|
1
|
Perona-Moratalla AB, Carrión B, Villar Gómez de las Heras K, Arias-Salazar L, Yélamos-Sanz B, Segura T, Serrano-Heras G. Dual Inhibition of HIF-1α and HIF-2α as a Promising Treatment for VHL-Associated Hemangioblastomas: A Pilot Study Using Patient-Derived Primary Cell Cultures. Biomedicines 2025; 13:1234. [PMID: 40427061 PMCID: PMC12108798 DOI: 10.3390/biomedicines13051234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 05/12/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system (CNS-HBs). The standard treatment for these brain tumors is neurosurgical resection. However, multiple surgeries are often necessary due to tumor recurrence, which increases the risk of neurological sequelae. Thus, elucidation of the proliferative behavior of hemangioblastomas (with the aim of identifying biomarkers associated with tumor progression) and the development of pharmacological therapies could reduce the need for repeated surgical interventions and provide alternative treatment options for unresectable CNS-HBs. Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies. Results: In this study, primary cell cultures were successfully established from CNS-HB tissue samples of VHL patients, achieving a 75% success rate. These cultures were predominantly composed of stromal cells and pericytes. The proliferative patterns of patient-derived HB cell cultures significantly correlated with tumor burden and recurrence in VHL patients. Furthermore, flow cytometry, reverse transcription-PCR, and Western blot analyses revealed marked overexpression of both HIF-1α and HIF-2α isoforms in primary HB cells. In addition, evaluation of the therapeutic potential of acriflavine, a dual HIF-1α/HIF-2α inhibitor, demonstrated reduced HB cells viability, induced G2/M cell cycle arrest, and predominantly triggered necrotic cell death in patient-derived HB cultures. Conclusions: These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy.
Collapse
Affiliation(s)
- Ana B. Perona-Moratalla
- Department of Neurology, General University Hospital of Albacete, Hermanos Falcó, 37, 02008 Albacete, Spain;
| | - Blanca Carrión
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Department of Medicine, Faculty of Medicine, Health and Sports, Universidad Europea de Madrid, 28670 Villaviciosa de Odón, Spain
| | | | - Lourdes Arias-Salazar
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Blanca Yélamos-Sanz
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Tomás Segura
- Department of Neurology, General University Hospital of Albacete, Hermanos Falcó, 37, 02008 Albacete, Spain;
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
- Biomedicine Institute of UCLM (IB-UCLM), Faculty of Medicine, University of Castilla-La Mancha, 02008 Albacete, Spain
| | - Gemma Serrano-Heras
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| |
Collapse
|
|
2
|
Ding W, Gong W, Bou T, Shi L, Lin Y, Wu H, Dugarjaviin M, Bai D. Pilot Study on the Profiling and Functional Analysis of mRNA, miRNA, and lncRNA in the Skeletal Muscle of Mongolian Horses, Xilingol Horses, and Grassland-Thoroughbreds. Animals (Basel) 2025; 15:1123. [PMID: 40281957 PMCID: PMC12024394 DOI: 10.3390/ani15081123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 04/06/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Muscle fibers, as the fundamental units of muscle tissue, play a crucial role in determining skeletal muscle function through their growth, development, and composition. To investigate changes in muscle fiber types and their regulatory mechanisms in Mongolian horses (MG), Xilingol horses (XL), and Grassland-Thoroughbreds (CY), we conducted histological and bioinformatic analyses on the gluteus medius muscle of these three horse breeds. Immunofluorescence analysis revealed that Grassland-Thoroughbreds had the highest proportion of fast-twitch muscle fibers at 78.63%, while Mongolian horses had the lowest proportion at 57.54%. Whole-transcriptome analysis identified 105 differentially expressed genes (DEGs) in the CY vs. MG comparison and 104 DEGs in the CY vs. XL comparison. Time-series expression profiling grouped the DEGs into eight gene sets, with three sets showing significantly up-regulated or down-regulated expression patterns (p < 0.05). Additionally, 280 differentially expressed long non-coding RNAs (DELs) were identified in CY vs. MG, and 213 DELs were identified in CY vs. XL. A total of 32 differentially expressed microRNAs (DEMIRs) were identified in CY vs. MG, while 44 DEMIRs were found in CY vs. XL. Functional enrichment analysis indicated that the DEGs were significantly enriched in essential biological processes, such as actin filament organization, muscle contraction, and protein phosphorylation. KEGG pathway analysis showed their involvement in key signaling pathways, including the mTOR signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. Furthermore, functional variation-based analyses revealed associations between non-coding RNAs and mRNAs, with some non-coding RNAs targeting genes potentially related to muscle function regulation. These findings provide valuable insights into the molecular basis for the environmental adaptability, athletic performance, and muscle characteristics in horses, offering new perspectives for the breeding of Grassland-Thoroughbreds.
Collapse
Affiliation(s)
- Wenqi Ding
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Wendian Gong
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Tugeqin Bou
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Lin Shi
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Yanan Lin
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Huize Wu
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Manglai Dugarjaviin
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Dongyi Bai
- Key Laboratory of Equus Germplasm Innovation (Co-Construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (W.D.); (W.G.); (T.B.); (L.S.); (Y.L.); (H.W.); (M.D.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| |
Collapse
|
|
3
|
Abou-Shanab AM, Gaser OA, Galal N, Mohamed A, Atta D, Kamar SS, Magdy S, Khedr MA, Elkhenany H, El-Badri N. PHD-2/HIF-1α axis mediates doxorubicin-induced angiogenesis in SH-SY5Y neuroblastoma microenvironment: a potential survival mechanism. Sci Rep 2025; 15:7487. [PMID: 40032892 PMCID: PMC11876694 DOI: 10.1038/s41598-025-89884-3] [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: 09/11/2024] [Accepted: 02/10/2025] [Indexed: 03/05/2025] Open
Abstract
The response of neuroblastoma (NB) cells to chemotherapeutics and their influence on NB microenvironment remain incompletely understood. Herein, we examined the underlying molecular mechanism via which Doxorubicin, a chemotherapeutic agent used for NB treatment, promotes proangiogenic response in the SH-SY5Y microenvironment. Doxorubicin treatment at 1 µg/ml reduced SH-SY5Y cell proliferation and primed the apoptosis pathway. Unexpectedly, SH-SY5Y cells treated with doxorubicin upregulated their expression of the pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelets-derived growth factor (PDGF), and matrix metalloprotease-2 (MMP-2) and secretion of nitric oxide. To assess the functional angiogenesis of SH-SY5Y cells pre-treated with doxorubicin, an indirect co-culture system with human umbilical vein endothelial cells (HUVEC) was established. These HUVECs acquired enhanced proliferation, migration capacity, and tube formation capability and exhibited increased nitric oxide (NO) production, in addition to upregulated α-smooth muscle actin expression, suggesting enhanced contractility. In-ovo studies of the neo-angiogenic response of SH-SY5Y pre-treated with doxorubicin further show their promoted neo-angiogenesis as indicated by the generated blood vessels and histological analysis of CD31 expression. Inhibition of PHD-2 could be a potential target for doxorubicin, as indicated by molecular docking, molecular dynamics (MD) simulation, and MM-GBSA calculations, leading to hypoxia-inducible factor-1 alpha (HIF-1α) stabilization. Bioinformatics analyses and enrichment analyses of RNA-seq data revealed activation of Pi3K pathway which is further validated in-vitro. These results provide evidence of the unexpected pro-angiogenic response of SH-SY5Y cells to doxorubicin treatment and suggest the potential use of multi-modal therapeutic regimens for a more comprehensive approach to NB treatment.
Collapse
Affiliation(s)
- Ahmed M Abou-Shanab
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Ola A Gaser
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Noha Galal
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Alaa Mohamed
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Dina Atta
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Samaa Samir Kamar
- Histology Department, Kasr Al-Ainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shireen Magdy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Mennatallah A Khedr
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Hoda Elkhenany
- Department of Surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, 22785, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt.
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt.
| |
Collapse
|
|
4
|
Aluru N, Venkataraman YR, Murray CS, DePascuale V. Gene expression and DNA methylation changes in response to hypoxia in toxicant-adapted Atlantic killifish (Fundulus heteroclitus). Biol Open 2025; 14:BIO061801. [PMID: 39760289 PMCID: PMC11744052 DOI: 10.1242/bio.061801] [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: 11/02/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Coastal fish populations are threatened by multiple anthropogenic impacts, including the accumulation of industrial contaminants and the increasing frequency of hypoxia. Some populations of the Atlantic killifish (Fundulus heteroclitus), like those in New Bedford Harbor (NBH), Massachusetts, USA, have evolved a resistance to dioxin-like polychlorinated biphenyls (PCBs) that may influence their ability to cope with secondary stressors. To address this question, we compared hepatic gene expression and DNA methylation patterns in response to mild or severe hypoxia in killifish from NBH and Scorton Creek (SC), a reference population from a relatively pristine environment. We hypothesized that NBH fish would show altered responses to hypoxia due to trade-offs linked to toxicant resistance. Our results revealed substantial differences between populations. SC fish demonstrated dose-dependent changes in gene expression in response to hypoxia, while NBH fish exhibited a muted transcriptional response to severe hypoxia. Interestingly, NBH fish showed significant DNA methylation changes in response to hypoxia, while SC fish did not exhibit notable epigenetic alterations. These findings suggest that toxicant-adapted killifish may face trade-offs in their molecular response to environmental stress, potentially impacting their ability to survive severe hypoxia in coastal habitats. Further research is needed to elucidate the functional implications of these epigenetic modifications and their role in adaptive stress responses.
Collapse
Affiliation(s)
- Neelakanteswar Aluru
- Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543,USA
- Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543,USA
| | | | | | - Veronica DePascuale
- Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543,USA
- College of Arts and Sciences, Oberlin College and Conservatory, Oberlin, OH 44074,USA
| |
Collapse
|
|
5
|
Pauzaite T, Nathan JA. A closer look at the role of deubiquitinating enzymes in the Hypoxia Inducible Factor pathway. Biochem Soc Trans 2024; 52:2253-2265. [PMID: 39584532 PMCID: PMC11668284 DOI: 10.1042/bst20230861] [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: 08/27/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024]
Abstract
Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.
Collapse
Affiliation(s)
- Tekle Pauzaite
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah, Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, U.K
| | - James A. Nathan
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah, Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, U.K
| |
Collapse
|
|
6
|
Aluru N, Venkataraman YR, Murray CS, DePascuale V. Gene expression and DNA methylation changes in response to hypoxia in toxicant-adapted Atlantic killifish ( Fundulus heteroclitus). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.01.620405. [PMID: 39554046 PMCID: PMC11565929 DOI: 10.1101/2024.11.01.620405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Coastal fish populations are threatened by multiple anthropogenic impacts, including the accumulation of industrial contaminants and the increasing frequency of hypoxia. Some populations of the Atlantic killifish (Fundulus heteroclitus), like those in New Bedford Harbor (NBH), Massachusetts, have evolved a resistance to dioxin-like polychlorinated biphenyls (PCBs) that may influence their ability to cope with secondary stressors. To address this question, we compared hepatic gene expression and DNA methylation patterns in response to mild or severe hypoxia in killifish from NBH and Scorton Creek (SC), a reference population from a relatively pristine environment. We hypothesized that NBH fish would show altered responses to hypoxia due to trade-offs linked to toxicant resistance. Our results revealed substantial differences between populations. SC fish demonstrated a dose-dependent changes in gene expression in response to hypoxia, while NBH fish exhibited a muted transcriptional response to severe hypoxia. Interestingly, NBH fish showed significant DNA methylation changes in response to hypoxia, while SC fish did not exhibit notable epigenetic alterations. These findings suggest that toxicant-adapted killifish may face trade-offs in their molecular response to environmental stress, potentially impacting their ability to survive severe hypoxia in coastal habitats. Further research is needed to elucidate the functional implications of these epigenetic modifications and their role in adaptive stress responses.
Collapse
Affiliation(s)
- Neelakanteswar Aluru
- Biology Department, Woods Hole, Massachusetts 02543
- Woods Hole Center for Oceans and Human Health Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543
| | | | | | - Veronica DePascuale
- Biology Department, Woods Hole, Massachusetts 02543
- College of Arts and Sciences, Oberlin College and Conservatory, Oberlin, Ohio 44074
| |
Collapse
|
|
7
|
Mal S, Majumder D, Birari P, Sharma AK, Gupta U, Jana K, Kundu M, Basu J. The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection. FEBS Lett 2024; 598:2592-2614. [PMID: 39155147 DOI: 10.1002/1873-3468.15001] [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: 03/03/2024] [Revised: 06/12/2024] [Accepted: 07/03/2024] [Indexed: 08/20/2024]
Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.
Collapse
Affiliation(s)
- Soumya Mal
- Department of Biological Sciences, Bose Institute, Unified Academic Campus, Kolkata, India
| | | | - Pankaj Birari
- Department of Chemical Sciences, Bose Institute, Kolkata, India
| | | | - Umesh Gupta
- National JALMA Institute of Leprosy and Other Mycobacterial Disease, Agra, India
| | - Kuladip Jana
- Department of Biological Sciences, Bose Institute, Unified Academic Campus, Kolkata, India
| | | | - Joyoti Basu
- Department of Chemical Sciences, Bose Institute, Kolkata, India
| |
Collapse
|
|
8
|
Lee PWT, Suwa T, Kobayashi M, Yang H, Koseki LR, Takeuchi S, Chow CCT, Yasuhara T, Harada H. Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner. Br J Cancer 2024; 131:37-48. [PMID: 38740970 PMCID: PMC11231347 DOI: 10.1038/s41416-024-02691-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear. METHODS Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques. RESULTS HMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells. CONCLUSION These results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis.
Collapse
Affiliation(s)
- Peter W T Lee
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Tatsuya Suwa
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Minoru Kobayashi
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Hui Yang
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Lina R Koseki
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Satoshi Takeuchi
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Christalle C T Chow
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Takaaki Yasuhara
- Laboratory of Genome Stress Response, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
- Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Hiroshi Harada
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
| |
Collapse
|
|
9
|
Rodriguez R, Harris M, Kennedy LM. Deleting the ribosomal prolyl hydroxylase OGFOD1 protects mice against diet-induced obesity and insulin resistance. PLoS One 2024; 19:e0304761. [PMID: 38843265 PMCID: PMC11156292 DOI: 10.1371/journal.pone.0304761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/19/2024] [Indexed: 06/09/2024] Open
Abstract
Type 2 diabetes predisposes patients to heart disease, which is the primary cause of death across the globe. Type 2 diabetes often accompanies obesity and is defined by insulin resistance and abnormal glucose handling. Insulin resistance impairs glucose uptake and results in hyperglycemia, which damages tissues such as kidneys, liver, and heart. 2-oxoglutarate (2-OG)- and iron-dependent oxygenases (2-OGDOs), a family of enzymes regulating various aspects of cellular physiology, have been studied for their role in obesity and diet-induced insulin resistance. However, nothing is known of the 2-OGDO family member 2-oxoglutarate and iron-dependent prolyl hydroxylase domain containing protein 1 (OGFOD1) in this setting. OGFOD1 deletion leads to protection in cardiac ischemia-reperfusion injury and cardiac hypertrophy, which are two cardiac events that can lead to heart failure. Considering the remarkable correlation between heart disease and diabetes, the cardioprotection observed in OGFOD1-knockout mice led us to challenge these knockouts with high-fat diet. Wildtype mice fed a high-fat diet developed diet-induced obesity, insulin resistance, and glucose intolerance, but OGFOD1 knockout mice fed this same diet were resistant to diet-induced obesity and insulin resistance. These results support OGFOD1 down-regulation as a strategy for preventing obesity and insulin handling defects.
Collapse
Affiliation(s)
- Rebeca Rodriguez
- National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, United States of America
| | - Michael Harris
- National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, United States of America
| | - Leslie M. Kennedy
- National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD, United States of America
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America
| |
Collapse
|
|
10
|
Zhu YN, He J, Wang J, Guo W, Liu H, Song Z, Kang L. Parental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA. Nat Commun 2024; 15:4328. [PMID: 38773155 PMCID: PMC11109280 DOI: 10.1038/s41467-024-48658-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 05/08/2024] [Indexed: 05/23/2024] Open
Abstract
Parental experiences can affect the phenotypic plasticity of offspring. In locusts, the population density that adults experience regulates the number and hatching synchrony of their eggs, contributing to locust outbreaks. However, the pathway of signal transmission from parents to offspring remains unclear. Here, we find that transcription factor Forkhead box protein N1 (FOXN1) responds to high population density and activates the polypyrimidine tract-binding protein 1 (Ptbp1) in locusts. FOXN1-PTBP1 serves as an upstream regulator of miR-276, a miRNA to control egg-hatching synchrony. PTBP1 boosts the nucleo-cytoplasmic transport of pre-miR-276 in a "CU motif"-dependent manner, by collaborating with the primary exportin protein exportin 5 (XPO5). Enhanced nuclear export of pre-miR-276 elevates miR-276 expression in terminal oocytes, where FOXN1 activates Ptbp1 and leads to egg-hatching synchrony in response to high population density. Additionally, PTBP1-prompted nuclear export of pre-miR-276 is conserved in insects, implying a ubiquitous mechanism to mediate transgenerational effects.
Collapse
Affiliation(s)
- Ya Nan Zhu
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing He
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jiawen Wang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Wei Guo
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Hongran Liu
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zhuoran Song
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Le Kang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100101, China.
- College of Life Science, Hebei University, Baoding, Hebei, 071002, China.
| |
Collapse
|
|
11
|
Cao Y, Wang H, Hu S, Xu Q, Ma J, Wang H, Xiong X, Wang W, Wang L. PICK1 modulates glycolysis and angiogenesis of hypoxic endothelial cells by regulating iron homeostasis. Mol Cell Biochem 2024; 479:1297-1312. [PMID: 37368155 DOI: 10.1007/s11010-023-04795-z] [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: 05/03/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in regulating glycolysis and angiogenesis of hypoxic vascular endothelial cells through its potential effect on TfR1, which features a supersecondary structure that interacts with the PDZ domain. Iron chelator deferoxamine and TfR1 siRNA were employed to assess the impact of iron accumulation on angiogenesis, while the effects of PICK1 siRNA and overexpressing lentivirus on TfR1-mediated iron accumulation were also investigated in hypoxic human umbilical vein vascular endothelial cells (HUVECs). The study found that 72-h hypoxia impaired the proliferation, migration, and tube formation of HUVECs, and reduced the upregulation of vascular endothelial growth factor, HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, and PICK1, while increasing the expression of TfR1 as compared to 24-h hypoxia. Administration of deferoxamine or TfR1 siRNA reversed these effects and led to increased glycolysis, ATP content, and phosphofructokinase activity, along with increased PICK1 expression. PICK1 overexpression improved glycolysis, enhanced angiogenic capacity, and attenuated TfR1 protein upregulation in hypoxic HUVECs, with higher expression of angiogenic markers, which could be significantly reversed by the PDZ domain inhibitor. PICK1 knockdown exerted opposite effects. The study concluded that PICK1 modulated intracellular iron homeostasis, thereby promoting glycolysis and angiogenesis of HUVECs in response to prolonged hypoxia, at least in part, by regulating TfR1 expression.
Collapse
Affiliation(s)
- Yu Cao
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Hongbo Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Shuyu Hu
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Qiaomin Xu
- Department of Anesthesiology, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, 321400, Zhejiang, China
| | - Jun Ma
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Huile Wang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiangqing Xiong
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China
| | - Wantie Wang
- Institute of Ischemia-Reperfusion Injury, Wenzhou, 325035, Zhejian, China
| | - Liangrong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai, Ouhai, Wenzhou, 325000, Zhejiang, China.
| |
Collapse
|
|
12
|
Dou X, Chen Z, Liu Y, Li Y, Ye J, Lu L. Zebrafish mutants in egln1 display a hypoxic response and develop polycythemia. Life Sci 2024; 344:122564. [PMID: 38492922 DOI: 10.1016/j.lfs.2024.122564] [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: 01/22/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/18/2024]
Abstract
AIMS Prolyl hydroxylase domain 2 (PHD2), encoded by the Egln1 gene, serves as a pivotal regulator of the hypoxia-inducible factor (HIF) pathway and acts as a cellular oxygen sensor. Somatic inactivation of Phd2 in mice results in polycythemia and congestive heart failure. However, due to the embryonic lethality of Phd2 deficiency, its role in development remains elusive. Here, we investigated the function of two egln1 paralogous genes, egln1a and egln1b, in zebrafish. MAIN METHODS The egln1 null zebrafish were generated using the CRISPR/Cas9 system. Quantitative real-time PCR assays and Western blot analysis were employed to detect the effect of egln1 deficiency on the hypoxia signaling pathway. The hypoxia response of egln1 mutant zebrafish were assessed by analyzing heart rate, gill agitation frequency, and blood flow velocity. Subsequently, o-dianisidine staining and in situ hybridization were used to investigate the role of egln1 in zebrafish hematopoietic function. KEY FINDINGS Our data show that the loss of egln1a or egln1b individually has no visible effects on growth rate. However, the egln1a; egln1b double mutant displayed significant growth retardation and elevated mortality at around 2.5 months old. Both egln1a-null and egln1b-null zebrafish embryo exhibited enhanced tolerance to hypoxia, systemic hypoxic response that include hif pathway activation, increased cardiac activity, and polycythemia. SIGNIFICANCE Our research introduces zebrafish egln1 mutants as the first congenital embryonic viable systemic vertebrate animal model for PHD2, providing novel insights into hypoxic signaling and the progression of PHD2- associated disease.
Collapse
Affiliation(s)
- Xuehan Dou
- Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao, China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Zhongyuan Chen
- Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao, China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Yunzhang Liu
- Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao, China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Yun Li
- Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao, China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Junli Ye
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Ling Lu
- Laboratory for Marine Drugs and Bioproducts of Laoshan Laboratory, Qingdao, China; Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
| |
Collapse
|
|
13
|
Feng X, Chen Y, Yan T, Lu H, Wang C, Zhao L. Effects of various living-low and training-high modes with distinct training prescriptions on sea-level performance: A network meta-analysis. PLoS One 2024; 19:e0297007. [PMID: 38635743 PMCID: PMC11025749 DOI: 10.1371/journal.pone.0297007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/22/2023] [Indexed: 04/20/2024] Open
Abstract
This study aimed to separately compare and rank the effect of various living-low and training-high (LLTH) modes on aerobic and anaerobic performances in athletes, focusing on training intensity, modality, and volume, through network meta-analysis. We systematically searched PubMed, Web of Science, Embase, EBSCO, and Cochrane from their inception date to June 30, 2023. Based on the hypoxic training modality and the intensity and duration of work intervals, LLTH was divided into intermittent hypoxic exposure, continuous hypoxic training, repeated sprint training in hypoxia (RSH; work interval: 5-10 s and rest interval: approximately 30 s), interval sprint training in hypoxia (ISH; work interval: 15-30 s), short-duration high-intensity interval training (s-IHT; short work interval: 1-2 min), long-duration high-intensity interval training (l-IHT; long work interval: > 5 min), and continuous and interval training under hypoxia. A meta-analysis was conducted to determine the standardized mean differences (SMDs) among the effects of various hypoxic interventions on aerobic and anaerobic performances. From 2,072 originally identified titles, 56 studies were included in the analysis. The pooled data from 53 studies showed that only l-IHT (SMDs: 0.78 [95% credible interval; CrI, 0.52-1.05]) and RSH (SMDs: 0.30 [95% CrI, 0.10-0.50]) compared with normoxic training effectively improved athletes' aerobic performance. Furthermore, the pooled data from 29 studies revealed that active intermittent hypoxic training compared with normoxic training can effectively improve anaerobic performance, with SMDs ranging from 0.97 (95% CrI, 0.12-1.81) for l-IHT to 0.32 (95% CrI, 0.05-0.59) for RSH. When adopting a program for LLTH, sufficient duration and work intensity intervals are key to achieving optimal improvements in athletes' overall performance, regardless of the potential improvement in aerobic or anaerobic performance. Nevertheless, it is essential to acknowledge that this study incorporated merely one study on the improvement of anaerobic performance by l-IHT, undermining the credibility of the results. Accordingly, more related studies are needed in the future to provide evidence-based support. It seems difficult to achieve beneficial adaptive changes in performance with intermittent passive hypoxic exposure and continuous low-intensity hypoxic training.
Collapse
Affiliation(s)
- Xinmiao Feng
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| | - Yonghui Chen
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| | - Teishuai Yan
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| | - Hongyuan Lu
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| | - Chuangang Wang
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| | - Linin Zhao
- Sports Coaching College, Beijing Sport University, Haidian, Beijing, China
| |
Collapse
|
|
14
|
Jurisic A, Sung P, Wappett M, Daubriac J, Lobb IT, Kung W, Crawford N, Page N, Cassidy E, Feutren‐Burton S, Rountree JSS, Helm MD, O'Dowd CR, Kennedy RD, Gavory G, Cranston AN, Longley DB, Jacq X, Harrison T. USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF. Clin Transl Med 2024; 14:e1648. [PMID: 38602256 PMCID: PMC11007818 DOI: 10.1002/ctm2.1648] [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: 11/13/2023] [Revised: 02/23/2024] [Accepted: 03/17/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts. METHODS To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs). RESULTS Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8-positive T-lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival. CONCLUSIONS USP7-mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well-characterized VEGF transcription factor, HIF-1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs).
Collapse
Affiliation(s)
| | - Pei‐Ju Sung
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | - Mark Wappett
- Almac Discovery Ltd., Health Science BuildingBelfastUK
- Patrick G Johnston Centre for Cancer ResearchQueen's University BelfastBelfastUK
| | | | - Ian T. Lobb
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | - Wei‐Wei Kung
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | | | - Natalie Page
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | - Eamon Cassidy
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | | | | | | | | | | | - Gerald Gavory
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | | | - Daniel B. Longley
- Almac Discovery Ltd., Health Science BuildingBelfastUK
- Patrick G Johnston Centre for Cancer ResearchQueen's University BelfastBelfastUK
| | - Xavier Jacq
- Almac Discovery Ltd., Health Science BuildingBelfastUK
| | | |
Collapse
|
|
15
|
Shirai Y, Suwa T, Kobayashi M, Koyasu S, Harada H. DDX5 enhances HIF-1 activity by promoting the interaction of HIF-1α with HIF-1β and recruiting the resulting heterodimer to its target gene loci. Biol Cell 2024; 116:e2300077. [PMID: 38031929 DOI: 10.1111/boc.202300077] [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: 09/03/2023] [Revised: 11/18/2023] [Accepted: 11/22/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND INFORMATION Cancer cells acquire malignant characteristics and therapy resistance by employing the hypoxia-inducible factor 1 (HIF-1)-dependent adaptive response to hypoxic microenvironment in solid tumors. Since the underlying molecular mechanisms remain unclear, difficulties are associated with establishing effective therapeutic strategies. RESULTS We herein identified DEAD-box helicase 5 (DDX5) as a novel activator of HIF-1 and found that it enhanced the heterodimer formation of HIF-1α and HIF-1β and facilitated the recruitment of the resulting HIF-1 to its recognition sequence, hypoxia-response element (HRE), leading to the expression of a subset of cancer-related genes under hypoxia. CONCLUSIONS This study reveals that the regulation of HIF-1 recruitment to HRE is an important regulatory step in the control of HIF-1 activity. SIGNIFICANCE The present study provides novel insights for the development of strategies to inhibit the HIF-1-dependent expression of cancer-related genes.
Collapse
Affiliation(s)
- Yukari Shirai
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Tatsuya Suwa
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Minoru Kobayashi
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Sho Koyasu
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Harada
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
16
|
Fleischhammer TM, Dienemann S, Ulber N, Pepelanova I, Lavrentieva A. Detection of Hypoxia in 2D and 3D Cell Culture Systems Using Genetically Encoded Fluorescent Hypoxia Sensors. Methods Mol Biol 2024; 2755:31-48. [PMID: 38319567 DOI: 10.1007/978-1-0716-3633-6_2] [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] [Indexed: 02/07/2024]
Abstract
In vivo oxygen availability varies widely between cellular microenvironments, depending on the tissue of origin and its cellular niche. It has long been known that too high or too low oxygen concentrations can act as a biological stressor. Thus, the precise control of oxygen availability should be a consideration for cell culture optimization, especially in the field of three-dimensional (3D) cell culture. In this chapter, we describe a system for visualizing oxygen limitations at a cellular level using human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) that were genetically modified to express a fluorescent hypoxia sensor. This sensor can detect the activation of hypoxia-induced factors (HIF) transcription factors that lead to the expression of the oxygen-independent fluorescent protein, UnaG, at low oxygen concentrations. The response of these hypoxia reporter cells can be evaluated in two-dimensional (2D) and 3D cultivation platforms during exposure to hypoxia (1% O2) and normoxia (21% O2) using fluorescence microscopy and flow cytometry. We show that hypoxia reporter MSCs exhibit a hypoxia-induced fluorescence signal in both 2D and 3D cultivation platforms with fast decay kinetics after reoxygenation, rendering it a valuable tool for studying the cellular microenvironment and regenerative potential of hAD-MSCs in an in vivo-like setting.
Collapse
Affiliation(s)
| | - Sandra Dienemann
- Institute of Technical Chemistry, Leibniz University of Hanover, Hanover, Germany
| | - Nico Ulber
- Institute of Technical Chemistry, Leibniz University of Hanover, Hanover, Germany
| | - Iliyana Pepelanova
- Institute of Technical Chemistry, Leibniz University of Hanover, Hanover, Germany
| | - Antonina Lavrentieva
- Institute of Technical Chemistry, Leibniz University of Hanover, Hanover, Germany.
| |
Collapse
|
|
17
|
Flood D, Lee ES, Taylor CT. Intracellular energy production and distribution in hypoxia. J Biol Chem 2023; 299:105103. [PMID: 37507013 PMCID: PMC10480318 DOI: 10.1016/j.jbc.2023.105103] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress during hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here, we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research.
Collapse
Affiliation(s)
- Darragh Flood
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland
| | - Eun Sang Lee
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland
| | - Cormac T Taylor
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland.
| |
Collapse
|
|
18
|
Sharma P, Sri Swetha Victoria V, Praneeth Kumar P, Karmakar S, Swetha M, Reddy A. Cross-talk between insulin resistance and nitrogen species in hypoxia leads to deterioration of tissue and homeostasis. Int Immunopharmacol 2023; 122:110472. [PMID: 37392570 DOI: 10.1016/j.intimp.2023.110472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 05/19/2023] [Accepted: 06/07/2023] [Indexed: 07/03/2023]
Abstract
Hypoxia has been linked with insulin resistance as it produces changes in the metabolism of the cell; in which the adipocytes impede the insulin receptor tyrosine, phosphorylation, directing at decreased levels of transport of glucose. At this juncture, we are focusing on cross-talk between insulin resistance and nitrogen species in hypoxia, leading to the deterioration of tissue and homeostasis. Physiological levels of nitric oxide play a very crucial role in acting as a priority effector and signaling molecule, arbitrating the body's responses to hypoxia. Both ROS and RNS are associated with a reduction in IRS1 phosphorylation in tyrosine, which leads to reduced levels of IRS1 content and insulin response, which further leads to insulin resistance. Cellular hypoxia is a trigger to inflammatory mediators which signal tissue impairment and initiate survival requirements. But, hypoxia-mediated inflammation act as a protective role by an immune response and promotes wound healing during infection. In this review, we abridge the crosstalk between the inflammation and highlight the dysregulation in physiological consequences due to diabetes mellitus. Finally, we review various treatments available for its related physiological complications.
Collapse
Affiliation(s)
- Priyanshy Sharma
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India
| | - V Sri Swetha Victoria
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India
| | - P Praneeth Kumar
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India
| | - Sarbani Karmakar
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India
| | - Mudduluru Swetha
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India
| | - Amala Reddy
- Animal Cell Culture Laboratory, Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nādu, India.
| |
Collapse
|
|
19
|
Aggarwal R, Jain AK, Mehta V, Rath G. Amalgamation of Toll-Like Receptor and Hypoxic Signaling in Etiology of Preeclampsia. Appl Immunohistochem Mol Morphol 2023; 31:429-437. [PMID: 37249078 DOI: 10.1097/pai.0000000000001129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 04/05/2023] [Indexed: 05/31/2023]
Abstract
Inflammation and oxidative stress are involved in the pathogenesis of preeclampsia. Therefore, the aim of this study was to investigate the expression of Toll-like receptor (TLR) (TLR-4, HMGB1, NFκB, IκBα) and hypoxic (HIF-1α, HIF-1β, PHD, pVHL) pathway proteins in the placenta of preeclamptic pregnant women after 28 weeks of gestational period. A possible association between these 2 pathways was also explored. A total of 194 placental tissues of preeclamptic as well as healthy pregnant women were analyzed by immunohistochemistry. On the basis of gestational age, the samples were divided into 2 groups, I (28-36 wk) and II (36 wk onwards), with 55 and 139 samples in the respective groups. The expression of both TLR (TLR-4, HMGB1, NFκB, IκBα) and hypoxic (HIF-1α, HIF-1β, PHD, pVHL) pathway proteins were significantly modulated in the placental tissues of preeclampsia as compared with control. The 2 pathways were interlinked in preeclampsia. This study highlights the intercorrelation of both TLR and hypoxic signalling pathways that may be a causative factor for the pathophysiology of preeclampsia.
Collapse
Affiliation(s)
- Ruby Aggarwal
- Department of Anatomy, VMMC & Safdarjung Hospital
- ICMR-National Institute of Pathology (ICMR-NIP), Safdarjung Hospital Campus, New Delhi, India
| | - Arun Kumar Jain
- ICMR-National Institute of Pathology (ICMR-NIP), Safdarjung Hospital Campus, New Delhi, India
| | | | - Gayatri Rath
- Department of Anatomy, VMMC & Safdarjung Hospital
| |
Collapse
|
|
20
|
Zhang M, Xu T, Tong D, Li S, Yu X, Liu B, Jiang L, Liu K. Research advances in endometriosis-related signaling pathways: A review. Biomed Pharmacother 2023; 164:114909. [PMID: 37210898 DOI: 10.1016/j.biopha.2023.114909] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/17/2023] [Accepted: 05/17/2023] [Indexed: 05/23/2023] Open
Abstract
Endometriosis (EM) is characterized by the existence of endometrial mucosa outside the uterine cavity, which causesinfertility, persistent aches, and a decline in women's quality of life. Both hormone therapies and nonhormone therapies, such as NSAIDs, are ineffective, generic categories of EM drugs. Endometriosis is a benign gynecological condition, yet it shares a number of features with cancer cells, including immune evasion, survival, adhesion, invasion, and angiogenesis. Several endometriosis-related signaling pathways are comprehensively reviewed in this article, including E2, NF-κB, MAPK, ERK, PI3K/Akt/mTOR, YAP, Wnt/β-catenin, Rho/ROCK, TGF-β, VEGF, NO, iron, cytokines and chemokines. To find and develop novel medications for the treatment of EM, it is essential to implicitly determine the molecular pathways that are disordered during EM development. Additionally, research on the shared pathways between EM and tumors can provide hypotheses or suggestions for endometriosis therapeutic targets.
Collapse
Affiliation(s)
- Manlin Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tongtong Xu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Deming Tong
- Department of General Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Siman Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaodan Yu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Boya Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lili Jiang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Kuiran Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| |
Collapse
|
|
21
|
Strauss E, Gotz-Więckowska A, Sobaniec A, Chmielarz-Czarnocińska A, Szpecht D, Januszkiewicz-Lewandowska D. Hypoxia-Inducible Pathway Polymorphisms and Their Role in the Complications of Prematurity. Genes (Basel) 2023; 14:genes14050975. [PMID: 37239335 DOI: 10.3390/genes14050975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Excessive oxidative stress resulting from hyperoxia or hypoxia is a recognized risk factor for diseases of prematurity. However, the role of the hypoxia-related pathway in the development of these diseases has not been well studied. Therefore, this study aimed to investigate the association between four functional single nucleotide polymorphisms (SNPs) in the hypoxia-related pathway, and the development of complications of prematurity in relation to perinatal hypoxia. A total of 334 newborns born before or on the 32nd week of gestation were included in the study. The SNPs studied were HIF1A rs11549465 and rs11549467, VEGFA rs2010963, and rs833061. The findings suggest that the HIF1A rs11549465T allele is an independent protective factor against necrotizing enterocolitis (NEC), but may increase the risk of diffuse white matter injury (DWMI) in newborns exposed to hypoxia at birth and long-term oxygen supplementation. In addition, the rs11549467A allele was found to be an independent protective factor against respiratory distress syndrome (RDS). No significant associations with VEGFA SNPs were observed. These findings indicate the potential involvement of the hypoxia-inducible pathway in the pathogenesis of complications of prematurity. Studies with larger sample sizes are needed to confirm these results and explore their clinical implications.
Collapse
Affiliation(s)
- Ewa Strauss
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland
| | - Anna Gotz-Więckowska
- Department of Ophthalmology, Poznan University of Medical Sciences, Szamarzewskiego 84, 60-569 Poznan, Poland
| | - Alicja Sobaniec
- Department of Neonatology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland
| | - Anna Chmielarz-Czarnocińska
- Department of Ophthalmology, Poznan University of Medical Sciences, Szamarzewskiego 84, 60-569 Poznan, Poland
| | - Dawid Szpecht
- Department of Neonatology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland
| | - Danuta Januszkiewicz-Lewandowska
- Department of Medical Diagnostics, Poznan University of Medical Sciences, Dobra Street 38a, 60-595 Poznan, Poland
- Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Szpitalna 27/33, 60-572 Poznan, Poland
| |
Collapse
|
|
22
|
Hazra R, Hubert H, Little-Ihrig L, Ghosh S, Ofori-Acquah S, Hu X, Novelli EM. Insulin-like Growth Factor-1 Prevents Hypoxia/Reoxygenation-Induced White Matter Injury in Sickle Cell Mice. Biomedicines 2023; 11:692. [PMID: 36979670 PMCID: PMC10045140 DOI: 10.3390/biomedicines11030692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 02/26/2023] Open
Abstract
Occlusion of cerebral blood vessels causes acute cerebral hypoxia-an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage-identified as white matter lesions-in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD.
Collapse
Affiliation(s)
- Rimi Hazra
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Holland Hubert
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Lynda Little-Ihrig
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Samit Ghosh
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Solomon Ofori-Acquah
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Xiaoming Hu
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15240, USA
| | - Enrico M Novelli
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| |
Collapse
|
|
23
|
Tanaka N, Sakamoto T. Mint3 as a Potential Target for Cooling Down HIF-1α-Mediated Inflammation and Cancer Aggressiveness. Biomedicines 2023; 11:biomedicines11020549. [PMID: 36831085 PMCID: PMC9953510 DOI: 10.3390/biomedicines11020549] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/11/2023] [Accepted: 02/12/2023] [Indexed: 02/16/2023] Open
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds to the factor inhibiting HIF-1 (FIH-1) and inhibits its suppressive effect, leading to HIF-1α activation. Defects in Mint3 generally lead to improved acute inflammation, which is regulated by HIF-1α and subsequent glycolysis, as well as the suppression of the proliferation and metastasis of cancer cells directly through its expression in cancer cells and indirectly through its expression in macrophages or fibroblasts associated with cancer. Mint3 in inflammatory monocytes enhances the chemotaxis into metastatic sites and the production of vascular endothelial growth factors, which leads to the expression of E-selectin at the metastatic sites and the extravasation of cancer cells. Fibroblasts express L1 cell adhesion molecules in a Mint3-dependent manner and enhance integrin-mediated cancer progression. In pancreatic cancer cells, Mint3 directly promotes cancer progression. Naphthofluorescein, a Mint3 inhibitor, can disrupt the interaction between FIH-1 and Mint3 and potently suppress Mint3-mediated inflammation, cancer progression, and metastasis without causing marked adverse effects. In this review, we will introduce the potential of Mint3 as a therapeutic target for inflammatory diseases and cancers.
Collapse
|
|
24
|
A Plasmodium falciparum ubiquitin-specific protease (PfUSP) is essential for parasite survival and its disruption enhances artemisinin efficacy. Biochem J 2023; 480:25-39. [PMID: 36511651 DOI: 10.1042/bcj20220429] [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: 08/15/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/14/2022]
Abstract
Proteins associated with ubiquitin-proteasome system (UPS) are potential drug targets in the malaria parasite. The ubiquitination and deubiquitination are key regulatory processes for the functioning of UPS. In this study, we have characterized the biochemical and functional role of a novel ubiquitin-specific protease (USP) domain-containing protein of the human malaria parasite Plasmodium falciparum (PfUSP). We have shown that the PfUSP is an active deubiquitinase associated with parasite endoplasmic reticulum (ER). Selection linked integration (SLI) method for C-terminal tagging and GlmS-ribozyme mediated inducible knock-down (iKD) of PfUSP was utilized to assess its functional role. Inducible knockdown of PfUSP resulted in a remarkable reduction in parasite growth and multiplication; specifically, PfUSP-iKD disrupted ER morphology and development, blocked the development of healthy schizonts, and hindered proper merozoite development. PfUSP-iKD caused increased ubiquitylation of specific proteins, disrupted organelle homeostasis and reduced parasite survival. Since the mode of action of artemisinin and the artemisinin-resistance are shown to be associated with the proteasome machinery, we analyzed the effect of dihydroartemisinin (DHA) on PfUSP-iKD parasites. Importantly, the PfUSP-knocked-down parasite showed increased sensitivity to dihydroartemisinin (DHA), whereas no change in chloroquine sensitivity was observed, suggesting a role of PfUSP in combating artemisinin-induced cellular stress. Together, the results show that Plasmodium PfUSP is an essential protease for parasite survival, and its inhibition increases the efficacy of artemisinin-based drugs. Therefore, PfUSP can be targeted to develop novel scaffolds for developing new antimalarials to combat artemisinin resistance.
Collapse
|
|
25
|
Zhang Y, Jing M, Cai C, Zhu S, Zhang C, Wang Q, Zhai Y, Ji X, Wu D. Role of hydrogen sulphide in physiological and pathological angiogenesis. Cell Prolif 2022; 56:e13374. [PMID: 36478328 PMCID: PMC9977675 DOI: 10.1111/cpr.13374] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/08/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
The role of hydrogen sulphide (H2 S) in angiogenesis has been widely demonstrated. Vascular endothelial growth factor (VEGF) plays an important role in H2 S-induced angiogenesis. H2 S promotes angiogenesis by upregulating VEGF via pro-angiogenic signal transduction. The involved signalling pathways include the mitogen-activated protein kinase pathway, phosphoinositide-3 kinase pathway, nitric oxide (NO) synthase/NO pathway, signal transducer and activator of transcription 3 (STAT3) pathway, and adenosine triphosphate (ATP)-sensitive potassium (KATP ) channels. H2 S has been shown to contribute to tumour angiogenesis, diabetic wound healing, angiogenesis in cardiac and cerebral ischaemic tissues, and physiological angiogenesis during the menstrual cycle and pregnancy. Furthermore, H2 S can exert an anti-angiogenic effect by inactivating Wnt/β-catenin signalling or blocking the STAT3 pathway in tumours. Therefore, H2 S plays a double-edged sword role in the process of angiogenesis. The regulation of H2 S production is a promising therapeutic approach for angiogenesis-associated diseases. Novel H2 S donors and/or inhibitors can be developed in the treatment of angiogenesis-dependent diseases.
Collapse
Affiliation(s)
- Yan‐Xia Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Mi‐Rong Jing
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Chun‐Bo Cai
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Shuai‐Gang Zhu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Chao‐Jing Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Qi‐Meng Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina
| | - Yuan‐Kun Zhai
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,School of StomatologyHenan UniversityKaifengHenanChina
| | - Xin‐Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina,Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical SciencesHenan UniversityKaifengHenanChina
| | - Dong‐Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical SciencesHenan UniversityKaifengHenanChina,Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular MedicineHenan UniversityKaifengHenanChina,School of StomatologyHenan UniversityKaifengHenanChina
| |
Collapse
|
|
26
|
High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages. mBio 2022; 13:e0108622. [PMID: 36121152 PMCID: PMC9600926 DOI: 10.1128/mbio.01086-22] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), but the mechanisms behind diabetes-TB comorbidity are still undefined. Here, we studied the role of hypoxia-inducible factor-1 (HIF-1), a main regulator of metabolic and inflammatory responses, in the outcome of Mycobacterium tuberculosis infection of bone marrow-derived macrophages (BMM). We observed that M. tuberculosis infection of BMM increased the expression of HIF-1α and HIF-1-regulated genes. Treatment with the hypoxia mimetic deferoxamine (DFO) further increased levels of HIF-1-regulated immune and metabolic molecules and diminished the intracellular bacterial load in BMM and in the lungs of infected mice. The expression of HIF-1-regulated immunometabolic genes was reduced, and the intracellular M. tuberculosis levels were increased in BMM incubated with high-glucose levels or with methylglyoxal (MGO), a reactive carbonyl compound elevated in DM. In line with the in vitro findings, high M. tuberculosis levels and low HIF-1-regulated transcript levels were found in the lungs from hyperglycemic Leprdb/db compared with wild-type mice. The increased intracellular M. tuberculosis growth and the reduced expression of HIF-1-regulated metabolic and inflammatory genes in BMM incubated with MGO or high glucose were reverted by additional treatment with DFO. Hif1a-deficient BMM showed ablated responses of immunometabolic transcripts after mycobacterial infection at normal or high-glucose levels. We propose that HIF-1 may be targeted for the control of M. tuberculosis during DM. IMPORTANCE People living with diabetes who are also infected with M. tuberculosis are more likely to develop tuberculosis disease (TB). Why diabetic patients have an increased risk for developing TB is not well understood. Macrophages, the cell niche for M. tuberculosis, can express microbicidal mechanisms or be permissive to mycobacterial persistence and growth. Here, we showed that high glucose and carbonyl stress, which mediate diabetes pathogenesis, impair the control of intracellular M. tuberculosis in macrophages. Infection with M. tuberculosis stimulated the expression of genes regulated by the transcription factor HIF-1, a major controller of the responses to hypoxia, resulting in macrophage activation. High glucose and carbonyl compounds inhibited HIF-1 responses by macrophages. Mycobacterial control in the presence of glucose or carbonyl stress was restored by DFO, a compound that stabilizes HIF-1. We propose that HIF-1 can be targeted to reduce the risk of developing TB in people with diabetes.
Collapse
|
|
27
|
Bai H, Guo X, Tan Y, Wang Y, Feng J, Lei K, Liu X, Xiao Y, Bao C. Hypoxia inducible factor-1 signaling pathway in macrophage involved angiogenesis in materials-instructed osteo-induction. J Mater Chem B 2022; 10:6483-6495. [PMID: 35971918 DOI: 10.1039/d2tb00811d] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Although osteo-inductive materials are regarded as promising candidates for critical-sized bone repair, their clinical application is limited by ambiguous mechanisms. The hypoxia-inducible factor (HIF)-1 signaling pathway, which responds to hypoxic conditions, is involved in both angiogenesis and osteogenesis. Strategies harnessing HIF-1 signaling to promote angiogenesis have been applied and have succeeded in repairing segmental bone defects. Meanwhile, macrophages have been shown to have important immunoregulatory effects on material-induced osteo-induction and correlate with HIF-1 activity. Thus, it is reasonable to assume that HIF-activated macrophages may also play important roles in the angiogenesis of material-induced osteo-induction. To verify this assumption, a classical type of osteo-inductive calcium phosphate (TCPs) was utilized. First, using RNA sequencing, we found that hypoxia activated the HIF signaling pathway in macrophages, which contributed to angiogenesis in TCPs. In addition, after treatment with a conditioned medium extracted from the co-culture system of macrophages and TCPs under hypoxic conditions, the migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) significantly increased. In vivo, inhibition of HIF-1 or clearance of macrophages could result in impaired angiogenesis in TCPs. Finally, more blood vessels were formed in the TCPs group than in the control group. In conclusion, this study elucidated the vital role of the HIF signaling pathway in infiltrating macrophages during early vessel growth in material-induced osteo-induction. It is beneficial in advancing the exploration of the related mechanism and providing possible support for optimizing the applicability of osteo-inductive materials in bone repair.
Collapse
Affiliation(s)
- Hetian Bai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Xiaodong Guo
- National Center of Stomatology & National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Key Laboratory of Digital Stomatology, Department of Prosthodontics, Peking University School and Hospital of Stomatology, 100081, Beijing, China
| | - Yujie Tan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Yue Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Jing Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Kexin Lei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Xian Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Yu Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| |
Collapse
|
|
28
|
Targeting HIF-1α by Natural and Synthetic Compounds: A Promising Approach for Anti-Cancer Therapeutics Development. Molecules 2022; 27:molecules27165192. [PMID: 36014432 PMCID: PMC9413992 DOI: 10.3390/molecules27165192] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 11/19/2022] Open
Abstract
Advancement in novel target detection using improved molecular cancer biology has opened up new avenues for promising anti-cancer drug development. In the past two decades, the mechanism of tumor hypoxia has become more understandable with the discovery of hypoxia-inducible factor-1α (HIF-1α). It is a major transcriptional regulator that coordinates the activity of various transcription factors and their downstream molecules involved in tumorigenesis. HIF-1α not only plays a crucial role in the adaptation of tumor cells to hypoxia but also regulates different biological processes, including cell proliferation, survival, cellular metabolism, angiogenesis, metastasis, cancer stem cell maintenance, and propagation. Therefore, HIF-1α overexpression is strongly associated with poor prognosis in patients with different solid cancers. Hence, pharmacological targeting of HIF-1α has been considered to be a novel cancer therapeutic strategy in recent years. In this review, we provide brief descriptions of natural and synthetic compounds as HIF-1α inhibitors that have the potential to accelerate anticancer drug discovery. This review also introduces the mode of action of these compounds for a better understanding of the chemical leads, which could be useful as cancer therapeutics in the future.
Collapse
|
|
29
|
Zheng Y, Ma G, Wang T, Hofmann A, Song J, Gasser RB, Young ND. Ubiquitination pathway model for the barber's pole worm - Haemonchus contortus. Int J Parasitol 2022; 52:581-590. [PMID: 35853501 DOI: 10.1016/j.ijpara.2022.06.001] [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: 03/22/2022] [Revised: 06/10/2022] [Accepted: 06/11/2022] [Indexed: 11/29/2022]
Abstract
The ubiquitin-mediated pathway has been comprehensively explored in the free-living nematode Caenorhabditis elegans, but very little is known about this pathway in parasitic nematodes. Here, we inferred the ubiquitination pathway for an economically significant and pathogenic nematode - Haemonchus contortus - using abundant resources available for C. elegans. We identified 215 genes encoding ubiquitin (Ub; n = 3 genes), ubiquitin-activating enzyme (E1; one), -conjugating enzymes (E2s; 21), ligases (E3s; 157) and deubiquitinating enzymes (DUBs; 33). With reference to C. elegans, Ub, E1 and E2 were relatively conserved in sequence and structure, and E3s and DUBs were divergent, likely reflecting functional and biological uniqueness in H. contortus. Most genes encoding ubiquitination pathway components exhibit high transcription in the egg compared with other stages, indicating marked protein homeostasis in this early developmental stage. The ubiquitination pathway model constructed for H. contortus provides a foundation to explore the ubiquitin-proteasome system, crosstalk between autophagy and the proteasome system, and the parasite-host interactions. Selected E3 and DUB proteins which are very divergent in sequence and structure from host homologues or entirely unique to H. contortus and related parasitic nematodes may represent possible anthelmintic targets.
Collapse
Affiliation(s)
- Yuanting Zheng
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Guangxu Ma
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia; College of Animal Sciences, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Tao Wang
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Andreas Hofmann
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia; Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Kulmbach, Germany
| | - Jiangning Song
- Department of Data Science and AI, Faculty of IT, Monash University, Victoria, Australia; Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; Monash Data Futures Institute, Monash University, Victoria, Australia
| | - Robin B Gasser
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia.
| | - Neil D Young
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia.
| |
Collapse
|
|
30
|
Bai H, Wang Y, Zhao Y, Chen X, Xiao Y, Bao C. HIF signaling: A new propellant in bone regeneration. BIOMATERIALS ADVANCES 2022; 138:212874. [PMID: 35913258 DOI: 10.1016/j.bioadv.2022.212874] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/04/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
Bone tissue destruction leads to severe pain, physical flaws, and loss of motility. Bone repair using biocompatible and osteo-inductive scaffolds is regarded as a viable and potential therapeutic approach. However, for large-scale bone regeneration, oxygen and nutrient supply have become limiting factors. Further, a considerable need exists for recruited cell activities and blood vessel growth. Hypoxia-inducible factor (HIF) signaling pathways induced by hypoxia are involved in angiogenesis and osteogenesis. As an important transcription factor, HIF-1 functions by modulating vital genes, such as VEGF, PDK1, and EPO, and is a crucial regulator that influences the final fate of bone regeneration. Collectively, to achieve better osteogenesis results, the in-depth molecular mechanisms that underpin the links between materials, cells, and HIF signaling pathways must be determined. This review aimed to provide an in-depth insight into recent progress in HIF-regulated bone regeneration. Hypoxia and cellular oxygen-sensing mechanisms and their correlations with osteogenesis were determined, and recent studies on hypoxia-inducing and hypoxia-mimicking strategies were briefly described. Finally, the potential applications of HIF signaling in bone regeneration were highlighted. This review provides theoretical support for establishing a novel and viable bone repair strategy in the clinic by harnessing HIF signaling.
Collapse
Affiliation(s)
- Hetian Bai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China
| | - Yue Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China
| | - Yi Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China
| | - Xin Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China
| | - Yu Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China.
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, No. 14, Section 3, Renmin Nan Road, Chengdu 610041, Sichuan, China
| |
Collapse
|
|
31
|
Liu Y, Kong XX, He JJ, Xu YB, Zhang JK, Zou LY, Ding KF, Xu D. OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis. BMC Cancer 2022; 22:424. [PMID: 35440019 PMCID: PMC9020043 DOI: 10.1186/s12885-022-09508-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 04/05/2022] [Indexed: 12/19/2022] Open
Abstract
Background Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. Patients and methods Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. Results OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3β, we verified GSK3β was over-activated in OLA1-KO cell lines. Conclusion OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3β. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09508-1.
Collapse
Affiliation(s)
- Yue Liu
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Xiang-Xing Kong
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Jin-Jie He
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Yan-Bo Xu
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Jian-Kun Zhang
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Lu-Yang Zou
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China
| | - Ke-Feng Ding
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China. .,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China.
| | - Dong Xu
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China. .,Cancer Center, Zhejiang University, Zhejiang, Hangzhou, China.
| |
Collapse
|
|
32
|
Proteasome Inhibitors Decrease the Viability of Pulmonary Arterial Smooth Muscle Cells by Restoring Mitofusin-2 Expression under Hypoxic Conditions. Biomedicines 2022; 10:biomedicines10040873. [PMID: 35453623 PMCID: PMC9030547 DOI: 10.3390/biomedicines10040873] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/01/2022] [Accepted: 04/07/2022] [Indexed: 02/04/2023] Open
Abstract
Pulmonary hypertension (PH) is a severe progressive disease, and the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the main causes. Mitofusin-2 (MFN2) profoundly inhibits cell growth and proliferation in a variety of tumor cell lines and rat vascular smooth muscle cells. Down-regulation of MFN2 is known to contribute to PH. Proteasome inhibitors have been shown to inhibit the proliferation of PASMCs; however, there is no study on the regulation of proteasome inhibitors through MFN-2 in the proliferation of PASMCs, a main pathophysiology of PH. In this study, PASMCs were exposed to hypoxic conditions and the expression of MFN2 and cleaved-PARP1 were detected by Western blotting. The effects of hypoxia and proteasome inhibitors on the cell viability of PASMC cells were detected by CCK8 assay. The results indicated that hypoxia increases the viability and reduces the expression of MFN2 in a PASMCs model. MFN2 overexpression inhibits the hypoxia-induced proliferation of PASMCs. In addition, proteasome inhibitors, bortezomib and marizomib, restored the decreased expression of MFN2 under hypoxic conditions, inhibited hypoxia-induced proliferation and induced the expression of cleaved-PARP1. These results suggest that bortezomib and marizomib have the potential to improve the hypoxia-induced proliferation of PASMCs by restoring MFN2 expression.
Collapse
|
|
33
|
Mdzinarishvili A, Houson H, Hedrick A, Awasthi V. Evaluation of anti-inflammatory diphenyldihaloketone EF24 in transient ischemic stroke model. Brain Inj 2022; 36:279-286. [PMID: 35254869 DOI: 10.1080/02699052.2022.2034959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
OBJECTIVES Revascularization is necessary in patients with ischemic stroke, however it does not address inflammation that contribute to reperfusion injury and the early growth of ischemic core. We investigated EF24, an anti-inflammatory agent, in a stroke model. METHODS Ischemic stroke was induced in mice by occluding middle cerebral artery for 1 h followed by reperfusion. EF24 was given either 10 min post-reperfusion (EF24Post) or 10 min before occlusion (prophylactic, EF24Pro). Survival, ipsilateral uptake of radioactive infarct marker 18F-fluoroglucaric acid (FGA), inflammatory cytokines, and tetrazolium chloride (TTC) staining were assessed. RESULTS Survival was increased in both EF24-treated groups compared to the stroke+vehicle group. Ipsilateral 18F-FGA uptake increased 2.6-fold in stroke+vehicle group compared to sham group (p < 0.05); the uptake in EF24-treated groups and sham group was not significantly different. TTC-staining also showed reduction in infarct size by EF24 treatment. Plasma IL-6, TNF-α, and corticosterone did not show significant changes among groups. However, ipsilateral tissue in stroke+vehicle mice showed increased IL-6 (>90-fold) and TNF-α (3-fold); the tissue IL-6 and TNF-α were significantly reduced in stroke+EF24Pro and stroke+EF24Post groups. 18F-FGA uptake significantly correlated with tissue IL-6 levels. CONCLUSIONS EF24 controls infarct growth and suppresses tissue inflammation in ischemic stroke, which can be monitored by 18F-FGA uptake.
Collapse
Affiliation(s)
- Alexander Mdzinarishvili
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Hailey Houson
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Andria Hedrick
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Vibhudutta Awasthi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| |
Collapse
|
|
34
|
Bharti H, Singal A, Saini M, Cheema PS, Raza M, Kundu S, Nag A. Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity. Sci Rep 2022; 12:918. [PMID: 35042884 PMCID: PMC8766476 DOI: 10.1038/s41598-021-04619-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 12/22/2021] [Indexed: 11/08/2022] Open
Abstract
Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.
Collapse
Affiliation(s)
- Hina Bharti
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Aakriti Singal
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Manisha Saini
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Pradeep Singh Cheema
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Mohsin Raza
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Suman Kundu
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India.
| |
Collapse
|
|
35
|
He Q, Ma Y, Liu J, Zhang D, Ren J, Zhao R, Chang J, Guo ZN, Yang Y. Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke. Front Immunol 2021; 12:801985. [PMID: 34966392 PMCID: PMC8710457 DOI: 10.3389/fimmu.2021.801985] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 11/26/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.
Collapse
Affiliation(s)
- Qianyan He
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yinzhong Ma
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jie Liu
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Dianhui Zhang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jiaxin Ren
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Ruoyu Zhao
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - JunLei Chang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zhen-Ni Guo
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yi Yang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
36
|
Chung C. From oxygen sensing to angiogenesis: Targeting the hypoxia signaling pathway in metastatic kidney cancer. Am J Health Syst Pharm 2021; 77:2064-2073. [PMID: 33016992 DOI: 10.1093/ajhp/zxaa308] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE This article summarizes examples of current and emerging therapies that target the hypoxia and angiogenesis signaling pathways in the clear cell type of renal cell cancer (RCC), with an emphasis on the hypoxia signaling pathway. SUMMARY Mammalian cells transduce signals of decreased oxygen to hypoxia inducible factor (HIF), an intracellular heterodimer that mediates the adaptation of normal and tumor cells to oxygen deprivation. HIF is frequently overexpressed in cancer cells and is involved in the transcriptional activation of many genes essential for cell invasion, migration, survival, and angiogenesis (including vascular endothelial growth factor [VEGF]). Moreover, HIF confers resistance to cytotoxic chemotherapy and radiation therapy and is associated with poor prognosis in patients with cancer. Blocking the activity of HIF inhibits the expression of VEGF and oncogenic pathways, resulting in the inhibition of tumor growth. Interestingly, activation of oncogenes and/or inactivation of tumor suppressor genes (eg, the gene encoding von Hippel-Lindau [VHL] tumor suppressor protein) can activate tumorigenesis even with normal levels of oxygen, providing support for the notion that the HIF-VHL-VEGF axis is amenable to targeted therapies for the treatment of RCC. This article highlights the current understanding of the hypoxia signaling pathway and its relevance to RCC development. Pharmacologic agents targeting the hypoxia and angiogenesis signaling pathways are discussed. CONCLUSION Development of novel therapeutic agents that target the hypoxia and angiogenesis signaling pathways holds promise in the management of metastatic clear cell RCC.
Collapse
|
|
37
|
Hung SW, Zhang R, Tan Z, Chung JPW, Zhang T, Wang CC. Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review. Med Res Rev 2021; 41:2489-2564. [PMID: 33948974 PMCID: PMC8252000 DOI: 10.1002/med.21802] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 12/23/2020] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF-κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor-β, Wnt/β-catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N-acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti-inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.
Collapse
Affiliation(s)
- Sze Wan Hung
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | - Ruizhe Zhang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou
| | - Zhouyurong Tan
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | | | - Tao Zhang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
| | - Chi Chiu Wang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong
- Reproduction and Development, Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong
- School of Biomedical SciencesThe Chinese University of Hong KongHong Kong
- Chinese University of Hong Kong‐Sichuan University Joint Laboratory in Reproductive MedicineThe Chinese University of Hong KongHong Kong
| |
Collapse
|
|
38
|
Hirota K. HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review. Biomedicines 2021; 9:biomedicines9050468. [PMID: 33923349 PMCID: PMC8146675 DOI: 10.3390/biomedicines9050468] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/11/2022] Open
Abstract
Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors.
Collapse
Affiliation(s)
- Kiichi Hirota
- Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| |
Collapse
|
|
39
|
Lin Y, Miao LH, Liu B, Xi BW, Pan LK, Ge XP. Molecular cloning and functional characterization of the hypoxia-inducible factor-1α in bighead carp (Aristichthys nobilis). FISH PHYSIOLOGY AND BIOCHEMISTRY 2021; 47:351-364. [PMID: 33474683 DOI: 10.1007/s10695-020-00917-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 12/11/2020] [Indexed: 06/12/2023]
Abstract
HIF-l is the earliest documented and most widely studied hypoxia-inducible factor (HIF) and plays a key role in the cell hypoxia signal transduction pathway. Particularly, the HIF-1α protein is sensitive to oxygen and plays a critical role in hypoxia regulation. This study is the first to report on the molecular cloning and characterization of HIF-1α in bighead carp (Aristichthys nobilis; anHIF-1α). The full-length cDNA of anHIF-1α was 2361 bp, and encodes an estimated 674 amino acids with a predicted molecular mass of 76.10 kDa and a theoretical isoelectric point of 7.72. Moreover, the conserved basic Helix-Loop-Helix domain along with two Per-ARNT-Sim domains (A/B), and C-TAD were identified in this protein. Interestingly, the tertiary structure of the anHIF-1α protein was found to be extremely similar to that of mice. Multiple comparison and phylogenetic tree results demonstrated that anHIF-1α was highly conserved. Under normoxic conditions, anHIF-1α mRNA transcripts could be detected in all tissues examined with the highest expression level in the heart. With gradually decreasing oxygen concentrations, anHIF-1α mRNA level was upregulated significantly in the gill, liver, kidney, spleen, intestine, brain, and muscle tissues (P < 0.05). Similarly, anHIF-1α was expressed in all examined bighead carp tissues, and the results suggested that the upregulation of anHIF-1α at the transcriptional level may be an important stress response adaptation to hypoxia in bighead carp. Finally, based on the tertiary structure comparative analyses between anHIF-1α with mouse HIF-1α, we think the physiological function, and protein structure of HIF-1α could be compared between fish and mammal in the future.
Collapse
Affiliation(s)
- Yan Lin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Ling-Hong Miao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Bo Liu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Bing-Wen Xi
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Liang-Kun Pan
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Xian-Ping Ge
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| |
Collapse
|
|
40
|
Joutsen J, Da Silva AJ, Luoto JC, Budzynski MA, Nylund AS, de Thonel A, Concordet JP, Mezger V, Sabéran-Djoneidi D, Henriksson E, Sistonen L. Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion. Cell Rep 2021; 30:583-597.e6. [PMID: 31940498 DOI: 10.1016/j.celrep.2019.12.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 10/15/2019] [Accepted: 12/12/2019] [Indexed: 12/13/2022] Open
Abstract
Maintenance of protein homeostasis, through inducible expression of molecular chaperones, is essential for cell survival under protein-damaging conditions. The expression and DNA-binding activity of heat shock factor 2 (HSF2), a member of the heat shock transcription factor family, increase upon exposure to prolonged proteotoxicity. Nevertheless, the specific roles of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained unknown. Here, we found that HSF2 is critical for cell survival during prolonged proteotoxicity. Strikingly, our RNA sequencing (RNA-seq) analyses revealed that impaired viability of HSF2-deficient cells is not caused by inadequate induction of molecular chaperones but is due to marked downregulation of cadherin superfamily genes. We demonstrate that HSF2-dependent maintenance of cadherin-mediated cell-cell adhesion is required for protection against stress induced by proteasome inhibition. This study identifies HSF2 as a key regulator of cadherin superfamily genes and defines cell-cell adhesion as a determinant of proteotoxic stress resistance.
Collapse
Affiliation(s)
- Jenny Joutsen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Alejandro Jose Da Silva
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Jens Christian Luoto
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Marek Andrzej Budzynski
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Anna Serafia Nylund
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Aurelie de Thonel
- CNRS, UMR 7216 "Epigenetic and Cell Fate," 75250 Paris Cedex 13, France; University of Paris Diderot, Sorbonne Paris Cité, 75250 Paris Cedex 13, France; Département Hospitalo-Universitaire DHU PROTECT, Paris, France
| | - Jean-Paul Concordet
- INSERM U1154, CNRS UMR 7196, Muséum National d'Histoire Naturelle, Paris, France
| | - Valérie Mezger
- CNRS, UMR 7216 "Epigenetic and Cell Fate," 75250 Paris Cedex 13, France; University of Paris Diderot, Sorbonne Paris Cité, 75250 Paris Cedex 13, France; Département Hospitalo-Universitaire DHU PROTECT, Paris, France
| | - Délara Sabéran-Djoneidi
- CNRS, UMR 7216 "Epigenetic and Cell Fate," 75250 Paris Cedex 13, France; University of Paris Diderot, Sorbonne Paris Cité, 75250 Paris Cedex 13, France; Département Hospitalo-Universitaire DHU PROTECT, Paris, France
| | - Eva Henriksson
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland
| | - Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland.
| |
Collapse
|
|
41
|
Satija S, Kaur H, Tambuwala MM, Sharma P, Vyas M, Khurana N, Sharma N, Bakshi HA, Charbe NB, Zacconi FC, Aljabali AA, Nammi S, Dureja H, Singh TG, Gupta G, Dhanjal DS, Dua K, Chellappan DK, Mehta M. Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression. Curr Mol Pharmacol 2021; 14:321-332. [PMID: 33494692 DOI: 10.2174/1874467214666210120154929] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/24/2020] [Accepted: 10/09/2020] [Indexed: 11/22/2022]
Abstract
Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.
Collapse
Affiliation(s)
- Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Harpreet Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Prabal Sharma
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Manish Vyas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Navneet Khurana
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Neha Sharma
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Hamid A Bakshi
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Nitin B Charbe
- Departamento de Quimica Organica, Facultad de Quimica y de Farmacia, Pontificia Universidad Católica de Chile, Av. Vicuna McKenna 4860, 7820436 Macul, Santiago, Chile
| | - Flavia C Zacconi
- Departamento de Quimica Organica, Facultad de Quimica y de Farmacia, Pontificia Universidad Católica de Chile, Av. Vicuna McKenna 4860, 7820436 Macul, Santiago, Chile
| | - Alaa A Aljabali
- Yarmouk University - Faculty of Pharmacy, Department of Pharmaceutical Sciences, Irbid, Jordan
| | - Srinivas Nammi
- School of Science and Health, Western Sydney University, Penrith NSW 2751, Australia
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Thakur G Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Gaurav Gupta
- School of Pharmaceutical Sciences, Suresh Gyan Vihar University, Jaipur, India
| | - Daljeet S Dhanjal
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara-144411, Punjab, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo NSW 2007, Australia
| | - Dinesh K Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Meenu Mehta
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara-144411, Punjab, India
| |
Collapse
|
|
42
|
Wang X, Zhao D, Xie H, Hu Y. Interplay of long non-coding RNAs and HIF-1α: A new dimension to understanding hypoxia-regulated tumor growth and metastasis. Cancer Lett 2020; 499:49-59. [PMID: 33217445 DOI: 10.1016/j.canlet.2020.11.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/11/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022]
Abstract
Hypoxia is a feature of the solid tumor microenvironment that is associated with poor clinical outcomes in multiple tumor types. Hypoxia-induced factor-1 alpha (HIF-1α) is a master regulator of hypoxic adaption, has been demonstrated to modulate hypoxic gene expression profiling and signaling transduction networks, and is thus a potential therapeutic target. Despite hypoxic response signaling having being extensively studied, the involvement of long non-coding RNAs (lncRNAs) in the hypoxic response has become a new focus of attention. Emerging evidence has documented complex interactions between HIF-1α and lncRNAs, which contribute to the acquisition of multiple hallmarks of cancer. In this review, we focus on recent advances in the study of hypoxia and HIF-1α-regulated lncRNAs, and summarize the molecular mechanisms and functional outcomes of the interplay between lncRNAs and HIF-1α, which may provide important insights into cancer diagnosis and prognosis, enabling better control of cancer.
Collapse
Affiliation(s)
- Xingwen Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China
| | - Dong Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China
| | - Hui Xie
- State Key Laboratory of Robotics and Systems, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China
| | - Ying Hu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, 518055, China.
| |
Collapse
|
|
43
|
Ren H, Luo JQ, Gao YC, Chen MY, Chen XP, Zhou HH, Jiang Y, Zhang W. Genetic association of hypoxia inducible factor 1-alpha ( HIF1A) Pro582Ser polymorphism with risk of diabetes and diabetic complications. Aging (Albany NY) 2020; 12:12783-12798. [PMID: 32658866 PMCID: PMC7377833 DOI: 10.18632/aging.103213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/17/2020] [Indexed: 04/11/2023]
Abstract
Diabetes is an age-related chronic disease associated with a number of complications, emerging as one of the major causes of morbidity and mortality worldwide. Several studies indicated that hypoxia-inducible factor 1-alpha (HIF1A) genetic polymorphisms may be associated with diabetes and diabetic complications. However, this association remains ambiguous. Thus, we performed a meta-analysis to provide more precise conclusion on this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were applied to assess the strength of the relationships. There was a protective association between HIF1A Pro582Ser polymorphism and diabetes under the heterozygous genetic model (OR = 0.70, 95% CI = 0.55-0.91; P = 0.007). Similar associations were observed in diabetic complications risk under the allelic (OR = 0.69, 95% CI = 0.57-0.83; P < 0.001), homozygous (OR = 0.51, 95% CI = 0.30-0.87; P = 0.014), recessive (OR = 0.73, 95% CI = 0.59-0.90; P = 0.004) and dominant (OR = 0.40, 95% CI = 0.25-0.65; P < 0.001) genetic models. No effects of the HIF1A Ala588Thr polymorphism were found in risk of diabetes and diabetic complications. Taken together, these findings revealed the protective effect of HIF1A Pro582Ser polymorphism against diabetes and diabetic complications.
Collapse
Affiliation(s)
- Huan Ren
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| | - Jian-Quan Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Yong-Chao Gao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| | - Man-Yun Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| | - Ying Jiang
- Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P.R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, P.R. China
| |
Collapse
|
|
44
|
Tregub PP, Malinovskaya NA, Morgun AV, Osipova ED, Kulikov VP, Kuzovkov DA, Kovzelev PD. Hypercapnia potentiates HIF-1α activation in the brain of rats exposed to intermittent hypoxia. Respir Physiol Neurobiol 2020; 278:103442. [DOI: 10.1016/j.resp.2020.103442] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/19/2020] [Accepted: 04/06/2020] [Indexed: 12/30/2022]
|
|
45
|
Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol 2020; 11:260-274. [PMID: 32728529 PMCID: PMC7360518 DOI: 10.5306/wjco.v11.i5.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.
Collapse
Affiliation(s)
- Mónica T Fernandes
- School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Sofia M Calado
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Leonardo Mendes-Silva
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| | - José Bragança
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| |
Collapse
|
|
46
|
Kietzmann T. The air that we breeze: From 'Noble' discoveries of a general oxygen-sensing principle to its clinical use. Acta Physiol (Oxf) 2020; 228:e13416. [PMID: 31755645 DOI: 10.1111/apha.13416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/16/2019] [Accepted: 11/16/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine University of Oulu Oulu Finland
| |
Collapse
|
|
47
|
Martano M, Altamura G, Power K, Restucci B, Carella F, Borzacchiello G, Maiolino P. Evaluation of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) in Equine Sarcoid: An Immunohistochemical and Biochemical Study. Pathogens 2020; 9:E58. [PMID: 31947661 PMCID: PMC7168668 DOI: 10.3390/pathogens9010058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND equine sarcoids are the most frequent skin tumors in equidae worldwide. It is well known that delta bovine papillomaviruses are their causative agents. We have recently shown the presence in equine sarcoids of abnormal vessel structures, which could cause a hypoxic condition. The aim of this study was to analyze the expression of hypoxia-inducible factor-1 alpha (HIF-1α) in a subset of BPV positive equine sarcoids and explore the relationship with vascular endothelial growth factor (VEGF) expression. RESULTS 80% of equine sarcoids showed strong cytoplasmic staining in >60% of neoplastic fibroblasts, while 20% of samples showed a moderate cytoplasmic staining in 40-60% of neoplastic fibroblasts for HIF-1α. Results of Western blotting (WB) were consistent with immunohistochemistry (IHC). Moreover, a positive correlation between HIF-1α and VEGF expression (r = 0.60, p < 0.01) was observed. CONCLUSION we have shown that HIF-1α was strongly expressed in equine sarcoid. The upregulation of HIF-1α has been described in numerous tumors and can be modulated by many proteins encoded by transforming viruses. Thus, it is also possible that BPV could have a relevant role in HIF-1α pathway regulation, contributing to the development of equine sarcoids by promoting HIF-1α/VEGF mediated tumor angiogenesis.
Collapse
Affiliation(s)
- Manuela Martano
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Gennaro Altamura
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Karen Power
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Brunella Restucci
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Francesca Carella
- Department of Biology, University of Naples Federico II, MSA, 80126 Naples, Italy;
| | - Giuseppe Borzacchiello
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Paola Maiolino
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| |
Collapse
|
|
48
|
Now a Nobel gas: oxygen. Pflugers Arch 2019; 471:1343-1358. [PMID: 31754831 DOI: 10.1007/s00424-019-02334-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 11/15/2019] [Accepted: 11/18/2019] [Indexed: 02/07/2023]
Abstract
The recent bestowal of the Nobel Prize 2019 in Physiology or Medicine to Gregg L. Semenza, Sir Peter J. Ratcliffe, and William G. Kaelin Jr. celebrates a series of remarkable discoveries that span from the physiological research question on how oxygen deficiency (hypoxia) induces the red blood cell forming hormone erythropoietin (Epo) to the first clinical application of a novel family of Epo-inducing drugs to treat patients suffering from renal anemia. This review looks back at the most important findings made by the three Nobel laureates, highlights current research trends, and sheds an eye on future perspectives of hypoxia research, including emerging and potential clinical applications.
Collapse
|
|
49
|
Bao L, Chen Y, Lai HT, Wu SY, Wang JE, Hatanpaa KJ, Raisanen JM, Fontenot M, Lega B, Chiang CM, Semenza GL, Wang Y, Luo W. Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration. Nucleic Acids Res 2019; 46:6576-6591. [PMID: 29860315 PMCID: PMC6061882 DOI: 10.1093/nar/gky449] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 05/09/2018] [Indexed: 12/22/2022] Open
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the α subunit of HIF-1 (HIF-1α) and catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1α transactivation domain function but not increased HIF-1α protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.
Collapse
Affiliation(s)
- Lei Bao
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yan Chen
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hsien-Tsung Lai
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shwu-Yuan Wu
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jennifer E Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kimmo J Hatanpaa
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jack M Raisanen
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Miles Fontenot
- Medical Scientist Training Program, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bradley Lega
- Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Cheng-Ming Chiang
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gregg L Semenza
- Vascular Program, The Johns Hopkins Institute for Cell Engineering, Baltimore, MD 21205, USA
| | - Yingfei Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Weibo Luo
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| |
Collapse
|
|
50
|
Encinas JFA, Foncesca CH, Perez MM, Simões DP, da Costa Aguiar Alves B, Bacci MR, Maifrino LBM, Fonseca FLA, da Veiga GL. Role of hypoxia-inducible factor 1α as a potential biomarker for renal diseases-A systematic review. Cell Biochem Funct 2019; 37:443-451. [PMID: 31317578 DOI: 10.1002/cbf.3425] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 04/01/2019] [Accepted: 06/26/2019] [Indexed: 01/14/2023]
Abstract
Renal cells need oxygen for homeostasis; it is known for adjusting cellular functioning and the energy obtainment have a broad relationship with cellular respiration, through the O2 bioavailability. O2 homeostasis regulation in the kidney is mediated by hypoxia-inducible factors (HIFs). HIF is divided into three α isoforms, represented by HIF-1α, HIF-2α, and HIF-3α in addition to three paralogs of HIF-1β; these are involved in some metabolic processes, as well as in the pathogenesis of several diseases. Renal biopsy analyses of patients and experimental animal models aim to understand the relationship between HIF and protection against developing renal diseases or the induction of their onset, being thus this molecule can be considered a potential biomarker of renal disease. We carried out a systematic review to which we included studies on HIF-1α and renal disease in the last 5 years (2013-2018) in researches with humans and/or animal model through searches in three databases: LILACS, PubMed, and SciELO by two researchers. We obtained 22 articles that discussed the relationship with HIF as inductor or protector against renal disease and no relation between HIF and renal. We observed controversies remain regarding the relation between of HIF with renal diseases; this may be related to the different intracellular pathways mediated by HIF-1α, thereby determining differentiated cellular responses.
Collapse
Affiliation(s)
| | - Carlos Henrique Foncesca
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil
| | - Matheus Moreira Perez
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil
| | - Diogo Pimenta Simões
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil.,Universidade Municipal de São Caetano do Sul/USCS - São Caetano do Sul, Sao Caetano do Sul, Brazil
| | | | - Marcelo Rodrigues Bacci
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil
| | | | - Fernando Luiz Affonso Fonseca
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil.,Universidade Federal de São Paulo/UNIFESP - Diadema, São Paulo, Brazil
| | - Glaucia Luciano da Veiga
- Department of Clinical Analysis, Faculdade de Medicina do ABC/FMABC - Santo André, Santo André, Brazil
| |
Collapse
|