findings The hallmarks of cancer, which represent elements of cancers that contribute to the disease's malignancy, yet elements within the brain tumor microenvironment, such as other cellular types as well as biochemical and biophysical cues that can each uniquely affect tumor cells, have not been well-described in this context and serve as potential targets for modulation. Summary Here, we highlight how the brain tumor microenvironment contributes to the progression and therapeutic response of tumor cells. Specifically, we examine these contributions through the lens of Hanahan & Weinberg's Hallmarks of Cancer in order to identify potential novel targets within the brain that may offer a means to treat brain cancers, including the deadliest brain cancer, glioblastoma.
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30
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Ferrer A, Roser CT, El-Far MH, Savanur VH, Eljarrah A, Gergues M, Kra JA, Etchegaray JP, Rameshwar P. Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy. Cancer Lett 2020; 488:9-17. [PMID: 32479768 DOI: 10.1016/j.canlet.2020.05.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022]
Abstract
Breast cancer (BC) remains a clinical challenge despite improved treatments and public awareness to ensure early diagnosis. A major issue is the ability of BC cells (BCCs) to survive as dormant cancer cells in the bone marrow (BM), resulting in the cancer surviving for decades with the potential to resurge as metastatic cancer. The experimental evidence indicates similarity between dormant BCCs and other stem cells, resulting in the preponderance of data to show dormant BCCs being cancer stem cells (CSCs). The BM niche and their secretome support BCC dormancy. Lacking in the literature is a comprehensive research to describe how the hypoxic environment within the BM may influence the behavior of BCCs. This information is relevant to understand the prognosis of BC in young and aged individuals whose oxygen levels differ in BM. This review discusses the changing information on vascularity in different regions of the BM and the impact on endogenous hematopoietic stem cells (HSCs). This review highlights the necessary information to provide insights on vascularity of different BM regions on the behavior of BCCs, in particular a dormant phase. For instance, how the transcription factor HIF1-α (hypoxia-inducible factor 1 alpha), functioning as first responder under hypoxic conditions, affects the expression of specific gene networks involved in energy metabolism, cell survival, tumor invasion and angiogenesis. This enables cell fate transition and facilitates tumor heterogeneity, which in turn favors tumor progression and resistance to anticancer treatments Thus, HIF1-α could be a potential target for cancer treatment. This review describes epigenetic mechanisms involved in hypoxic responses during cancer dormancy in the bone marrow. The varied hypoxic environment in the BM is relevant to understand the complex process of the aging bone marrow for insights on breast cancer outcome between the young and aged.
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Affiliation(s)
- Alejandra Ferrer
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA; Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, 07103, USA
| | - Christopher T Roser
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA
| | - Markos H El-Far
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA; Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, 07103, USA
| | - Vibha Harindra Savanur
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA; Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, 07103, USA
| | - Adam Eljarrah
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA
| | - Marina Gergues
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA; Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, 07103, USA
| | - Joshua A Kra
- Rutgers Cancer Institute of New Jersey at University Hospital, Newark, NJ, 07103, USA
| | | | - Pranela Rameshwar
- Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, 07103, USA.
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Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes. Cells 2019; 8:cells8121656. [PMID: 31861179 PMCID: PMC6952790 DOI: 10.3390/cells8121656] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/19/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Although autophagy is a well-known and extensively described cell pathway, numerous studies have been recently interested in studying the importance of its regulation at different molecular levels, including the translational and post-translational levels. Therefore, this review focuses on the links between autophagy and epigenetics in cancer and summarizes the. following: (i) how ATG genes are regulated by epigenetics, including DNA methylation and post-translational histone modifications; (ii) how epidrugs are able to modulate autophagy in cancer and to alter cancer-related phenotypes (proliferation, migration, invasion, tumorigenesis, etc.) and; (iii) how epigenetic enzymes can also regulate autophagy at the protein level. One noteable observation was that researchers most often reported conclusions about the regulation of the autophagy flux, following the use of epidrugs, based only on the analysis of LC3B-II form in treated cells. However, it is now widely accepted that an increase in LC3B-II form could be the consequence of an induction of the autophagy flux, as well as a block in the autophagosome-lysosome fusion. Therefore, in our review, all the published results describing a link between epidrugs and autophagy were systematically reanalyzed to determine whether autophagy flux was indeed increased, or inhibited, following the use of these potentially new interesting treatments targeting the autophagy process. Altogether, these recent data strongly support the idea that the determination of autophagy status could be crucial for future anticancer therapies. Indeed, the use of a combination of epidrugs and autophagy inhibitors could be beneficial for some cancer patients, whereas, in other cases, an increase of autophagy, which is frequently observed following the use of epidrugs, could lead to increased autophagy cell death.
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Cheng S, Xie W, Miao Y, Guo J, Wang J, Li C, Zhang Y. Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles. J Transl Med 2019; 17:407. [PMID: 31796052 PMCID: PMC6892283 DOI: 10.1186/s12967-019-02148-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tumor surrounding the internal carotid artery or invading to the cavernous sinus is an important characteristic of invasive pituitary adenoma, and a pivotal factor of tumor residue and regrowth. Without specific changes in serum hormone related to the adenohypophyseal cell of origin, clinically non-functioning pituitary adenoma is more likely to be diagnosed at invasive stages compared with functioning pituitary adenoma. The underlying mechanism of tumor invasion remains unknown. In this study, we aimed to identify key genes in tumor invasion by integrating analyses of DNA methylation and gene expression profiles. METHOD Genome-wide DNA methylation and mRNA microarray analysis were performed for tumor samples from 68 patients at the Beijing Tiantan Hospital. Differentially expressed genes and methylated probes were identified based on an invasive vs non-invasive grouping. Differentially methylated probes in the promoter region of targeted genes were assessed. Pearson correlation analysis was used to identify genes with a strong association between DNA methylation status and expression levels. Pyrosequencing and RT-PCR were used to validate the methylation status and expression levels of candidate genes, respectively. RESULTS A total of 8842 differentially methylated probes, located on 4582 genes, and 661 differentially expressed genes were identified. Both promoter methylation and expression alterations were observed for 115 genes with 58 genes showing a negative correlation between DNA methylation status and expression level. Nineteen genes that exhibited notably negative correlations between DNA methylation and gene expression levels, are involved in various gene ontologies and pathways, or played an important role in different diseases, were regarded as candidate genes. We found an increased methylation with a decreased expression of PHYHD1, LTBR, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6, and a decreased methylation with an increased expression of MYBPHL. The methylation status and expression levels of these genes were validated by pyrosequencing and RT-PCR. CONCLUSIONS The DNA methylation and expression levels of PHYHD1, LTBR, MYBPHL, C22orf42, PRR5, ANKDD1A, RAB13, CAMKV, KIFC3, WNT4 and STAT6 are associated with tumor invasion, and these genes may become the potential genes for targeted therapy.
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Affiliation(s)
- Sen Cheng
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070 China
| | - Weiyan Xie
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070 China
| | - Yazhou Miao
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070 China
| | - Jing Guo
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070 China
| | - Jichao Wang
- People’s Hospital of Xin Jiang Uygur Autonomous Region, Urumqi, 830001 China
| | - Chuzhong Li
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Institute for Brain Disorders Brain Tumor Center, China National Clinical Research Center for Neurological Diseases, Key Laboratory of Central Nervous System Injury Research, Beijing, 100070 China
| | - Yazhuo Zhang
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Institute for Brain Disorders Brain Tumor Center, China National Clinical Research Center for Neurological Diseases, Key Laboratory of Central Nervous System Injury Research, Beijing, 100070 China
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33
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Su J, Ma Q, Long W, Tang H, Wu C, Luo M, Wang X, Xiao K, Li Y, Xiao Q, Zhang C, Li H, Liu Q. LCTL Is a Prognostic Biomarker and Correlates With Stromal and Immune Infiltration in Gliomas. Front Oncol 2019; 9:1083. [PMID: 31681612 PMCID: PMC6803540 DOI: 10.3389/fonc.2019.01083] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/01/2019] [Indexed: 01/08/2023] Open
Abstract
Immune evasion in glioma strongly correlates with clinical outcomes; however, the molecular mechanisms driving the maintenance of immunosuppression remain largely unknown. Recently studies demonstrate that Klothos are aberrantly expressed in several cancers and are potential therapeutic targets in cancers. However, their roles are still unclear in glioma. Here, we show that LCTL is highly expressed in gliomas and that its expression is regulated by DNA methylation status at the promoter. LCTL expression is also found to be significantly associated with high tumor aggressiveness and poor outcomes for glioma patients. Mechanistically, results suggested that LCTL might play an important immunosuppressive role by recruiting immunosuppressive cells and regulating tumor-associated macrophages polarization, T cell exhaustion, and epithelial–mesenchymal transition through FGF signaling in glioma. Our results establish LCTL as a key biomarker for prognosis that could be considered a potential epigenetic and immunotherapeutic target for treatment.
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Affiliation(s)
- Jun Su
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qianquan Ma
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Wenyong Long
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Hailin Tang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Changwu Wu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Luo
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xiangyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kai Xiao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yang Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qun Xiao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Chi Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Haoyu Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,Institute of Skull Base Surgery & Neuro-oncology at Hunan, Changsha, China
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Eser Ocak P, Ocak U, Tang J, Zhang JH. The role of caveolin-1 in tumors of the brain - functional and clinical implications. Cell Oncol (Dordr) 2019; 42:423-447. [PMID: 30993541 DOI: 10.1007/s13402-019-00447-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Caveolin-1 (cav-1) is the major structural protein of caveolae, the flask-shaped invaginations of the plasma membrane mainly involved in cell signaling. Today, cav-1 is believed to play a role in a variety of disease processes including cancer, owing to the variations of its expression in association with tumor progression, invasive behavior, metastasis and therapy resistance. Since first detected in the brain, a number of studies has particularly focused on the role of cav-1 in the various steps of brain tumorigenesis. In this review, we discuss the different roles of cav-1 and its contributions to the molecular mechanisms underlying the pathobiology and natural behavior of brain tumors including glial, non-glial and metastatic subtypes. These contributions could be attributed to its co-localization with important players in tumorigenesis within the lipid-enriched domains of the plasma membrane. In that regard, the ability of cav-1 to interact with various cell signaling molecules as well as the impact of caveolae depletion on important pathways acting in brain tumor pathogenesis are noteworthy. We also discuss conversant causes hampering the treatment of malignant glial tumors such as limited transport of chemotherapeutics across the blood tumor barrier and resistance to chemoradiotherapy, by focusing on the molecular fundamentals involving cav-1 participation. CONCLUSIONS Cav-1 has the potential to pivot the molecular basis underlying the pathobiology of brain tumors, particularly the malignant glial subtype. In addition, the regulatory effect of cav-1-dependent and caveola-mediated transcellular transport on the permeability of the blood tumor barrier could be of benefit to overcome the restricted transport across brain barriers when applying chemotherapeutics. The association of cav-1 with tumors of the brain other than malignant gliomas deserves to be underlined, as well given the evidence suggesting its potential in predicting tumor grade and recurrence rates together with determining patient prognosis in oligodendrogliomas, ependymomas, meningiomas, vestibular schwannomas and brain metastases.
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Affiliation(s)
- Pinar Eser Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Umut Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
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35
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Chatrath A, Kiran M, Kumar P, Ratan A, Dutta A. The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients. Mol Cancer Res 2019; 17:1075-1086. [PMID: 30651372 DOI: 10.1158/1541-7786.mcr-18-0996] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/22/2018] [Accepted: 01/07/2019] [Indexed: 01/01/2023]
Abstract
Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically. They often recur following resection and progress, resulting in death. Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in patients with glioma. In this study, we present an approach to identify the small fraction of prognostic germline variants from the pool of over four million variants that we variant called in The Cancer Genome Atlas whole-exome sequencing and RNA sequencing datasets. We identified two germline variants that are predictive of poor patient outcomes by Cox regression, controlling for eleven covariates. rs61757955 is a germline variant found in the 3' UTR of GRB2 associated with increased KRAS signaling, CIC mutations, and 1p/19q codeletion. rs34988193 is a germline variant found in the tumor suppressor gene ANKDD1a that causes an amino acid change from lysine to glutamate. This variant was found to be predictive of poor prognosis in two independent lower grade glioma datasets and is predicted to be within the top 0.06% of deleterious mutations across the human genome. The wild-type residue is conserved in all 22 other species with a homologous protein. IMPLICATIONS: This is the first study presenting an approach to screening many germline variants to identify variants predictive of survival and our application of this methodology revealed the germline variants rs61757955 and rs34988193 as being predictive of survival in patients with lower grade glioma.
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Affiliation(s)
- Ajay Chatrath
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Manjari Kiran
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Pankaj Kumar
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
| | - Aakrosh Ratan
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Anindya Dutta
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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