1
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Sonar S, Das A, Kalele K, Subramaniyan V. Exosome-based cancer vaccine: a cell-free approach. Mol Biol Rep 2025; 52:421. [DOI: 10.1007/s11033-025-10519-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/15/2025] [Indexed: 05/04/2025]
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2
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Chen X, Jiang J, He B, Luo S, Tan Q, Yao Y, Wan R, Xu H, Liu S, Pan X, Chen X, Li J. Piezo1 aggravates ischemia/reperfusion-induced acute kidney injury by Ca 2+-dependent calpain/HIF-1α/Notch signaling. Ren Fail 2025; 47:2447801. [PMID: 39780511 PMCID: PMC11721879 DOI: 10.1080/0886022x.2024.2447801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/08/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025] Open
Abstract
Macrophages play a vital role in the inflammation and repair processes of ischemia/reperfusion-induced acute kidney injury (IR-AKI). The mechanosensitive ion channel Piezo1 is significant in these inflammatory processes. However, the exact role of macrophage Piezo1 in IR-AKI is unknown. The main purpose of this study was to determine the role of macrophage Piezo1 in the injury and repair process in IR-AKI. Genetically modified mice with targeted knockout of Piezo1 in myeloid cells were established, and acute kidney injury was induced by bilateral renal vascular clamping surgery. Additionally, hypoxia treatment was performed on bone marrow-derived macrophages in vitro. Our data indicate that Piezo1 is upregulated in renal macrophages in mice with IR-AKI. Myeloid Piezo1 knockout provided protective effects in mice with IR-AKI. Mechanistically, the regulatory effects of Piezo1 on macrophages are at least partially linked to calpain signaling. Piezo1 activates Ca2+-dependent calpain signaling, which critically upregulates HIF-1α signaling. This key pathway subsequently influences the Notch and CCL2/CCR2 pathways, driving the polarization of M1 macrophages. In conclusion, our findings elucidate the biological functions of Piezo1 in renal macrophages, underscoring its role as a crucial mediator of acute kidney injury. Consequently, the genetic or pharmacological inhibition of Piezo1 presents a promising strategy for treating IR-AKI.
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Affiliation(s)
- Xiaoting Chen
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jintao Jiang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin He
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shangfei Luo
- Medical Research Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qiaorui Tan
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Youfen Yao
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rentao Wan
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Honglin Xu
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Silin Liu
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xianmei Pan
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin Chen
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Li
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- Medical Research Center, Shandong University of Traditional Chinese Medicine, Jinan, China
- Faculty of Biological Sciences, University of Leeds, UK
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3
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Alvarado-Ortiz E, Castañeda-Patlán MC, Moreno-Londoño AP, Tinajero-Rodríguez JM, Briseño-Díaz P, Sarabia-Sánchez MA, Vargas M, Ortiz-Sánchez E, Robles-Flores M. Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119968. [PMID: 40268059 DOI: 10.1016/j.bbamcr.2025.119968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.
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Affiliation(s)
- Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | | | - Paola Briseño-Díaz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Angel Sarabia-Sánchez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Vargas
- Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Martha Robles-Flores
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
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4
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Sipoloni VM, Silva-Silva JV, Ferreira EG, Lee EY, Junior JMB, Uemi M, de Medeiros LS, Jimenez PC, Veiga TAM. Rotenoids from the Roots of Vicia faba L. (Fabaceae): Structural Characterization, Cytotoxic Effects, and Molecular Docking. Chem Biodivers 2025:e01091. [PMID: 40418826 DOI: 10.1002/cbdv.202501091] [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: 03/28/2025] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025]
Abstract
The chemical study of the ethanolic extract from the roots of Vicia faba led to the isolation of two isoflavonoids, alfalone and 8-O-methylretusine, as well as a mixture of rotenoids, including clitoriacetal and clitoriacetal B, the latter of which is reported for the first time. These compounds were characterized through nuclear magnetic resonance and vibrational circular dichroism spectroscopies, and density functional theory calculations. The rotenoid mixture exhibited cytotoxic activity against HCT-116, MCF-7, and 501Mel cell lines, while showing no significant toxicity to NIH/3T3 cells. The predictive analysis identified several shared therapeutic targets across colorectal cancer, breast cancer, and melanoma. Key sites, including hypoxia-inducible factor 1-alpha (HIF1A), estrogen receptor, heat shock protein HSP 90-beta, and heat shock protein HSP 90-alpha, were highlighted for their critical roles in tumor progression and therapeutic resistance. Notably, clitoriacetal demonstrated an affinity for HIF1A, suggesting its involvement in the observed antitumor effects, likely through modulation of the HIF1A pathway. These findings underscore the potential of V. faba root-derived compounds as promising candidates for targeted cancer therapies.
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Affiliation(s)
- Victor Menezes Sipoloni
- Programa de Pós-Graduação em Biologia Química, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, Brazil
| | - João Victor Silva-Silva
- Laboratório de Química Medicinal e Computacional, Instituto de Física de São Carlos, Universidade de São Paulo, Sao Carlos, Brazil
| | - Elthon G Ferreira
- Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Sao Paulo, Brazil
| | - Eric Yoshitaka Lee
- Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, Sao Jose dos Campos, Brazil
| | | | - Miriam Uemi
- Departamento de Química, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, Brazil
| | - Lívia Soman de Medeiros
- Departamento de Química, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, Brazil
| | - Paula C Jimenez
- Departamento de Ciências do Mar, Instituto do Mar, Universidade Federal de São Paulo, Santos, Brazil
| | - Thiago A M Veiga
- Departamento de Química, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, Brazil
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5
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Maloba GO, Were T, Barasa E, Mohamed N, Arshi A, Gallyas F. Synergistic Effects of 2-Deoxyglucose and Diclofenac Sodium on Breast Cancer Cells: A Comparative Evaluation of MDA-231 and MCF7 Cells. Int J Mol Sci 2025; 26:4894. [PMID: 40430033 DOI: 10.3390/ijms26104894] [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: 04/17/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Resistance of breast cancers to chemotherapy remains a global challenge to date. Drug combination studies between anti-cancer agents are increasingly becoming therapeutic strategies, geared towards alleviating breast cancers. Previously, 2-deoxyglucose has been shown to target and interrupt glycolysis. Available evidence also suggests that diclofenac, which was originally designed as a pain reliever, could inhibit the proliferation of breast cancer cells. However, the reverse Warburg effect and other metabolic reprogramming mechanisms in breast cancers limit the pharmacological application of both 2-deoxyglucose and diclofenac as mono-therapeutic agents. The present study explores the additive anti-cancer effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells. In this study, MDA-231 and MCF7 cells were treated with 2-deoxyglucose and diclofenac sodium in single and combination doses before being evaluated for viability, cell growth, reactive oxygen species, apoptotic and necrotic phases, and migration abilities. Additionally, immunoblotting of pro-apoptotic proteins, Caspase-3 and Caspase-9, and a hypoxia-inducible factor-1 alpha, was also performed. The results showed that combination treatments of the cells with the drugs exhibited additive anti-cancer effects by limiting proliferation, enhancing cytotoxic reactive oxygen species generation, enhancing apoptosis and necrosis, limiting colony formation and expansion of cells, and inhibiting cell migration. The degrees of cytotoxicity of combined treatments were almost similar in both cell lines, although with minimal differences. Put together, these results reveal the novel synergistic effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells, hence potentially elevating their pharmacological profile in the overall breast cancer therapy.
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Affiliation(s)
- Geofrey Ouma Maloba
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary
| | - Tom Were
- Department of Pathology, Masinde Muliro University of Science and Technology, Kakamega 190-50100, Kenya
| | - Erick Barasa
- Department of Pathology, Masinde Muliro University of Science and Technology, Kakamega 190-50100, Kenya
| | - Nasreldeen Mohamed
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary
| | - Arshi Arshi
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary
| | - Ferenc Gallyas
- Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary
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6
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Benchia D, Bîcă OD, Sârbu I, Savu B, Farcaș D, Miron I, Postolache AL, Cojocaru E, Abbo O, Ciongradi CI. Targeting Pathways in Neuroblastoma: Advances in Treatment Strategies and Clinical Outcomes. Int J Mol Sci 2025; 26:4722. [PMID: 40429864 DOI: 10.3390/ijms26104722] [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: 04/14/2025] [Revised: 05/10/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Neuroblastoma (NB) is a childhood cancer originating from neural crest cells of the sympathetic nervous system. Despite the advances in multimodal therapy, the treatment of high-risk NB remains challenging. The present review outlines several evidence-related insights into the molecular mechanisms of NB pathogenesis, focusing on genetic drivers (e.g., MYCN amplification) and disrupted signaling pathways (PI3K/Akt/mTOR; Notch; Jak2/STAT3), as well as on the tumor microenvironment's role in progression and resistance. The authors highlight current and emerging therapeutic strategies, including molecularly targeted agents; immunotherapies; and differentiation approaches under investigation. The complexity and heterogeneity of NB underscores the need for continued translational research and for combined strategies aimed at improving outcomes for affected children, highlighting the need for integration of molecular profiling and precision medicine to guide treatment.
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Affiliation(s)
- Diana Benchia
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ovidiu Daniel Bîcă
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ioan Sârbu
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Bogdan Savu
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Diana Farcaș
- Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ingrith Miron
- Department of Mother and Child Medicine-Pediatrics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Anca Lavinia Postolache
- Department of Mother and Child Medicine-Pediatrics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I-Pathology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Olivier Abbo
- Department of Pediatric Surgery, Faculté de Médecine Purpan, Université Toulouse III-Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31300 Toulouse, France
| | - Carmen Iulia Ciongradi
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
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7
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Yamamoto M, Takai M, Yashiro N, Tamura M, Kusumoto Y, Nagano S, Taniguchi A, Shimomura N, Tsujiuchi T. Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions. Adv Biol Regul 2025; 96:101098. [PMID: 40345063 DOI: 10.1016/j.jbior.2025.101098] [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: 03/24/2025] [Revised: 04/18/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl2) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA1 to LPA6) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl2. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl2. CoCl2 treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl2 was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl2-treated DLD-1 cells was suppressed by AM966 (LPA1 antagonist) and enhanced by GRI-977143 (LPA2 agonist). Conversely, CoCl2 treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl2-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl2-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl2-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl2 treatment.
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Affiliation(s)
- Mao Yamamoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Miwa Takai
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Narumi Yashiro
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Moemi Tamura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Yuka Kusumoto
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Shion Nagano
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Anri Taniguchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Nanami Shimomura
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan.
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8
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Owida HA, Saleh RO, Mohammad SI, Vasudevan A, Roopashree R, Kashyap A, Nanda A, Ray S, Hussein A, Yasin HA. Deciphering the role of circular RNAs in cancer progression under hypoxic conditions. Med Oncol 2025; 42:191. [PMID: 40314834 DOI: 10.1007/s12032-025-02727-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 04/14/2025] [Indexed: 05/03/2025]
Abstract
Hypoxia, characterized by reduced oxygen levels, plays a pivotal role in cancer progression, profoundly influencing tumor behavior and therapeutic responses. A hallmark of solid tumors, hypoxia drives significant metabolic adaptations in cancer cells, primarily mediated by hypoxia-inducible factor-1α (HIF-1α), a key transcription factor activated in low-oxygen conditions. This hypoxic environment promotes epithelial-mesenchymal transition (EMT), enhancing cancer cell migration, metastasis, and the development of cancer stem cell-like properties, which contribute to therapy resistance. Moreover, hypoxia modulates the expression of circular RNAs (circRNAs), leading to their accumulation in the tumor microenvironment. These hypoxia-responsive circRNAs regulate gene expression and cellular processes critical for cancer progression, making them promising candidates for diagnostic and prognostic biomarkers in various cancers. This review delves into the intricate interplay between hypoxic circRNAs, microRNAs, and RNA-binding proteins, emphasizing their role as molecular sponges that modulate gene expression and signaling pathways involved in cell proliferation, apoptosis, and metastasis. It also explores the relationship between circRNAs and the tumor microenvironment, particularly how hypoxia influences their expression and functional dynamics. Additionally, the review highlights the potential of circRNAs as diagnostic and prognostic tools, as well as their therapeutic applications in innovative cancer treatments. By consolidating current knowledge, this review underscores the critical role of circRNAs in cancer biology and paves the way for future research aimed at harnessing their unique properties for clinical advancements. Specifically, this review examines the biogenesis, expression patterns, and mechanistic actions of hypoxic circRNAs, focusing on their ability to act as molecular sponges for microRNAs and their interactions with RNA-binding proteins. These interactions impact key signaling pathways related to tumor growth, metastasis, and drug resistance, offering new insights into the complex regulatory networks governed by circRNAs under hypoxic stress.
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Affiliation(s)
- Hamza Abu Owida
- Department of Medical Engineering, Faculty of Engineering, Al-Ahliyya Amman University, Amman, Jordan
| | - Raed Obaid Saleh
- Department of Medical Laboratories Techniques, College of Health and Medical Techniques, University of Al Maarif, Al Anbar, 31001, Iraq.
| | - Suleiman Ibrahim Mohammad
- Research Follower, INTI International University, 71800, Negeri Sembilan, Malaysia.
- Electronic Marketing and Social Media, Economic and Administrative Sciences, Zarqa University, Zarqa, Jordan.
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anima Nanda
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751003, India
| | - Ahmed Hussein
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
| | - Hatif Abdulrazaq Yasin
- Department of Medical Laboratories Technology, Al-Nisour University College, Nisour Seq. Karkh, Baghdad, Iraq
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9
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Jeng LB, Shih FY, Liao YW, Shyu WC, Teng CF. Hypoxic tumor cell line lysate-pulsed dendritic cell vaccine exhibits better therapeutic effects on hepatocellular carcinoma. Br J Cancer 2025; 132:837-848. [PMID: 40050434 PMCID: PMC12041587 DOI: 10.1038/s41416-025-02975-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/03/2025] [Accepted: 02/26/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Dendritic cell (DC) vaccine is a promising immunotherapy for hepatocellular carcinoma (HCC) via triggering antigen-specific anti-tumor immunity. Hypoxia contributes to higher level and broader spectrum of antigen expression in tumor cells. METHODS This study aims to compare immunological activity and therapeutic efficacy between hypoxic and normoxic HCC cell line lysate-pulsed DC vaccines. RESULTS The results showed that hypoxic HCC cell line lysate-pulsed DC vaccines exhibited a stronger activity in producing interleukin-12 and promoting T cell proliferation and cytotoxicity in vitro. In HCC mice, hypoxic HCC cell line lysate-pulsed DC vaccines displayed a better efficacy in improving survival time and tumor volume and inducing intratumoral cytotoxic T cell infiltration and activation as well as tumor cell apoptosis. Adenylate kinase 4-derived antigens were important for hypoxic HCC cell line lysate-pulsed DC vaccine-elicited T cell killing. CONCLUSIONS In conclusion, this study demonstrated hypoxic HCC cell line lysate-pulsed DC vaccine as a potential therapeutic strategy for HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan, ROC
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
- Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan, ROC
- School of Medicine, China Medical University, Taichung, Taiwan, ROC
| | - Fu-Ying Shih
- Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, Taiwan, ROC
| | - Yu-Wen Liao
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC
| | - Woei-Cherng Shyu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC
- Translational Medicine Research Center, China Medical University Hospital, Taichung, 404, Taiwan, ROC
- Department of Neurology, China Medical University Hospital, Taichung, Taiwan, ROC
- Department of Occupational Therapy, Asia University, Taichung, Taiwan, ROC
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan, ROC.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan, ROC.
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10
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Huang Z, Wang M, Kong Y, Li G, Tian H, Wu H, Zheng J, Mo S, Xu J, Dong F. Photoacoustic-Based Intra- and Peritumoral Radiomics Nomogram for the Preoperative Prediction of Expression of Ki-67 in Breast Malignancy. Acad Radiol 2025; 32:2422-2434. [PMID: 39572295 DOI: 10.1016/j.acra.2024.10.036] [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: 08/27/2024] [Revised: 10/12/2024] [Accepted: 10/22/2024] [Indexed: 01/12/2025]
Abstract
RATIONALE AND OBJECTIVES This study investigated the preoperative predictive efficiency of radiomics derived from photoacoustic (PA) imaging, integrated with the clinical features of Ki-67 expression in malignant breast cancer (BC), with a focus on both intratumoral and peritumoral regions. METHODS This study involved 359 patients, divided into a training set (n = 251) and a testing set (n = 108). Radiomic features were extracted from intratumoral and peritumoral regions using PA imaging. Multivariate logistic regression was employed to identify significant clinical factors. LASSO regression was used to select the features extracted from the training set. The selected radiomics features were combined with clinical features to develop a radiomics nomogram. The predictive efficiency of the model was assessed using the area under the receiver operating characteristic curve (AUC), and its clinical utility and accuracy were evaluated through decision curve analysis and calibration curves, respectively. RESULTS The developed nomogram combined 6 mm peritumoral data with intratumoral and clinical features and showed excellent diagnostic performance, achieving an AUC of 0.899 in the testing set. They both showed good calibrations. The outperformed models based solely on clinical features or other radiomics methods, with the 6 mm surrounding tumor area proving most effective in identifying Ki-67 status in BC patients. CONCLUSION Integrating PA radiomics with clinical features offers a robust preoperative tool for predicting Ki-67 status in BC, optimizing the delineation of peritumoral regions for enhanced diagnostic precision. The model's strong performance supports its potential as a non-invasive adjunct to traditional biopsy methods, aiding in the personalized management of BC treatment.
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Affiliation(s)
- Zhibin Huang
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Mengyun Wang
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Yao Kong
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Guoqiu Li
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Hongtian Tian
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Huaiyu Wu
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Jing Zheng
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Sijie Mo
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Jinfeng Xu
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.)
| | - Fajin Dong
- Department of Ultrasound, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, Guangdong, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.); The Second Clinical Medical College, Jinan University, Shenzhen 518020, China (Z.H., M.W., Y.K., G.L., H.T., H.W., J.Z., S.M., J.X., F.D.).
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11
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Zhang Y, Xie Y, Xia S, Ge X, Li J, Liu F, Jia F, Wang S, Zhou Q, Gao M, Fang W, Zheng C. The Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411980. [PMID: 40125821 PMCID: PMC12097124 DOI: 10.1002/advs.202411980] [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] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/10/2025] [Indexed: 03/25/2025]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP-treated mice. TZP inhibited glucose uptake and destabilized hypoxia-inducible factor-1 alpha (HIF-1α) with reduced expression and activity of the rate-limiting enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK-1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient-derived xenograft (PDX) mouse model accompanied by HIF-1α mediated PFKFB3-PFK-1 inhibition. Therefore, the study provides strong evidence that glycolysis-blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies.
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Affiliation(s)
- Yikai Zhang
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Yi Xie
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Shenglong Xia
- Department of GastroenterologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Xinnuo Ge
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Jiaying Li
- Center for Basic and Translational ResearchThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Fang Liu
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Fan Jia
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of EducationDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou310009P. R. China
| | - Shengyao Wang
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Qiao Zhou
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Menghan Gao
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Weihuan Fang
- Department of Veterinary MedicineZhejiang UniversityHangzhou310009P. R. China
| | - Chao Zheng
- Department of EndocrinologyThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009P. R. China
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12
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Supriya M, Singh MK, Singh L, Sharma S, Meel R, Lomi N, Sen S, Kashyap S. Exploring metabolic biomarkers in primary and chemoreduced retinoblastoma with patient outcome. Br J Ophthalmol 2025:bjo-2024-326495. [PMID: 40216531 DOI: 10.1136/bjo-2024-326495] [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: 09/12/2024] [Accepted: 03/27/2025] [Indexed: 04/23/2025]
Abstract
AIMS The goal of this study is to identify the pathological findings and expression of metabolic markers (GLUT-1, PDK-1 and PGC1α) in the tumour microenvironment of both primary and chemoreduced retinoblastoma (Rb) and to correlate with clinicopathological parameters and patient outcome. METHODS 81 prospective cases were included, in which 53 cases underwent primary enucleation and 28 cases received chemotherapy before enucleation. Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of metabolic markers in primary and chemoreduced Rb. RESULTS Tumour microenvironment and histopathological findings were different for both primary and chemoreduced Rb. Increased immunohistochemical expression of GLUT-1, PDK-1 and PGC1α was found in primary Rb as compared with chemoreduced Rb. mRNA expression was also found to be upregulated in primary Rb compared with chemoreduced. On univariate analysis, the presence of more than one histopathological high-risk factor (HRFs>1) and PDK-1 immunoexpression was statistically significant with overall survival. On prognostication in primary and chemoreduced cases with hypoxia, we found increased HR in cases with retrolaminar ON invasion, presence of more than one HRF, and presence of PDK-1 and PGC-1α immunoexpression. CONCLUSIONS This is the first of its kind study predicting a relevant role of the metabolic markers in primary and chemoreduced Rb with prognostic significance. Differential expression of these markers in both groups of Rb is a novel finding and might be an interesting and beneficial target for the management of Rb patients.
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Affiliation(s)
- Manisha Supriya
- Ocular Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Mithalesh Kumar Singh
- Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, USA
- All India Institute of Medical Sciences, New Delhi, India
| | - Lata Singh
- Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Shivam Sharma
- Ophthalmology, All India Institute of Medical Sciences, New Delhi, India
| | - Rachna Meel
- Ophthalmology, All India Institute of Medical Sciences, New Delhi, India
| | - Neiwete Lomi
- Ophthalmology, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Sen
- Ocular Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Kashyap
- Ocular Pathology, All India Institute of Medical Sciences, New Delhi, India
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13
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Li Y, Liu X, Dong Y, Zhou Y. Angiogenesis causes and vasculogenic mimicry formation in the context of cancer stem cells. Biochim Biophys Acta Rev Cancer 2025; 1880:189323. [PMID: 40239849 DOI: 10.1016/j.bbcan.2025.189323] [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: 11/14/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/18/2025]
Abstract
Tumor occurrence, development, invasion, and metastasis are regulated by multiple mechanisms. Among these, angiogenesis promotes tumor progression mainly by supplying tumor tissue and providing channels for tumor metastasis. Cancer stem cells (CSCs) are another important factor affecting tumor progression by involving in tumor initiation and development, while remaining insensitive to conventional antitumor treatments. Among treatment strategies for them, owing to the existence of alternative angiogenic pathways or the risk of damaging normal stem cells, the clinical effect is not ideal. Angiogenesis and CSCs may influence each other in this process. Tumor angiogenesis can support CSC self-renewal by providing a suitable microenvironment, whereas CSCs can regulate tumor neovascularization and mediate drug resistance to anti-angiogenic therapy. This review summarized the role of vascular niche formed by angiogenesis in CSC self-renewal and stemness maintenance, and the function of CSCs in endothelial progenitor cell differentiation and pro-angiogenic factor upregulation. We also elucidated the malignant loop between CSCs and angiogenesis promoting tumor progression. Additionally, we summarized and proposed therapeutic targets, including blocking tumor-derived endothelial differentiation, inhibiting pro-angiogenic factor upregulation, and directly targeting endothelial-like cells comprising CSCs. And we analyzed the feasibility of these strategies to identify more effective methods to improve tumor treatment.
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Affiliation(s)
- Ying Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaofang Liu
- Department of Anus and Intestine Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaodong Dong
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
| | - Yingying Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
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14
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Ibrahim E, Sohail SK, Ihunwo A, Eid RA, Al-Shahrani Y, Rezigalla AA. Effect of high-altitude hypoxia on function and cytoarchitecture of rats' liver. Sci Rep 2025; 15:12771. [PMID: 40229399 PMCID: PMC11997024 DOI: 10.1038/s41598-025-97863-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: 07/08/2024] [Accepted: 04/08/2025] [Indexed: 04/16/2025] Open
Abstract
The liver is central to metabolic, detoxification, and homeostatic functions. Exposure to hypobaric hypoxia at high altitudes causes detrimental effects on the liver, leading to injury. This study evaluated the effect of hypoxia-induced at high altitudes on liver function, oxidative stress, and histopathological changes in rats. This study used 24 male Wistar rats (aged 8-10 weeks). The hypoxia (hypobaric hypoxia) was inducted at a high altitude of 2,100 m above sea level. Normoxia is defined as 40 m above the sea level. The rats were randomly divided into two groups: a control group maintained at low altitudes and an experimental group exposed to high altitudes for eight weeks. Blood samples were collected from all rats through a cardiac puncture, and liver samples were taken through an abdominal approach. All samples were processed through standard methods and evaluated for liver function tests and histopathological assessment. Serum aspartate aminotransferase and alanine transaminase levels significantly increased by 25% and 30%, respectively, in the high-altitude group compared to controls (p < 0.01), indicating mild hepatocellular damage. Oxidative stress assessment indicated a significant elevation in malondialdehyde by 42% in the liver homogenates of high-altitude rats compared to controls (p < 0.001). Moreover, Superoxide dismutase activity and glutathione content decreased by 18% and 22% in the high-altitude group (p < 0.01), confirming the increased oxidative stress. Histologically, minimal inflammatory infiltration was observed in the rat livers at high altitudes, with no signs of necrosis or severe structural changes. Subclinical liver dysfunction, as evidenced by altered serum enzyme levels and increased oxidative stress with mild histological changes, is induced by high-altitude hypoxia in rats. This study's results support that a hypobaric hypoxic environment physiologically stresses the liver. Further research into the long-term implications of hypobaric hypoxia and the adaptive responses of the liver is warranted.
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Grants
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- UB-14-1442 Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
- Deputyship for Research & Innovation, Ministry of Education, in Saudi Arabia, which has supported this research work with the project number (UB-14-1442).
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Affiliation(s)
- Elwathiq Ibrahim
- Department of Anatomy, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | - Shahzada Khalid Sohail
- Department of Pathology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | - Amadi Ihunwo
- School of Anatomical Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Refaat A Eid
- Department of Pathology, College of Medicine, King Khalid University, Abha, 62529, 12573, Saudi Arabia
| | - Yazeed Al-Shahrani
- Department of Emergency Medicine, King Abdalla Hospital, Health Affairs Administration, Bisha, Saudi Arabia
| | - Assad Ali Rezigalla
- Department of Anatomy, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia.
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15
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Kim D, Nam HJ, Baek SH. Ubiquitination of transcription factors in cancer: unveiling therapeutic potential. Mol Oncol 2025. [PMID: 40227962 DOI: 10.1002/1878-0261.70033] [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: 11/13/2024] [Revised: 03/05/2025] [Accepted: 03/21/2025] [Indexed: 04/16/2025] Open
Abstract
Transcription factors, pivotal in gene expression regulation, are essential in cancer progression. Their function is meticulously regulated by post-translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the function of transcription factors, contingent on the context. In cancers, dysregulated ubiquitination of transcription factors contributes to the hallmark of uncontrolled growth and survival of tumors. For example, tumor suppressors such as p53 might be degraded prematurely due to abnormal ubiquitination, causing genomic instability. On the other hand, oncogenic transcription factors may gain stability via ubiquitination, thus facilitating tumorigenesis. Targeting the ubiquitin-proteasome system (UPS) therefore could be a viable therapeutic approach in cancer. Emerging treatments aim to block the ubiquitination of oncogenic transcription factors or to stabilize tumor suppressors. This review underscores the critical impact of transcription factor-altered ubiquitination on cancer progression. Additionally, it outlines innovative therapeutic approaches that involve inhibitors or drugs directed at specific ubiquitin E3 ligases and deubiquitinases (DUBs) that regulate transcription factor activity.
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Affiliation(s)
- Dongha Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Jin Nam
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Korea
- Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Korea
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Korea
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16
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Najary S, Nokhbatolfoghahaei H, Khojasteh A. The effect of Hypoxia-Inducible Factor-1a stabilization on bone regeneration during distraction osteogenesis: A systematic review of animal studies. Arch Oral Biol 2025; 172:106184. [PMID: 39893997 DOI: 10.1016/j.archoralbio.2025.106184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/07/2025] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
OBJECTIVE This systematic review described Hypoxia-Inducible Factor-1a stabilization or upregulation approaches along with underlying signaling pathways and assessed bone regeneration, angiogenesis, and consolidation time during DO in animal models. DESIGN A comprehensive and systematic search of electronic databases including PubMed, Scopus, and ScienceDirect was performed till December 26, 2023. The search was limited to English articles, and no time restrictions were applied. RESULTS A total of 14 studies met the inclusion criteria and were included for final review. Four methods have been shown to activate the HIF pathway including genetic, pharmacological, mechanical, and cell preconditioning approaches. Deferoxamine (DFO) was administered as a pharmacological hypoxia-mimicking agent in many studies reporting acceptable outcomes on bone regeneration and acceleration of bone consolation. Applying mechanical loads at the optimal rate and amplitude serves as a minimally invasive approach with acceptable results. HIF-related signaling pathways increase osteogenesis and angiogenesis during DO, potentially through VHL/HIF-1a/VEGF, Wnt/β-catenin, and Mesenchymal-Epithelial transition (MET) signaling pathways. CONCLUSION Activation of HIF-related signaling pathways enhances and accelerates bone regeneration during the consolidation phase of distraction osteogenesis. The most feasible approach with the least side effects must be selected for further clinical studies.
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Affiliation(s)
- Shaghayegh Najary
- Student Research Committee, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hanieh Nokhbatolfoghahaei
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Arash Khojasteh
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Cranio-Maxillofacial Surgery, University Hospital, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
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17
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Wang Y, Zhou H, Ju S, Dong X, Zheng C. The solid tumor microenvironment and related targeting strategies: a concise review. Front Immunol 2025; 16:1563858. [PMID: 40207238 PMCID: PMC11979131 DOI: 10.3389/fimmu.2025.1563858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/12/2025] [Indexed: 04/11/2025] Open
Abstract
The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
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18
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Wei D, Zhai B, Zeng H, Liu L, Gao H, Xiang S, Liu X, Ma J, Lin Y, Yao Y, Wang P. TRMT10A regulates tRNA-ArgCCT m 1G9 modification to generate tRNA-derived fragments influencing vasculogenic mimicry formation in glioblastoma. Cell Death Dis 2025; 16:209. [PMID: 40140670 PMCID: PMC11947273 DOI: 10.1038/s41419-025-07548-6] [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: 09/17/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025]
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor. The formation of vasculogenic mimicry (VM) in GBM is closely related to poor patient prognosis. Therefore, it is urgently necessary to explore the mechanisms that promote VM formation in GBM and identify therapeutic targets. CGGA data analysis revealed that TRMT10A expression is significantly downregulated in WHO grade IV primary glioma samples compared to grade II samples, consistent with the protein expression levels. Additionally, GBM patients with low TRMT10A expression have poorer prognoses. In human glioma cells, TRMT10A expression is significantly lower than in human astrocytes. Knockdown of TRMT10A reduces m1G9 modification of tRNA-ArgCCT, upregulates tRF-22 expression, and promotes glioma cell proliferation, migration, invasion, and tube formation. Overexpression of tRF-22 in glioma cells significantly downregulates MXD1 expression. tRF-22 negatively regulates MXD1 expression by binding to its 3'UTR, reducing MXD1's transcriptional inhibition of HIF1A, thereby promoting glioma cell proliferation, migration, invasion, and tube formation. Overexpression of TRMT10A combined with tRF-22 inhibition significantly reduces the number of VM channels and inhibits tumor growth in xenograft models in nude mice. This study elucidates the mechanism by which TRMT10A affects VM formation in glioma and provides a novel therapeutic target for GBM.
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Affiliation(s)
- Deng Wei
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Bei Zhai
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Hui Zeng
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Long Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Han Gao
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Shiqi Xiang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Xiaobai Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Yang Lin
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Yilong Yao
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ping Wang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China.
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19
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Wu J, Li R, Wang J, Zhu H, Ma Y, You C, Shu K. Reactive Astrocytes in Glioma: Emerging Opportunities and Challenges. Int J Mol Sci 2025; 26:2907. [PMID: 40243478 PMCID: PMC11989224 DOI: 10.3390/ijms26072907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/16/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Gliomas are the most prevalent malignant tumors in the adult central nervous system (CNS). Glioblastoma (GBM) accounts for approximately 60-70% of primary gliomas. It is a great challenge to human health because of its high degree of malignancy, rapid progression, short survival time, and susceptibility to recurrence. Owing to the specificity of the CNS, the glioma microenvironment often contains numerous glial cells. Astrocytes are most widely distributed in the human brain and form reactive astrocyte proliferation regions around glioma tissue. In addition, astrocytes are activated under pathological conditions and regulate tumor and microenvironmental cells through cell-to-cell contact or the secretion of active substances. Therefore, astrocytes have attracted attention as important components of the glioma microenvironment. Here, we focus on the mechanisms of reactive astrocyte activation under glioma conditions, their contribution to the mechanisms of glioma genesis and progression, and their potential value as targets for clinical intervention in gliomas.
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Affiliation(s)
| | | | | | | | | | - Chao You
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jie Fang Avenue, Qiao Kou District, Wuhan 430030, China; (J.W.); (J.W.); (H.Z.); (Y.M.)
| | - Kai Shu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095, Jie Fang Avenue, Qiao Kou District, Wuhan 430030, China; (J.W.); (J.W.); (H.Z.); (Y.M.)
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20
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Onyiba CI, Kumar NK, Scarlett CJ, Weidenhofer J. Cell Progression and Survival Functions of Enzymes Secreted in Extracellular Vesicles Associated with Breast and Prostate Cancers. Cells 2025; 14:468. [PMID: 40214422 PMCID: PMC11988166 DOI: 10.3390/cells14070468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/16/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound cargoes secreted by normal and pathological cells. Through their protein, nucleic acid, and lipid cargoes, EVs mediate several cellular processes, such as cell-cell communication, cell development, immune response, and tissue repair. Most importantly, through their enzyme cargo, EVs mediate pathophysiological processes, including the pathogenesis of cancer. In this review, we enumerate several enzymes secreted in EVs (EV enzyme cargo) from cells and patient clinical samples of breast and prostate cancers and detail their contributions to the progression and survival of both cancers. Findings in this review reveal that the EV enzyme cargo could exert cell progression functions via adhesion, proliferation, migration, invasion, and metastasis. The EV enzyme cargo might also influence cell survival functions of chemoresistance, radioresistance, angiogenesis, cell death inhibition, cell colony formation, and immune evasion. While the current literature provides evidence of the possible contributions of the EV enzyme cargo to the progression and survival mechanisms of breast and prostate cancers, future studies are required to validate that these effects are modified by EVs and provide insights into the clinical applications of the EV enzyme cargo in breast and prostate cancer.
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Affiliation(s)
- Cosmos Ifeanyi Onyiba
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Niwasini Krishna Kumar
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Christopher J. Scarlett
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Ourimbah, NSW 2258, Australia
| | - Judith Weidenhofer
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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21
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Zanchetta M, Adani GL, Micheletti G, Poto GE, Piccioni SA, Carbone L, Monteleone I, Sandini M, Marrelli D, Calomino N. Perforated Calculous Cholecystitis and Incidental Squamous Cell Carcinoma of the Gallbladder-A Complex Relationship with a Difficult Management in the Acute Setting. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:452. [PMID: 40142263 PMCID: PMC11944027 DOI: 10.3390/medicina61030452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
The worldwide prevalence of gallstones (GSs) is estimated to be between 10% and 15% in the general population. Gallbladder carcinoma (GBC) is the most common biliary tract neoplasia, and it is characterized by highly aggressive behavior and poor overall prognosis. Long-standing GSs and chronic inflammatory state represent the most common risk factors for GBC, promoting a carcinogenic microenvironment. Long-standing GSs expose patients to potentially severe surgical and oncological complications. A 71-year-old gentleman, who had never experienced biliary symptoms and had diabetes mellitus (DM), presented with severe peritonitis due to perforated acute calculous cholecystitis. The patient underwent an emergent laparotomic cholecystectomy. Histopathology found a rare pT2b poorly differentiated squamocellular carcinoma of the gallbladder. Although more difficult due to the concomitant inflammatory context, it is critical to identify suspicious lesions during preoperative imaging in patients at high risk of malignancy presenting with complex acute gallbladder pathologies. A review of the literature was conducted to gain a deeper insight into the relationship between long-standing GSs and GBC, evaluating also the difficult diagnosis and management of malignancy in the acute setting. Considering the existing literature, the choice to pursue a prophylactic cholecystectomy may be justifiable in selected asymptomatic GS patients at high risk for GBC.
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Affiliation(s)
- Matteo Zanchetta
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gian Luigi Adani
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Giorgio Micheletti
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gianmario Edoardo Poto
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Stefania Angela Piccioni
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ludovico Carbone
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ilaria Monteleone
- Diagnostic Imaging Unit, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Azienda Ospedaliera Universitaria Senese, Viale Bracci 10, 53100 Siena, Italy
| | - Marta Sandini
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Daniele Marrelli
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Natale Calomino
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
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22
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Alsavaf MB, Marquardt M, Abouammo MD, Xu M, Elguindy A, Grecula J, Baliga S, Konieczkowski D, Gogineni E, Bhateja P, Rocco JW, Old MO, Blakaj DM, Carrau RL, VanKoevering KK, Bonomi M. Patient Characteristics and Treatment Outcomes of Nasopharyngeal Carcinoma in Nonendemic Regions. JAMA Netw Open 2025; 8:e251895. [PMID: 40136303 PMCID: PMC11947841 DOI: 10.1001/jamanetworkopen.2025.1895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/24/2025] [Indexed: 03/27/2025] Open
Abstract
Importance Nasopharyngeal carcinoma (NPC) presents unique challenges in nonendemic regions, with varying patient characteristics and outcomes compared with endemic populations. Objective To fill gaps in the current understanding of NPC by focusing on a US population, comparing patient characteristics and treatment outcomes with endemic populations, and identifying key factors to inform management and follow-up protocols in Western health care settings. Design, Setting, and Participants This retrospective cohort study included patients with NPC treated at a single large US tertiary academic medical center from 2000 to 2023. The study analyzed patient demographics, tumor characteristics, treatment modalities, and survival outcomes. Data were analyzed from January to July 2024. Main Outcomes and Measures Overall survival (OS), progression-free survival (PFS), and recurrence-free survival, stratified by patient characteristics, tumor types, Epstein-Barr virus (EBV) status, and p16 expression. Results The sample included 159 adult patients with NPC (median [range] age, 53.5 [18-90] years; 117 [73.6%] male), with 23 African American patients (15.3%), 21 Asian patients (14.0%), and 106 White patients (70.7%). World Health Organization type III tumors predominated (88 patients [68.8%]), followed by type II (25 patients [19.5%]) and type I (15 patients [11.7%]). EBV positivity rates varied significantly by race (Asian: 13 patients [81.3%]; African American: 17 patients [63.0%]; White: 40 patients [47.0%]; P = .03) and WHO type (type III: 50 patients [72.5%]; type II: 10 patients [48.0%]; type I: 0 patients; P < .001). p16 status, a proxy for human papillomavirus status, did not vary by race but did vary by histopathologies (type III: 12 patients [28.5%]; type II: 12 patients [63.0%]; type I: 3 patients [43.0%]; P = .04). On Kaplan-Meier curves, stratifying p16 by EBV status eliminated its assumed association with OS. Multivariate analysis revealed that increasing age (hazard ratio [HR] per 1-year increase, 1.03 [95% CI, 1.00-1.05]; P = .04) and former smoking status (HR, 2.29 [95% CI, 1.03-5.10]; P = .04) were associated with inferior OS, while WHO type III tumors were associated with better OS compared with type I (HR, 0.38 [95% CI, 0.17-0.87]; P = .02). Male sex was associated with worse PFS (HR, 5.35 [95% CI, 1.23-23.30]; P = .03). For recurrence-free survival, former smokers (HR, 25.24 [95% CI, 2.56-249.23]; P = .006), current smokers (HR, 44.97 [95% CI, 2.27-892.10]; P = .01), and patients with advanced stages (IVa/b) (HR, 261.34 [95% CI, 3.96-17 258.06]; P = .009) had significantly increased risk. Conclusions and Relevance This cohort study contributes to the evolving body of knowledge on NPC in nonendemic regions, finding a shift toward WHO type III tumors and underscoring the association of EBV status with survival outcomes, while highlighting the lack of association between human papillomavirus status and outcomes. Smoking history, advanced stage at diagnosis, male sex, and increasing age emerged as adverse factors. Notably, WHO type I tumors demonstrated particularly poor outcomes, highlighting the need for more intensive follow-up in this subgroup.
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Affiliation(s)
- Mohammad Bilal Alsavaf
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | | | - Moataz D. Abouammo
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Menglin Xu
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - Ahmed Elguindy
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - John Grecula
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - Sujith Baliga
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - David Konieczkowski
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - Emile Gogineni
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - Priyanka Bhateja
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - James W. Rocco
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Matthew O. Old
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Dukagjin M. Blakaj
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus
| | - Ricardo L. Carrau
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Kyle K. VanKoevering
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Marcelo Bonomi
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus
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23
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Wang T, Jiang R, Tang X, Yao Y, Jiang P. SOX2 promotes the glycolysis process to accelerate cervical cancer progression by regulating the expression of HK2. Acta Histochem 2025; 127:152230. [PMID: 39823909 DOI: 10.1016/j.acthis.2025.152230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/13/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
BACKGROUND Cervical cancer is a major health burden in females worldwide, available studies indicated that sex-determining region Y-box 2 (SOX2) is closely related to the malignant phenotypes of multiple cancers including cervical cancer. However, the underlying mechanisms were blurred. EXPERIMENTAL PROCEDURES A bioinformatics analysis was conducted to investigate the clinical correlation between SOX2 and cervical cancer. Transient transfection and lentivirus infection were utilized to achieve overexpression and knockdown of SOX2, respectively. The role of SOX2 in cervical cancer was confirmed by transwell and colony-forming assays. Immunoblot, dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and biochemical experiments were employed. In addition, the xenograft models and immunohistochemistry (IHC) experiments were performed to validate the findings in vivo. RESULTS The expression of SOX2 was significantly positively associated with the cell migration, invasion, and colony-forming abilities of cervical cancer cells. The following immunoblots revealed that the SOX2-induced malignant phenotypes might be related to the glycolysis process, since overexpressing SOX2 significantly promoted the hexokinase 2 (HK2) and glucose transporter-1 (GLUT1) expression, and increased the content of glucose and lactic acid. The further dual-luciferase reporter and ChIP experiments confirmed a binding relationship between SOX2 and HK2 promoter. More importantly, overexpressing SOX2 promoted tumor growth concomitant with a hyper-expression of HK2 and GLUT1 in xenograft tumor tissues, yet the treatment of glycolysis inhibitor significantly reversed those outcomes. CONCLUSION SOX2 promotes the malignant progression of cervical cancer by facilitating glycolysis.
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Affiliation(s)
- Ting Wang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Ruoan Jiang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Xueling Tang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Yingsha Yao
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Peiyue Jiang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
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24
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Ghimire K, Awasthi BP, Yadav K, Lee J, Kim H, Jeong BS, Kim JA. Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic reprogramming. Chem Biol Interact 2025; 408:111393. [PMID: 39842705 DOI: 10.1016/j.cbi.2025.111393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 01/24/2025]
Abstract
Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl2 treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl2. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumour efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumour effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.
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Affiliation(s)
- Kalpana Ghimire
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | | | - Kiran Yadav
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jiwoo Lee
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hyunjin Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
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25
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Daumova L, Manakov D, Petrak J, Sovilj D, Behounek M, Andera L, Vit O, Souckova O, Havranek O, Dolnikova A, Renesova N, Tuskova L, Winkowska L, Bettazova N, Kupcova K, Kalbacova MH, Sikorova M, Trneny M, Klener P. Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors. Cell Death Discov 2025; 11:65. [PMID: 39966387 PMCID: PMC11836139 DOI: 10.1038/s41420-025-02341-y] [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: 08/05/2024] [Accepted: 02/05/2025] [Indexed: 02/20/2025] Open
Abstract
A large body of evidence suggests that hypoxia drives aggressive molecular features of malignant cells irrespective of cancer type. Non-Hodgkin lymphomas (NHL) are the most common hematologic malignancies characterized by frequent involvement of diverse hypoxic microenvironments. We studied the impact of long-term deep hypoxia (1% O2) on the biology of lymphoma cells. Only 2 out of 6 tested cell lines (Ramos, and HBL2) survived ≥ 4 weeks under hypoxia. The hypoxia-adapted (HA)b Ramos and HBL2 cells had a decreased proliferation rate accompanied by significant suppression of both oxidative phosphorylation and glycolytic pathways. Transcriptome and proteome analyses revealed marked downregulation of genes and proteins of the mitochondrial respiration complexes I and IV, and mitochondrial ribosomal proteins. Despite the observed suppression of glycolysis, the proteome analysis of both HA cell lines showed upregulation of several proteins involved in the regulation of glucose utilization including the active catalytic component of prolyl-4-hydroxylase P4HA1, an important druggable oncogene. HA cell lines demonstrated increased transcription of key regulators of auto-/mitophagy, e.g., neuritin, BCL2 interacting protein 3 (BNIP3), BNIP3-like protein, and BNIP3 pseudogene. Adaptation to hypoxia was further associated with deregulation of apoptosis, namely upregulation of BCL2L1/BCL-XL, overexpression of BCL2L11/BIM, increased binding of BIM to BCL-XL, and significantly increased sensitivity of both HA cell lines to A1155463, a BCL-XL inhibitor. Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor. In conclusion, our data report on several shared mechanisms of lymphoma cell adaptation to long-term hypoxia including: 1. Upregulation of proteins responsible for glucose utilization, 2. Degradation of mitochondrial proteins for potential mitochondrial recycling (by mitophagy), and 3. Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells.
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Affiliation(s)
- Lenka Daumova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Dmitry Manakov
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jiri Petrak
- BIOCEV Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Dana Sovilj
- Institute of Biotechnology, Czech Academy of Sciences / BIOCEV, Vestec, Czech Republic
| | - Matej Behounek
- BIOCEV Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Ladislav Andera
- Institute of Biotechnology, Czech Academy of Sciences / BIOCEV, Vestec, Czech Republic
- Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic
| | - Ondrej Vit
- BIOCEV Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Olga Souckova
- OMICS Mass Spectrometry Core Facility, Biology Departments, BIOCEV, Faculty of Science, Charles University, Vestec, Czech Republic
| | - Ondrej Havranek
- BIOCEV Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Vestec, Czech Republic
- First Department of Medicine- Hematology, University General Hospital Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alex Dolnikova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Nicol Renesova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Liliana Tuskova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
- First Department of Medicine- Hematology, University General Hospital Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Lucie Winkowska
- CLIP, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Nardjas Bettazova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kristyna Kupcova
- BIOCEV Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Vestec, Czech Republic
- First Department of Medicine- Hematology, University General Hospital Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marie Hubalek Kalbacova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Miriama Sikorova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marek Trneny
- First Department of Medicine- Hematology, University General Hospital Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Pavel Klener
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- First Department of Medicine- Hematology, University General Hospital Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic.
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26
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Branco H, Xavier CPR, Riganti C, Vasconcelos MH. Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment. Biochim Biophys Acta Rev Cancer 2025; 1880:189244. [PMID: 39672279 DOI: 10.1016/j.bbcan.2024.189244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 12/15/2024]
Abstract
In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.
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Affiliation(s)
- Helena Branco
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Cristina P R Xavier
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, 4585-116 Gandra, Portugal.
| | - Chiara Riganti
- Department of Oncology, University of Torino, 10126 Torino, Italy; Interdepartmental Research Center for Molecular Biotechnology "G. Tarone", University of Torino, 10126 Torino, Italy
| | - M Helena Vasconcelos
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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Lopez‐Mejia A, Moreno‐Londoño AP, Fonseca Camarillo G, Yamamoto‐Furusho JK, Villanueva‐Herrero JA, de Leon‐Rendón JL, Castañeda Patlán MC, Robles‐Flores M. Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells. IUBMB Life 2025; 77:e70007. [PMID: 39981666 PMCID: PMC11843525 DOI: 10.1002/iub.70007] [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: 09/23/2024] [Accepted: 01/24/2025] [Indexed: 02/22/2025]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1α, HIF-2α, and HIF-3α. However, in contrast to HIF-1α and HIF-2α, a specific role for HIF-3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3α in colon cancer. As reported previously for HIF-1α and HIF-2α, we found that HIF-3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3α displays high stability in cells compared with HIF-1α and HIF-2α. Progno Scan data analysis showed that overexpression of HIF-3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3α knockdown compared with control HIF-3α expressing cells. In addition, HIF-3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.
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Affiliation(s)
- Alejandro Lopez‐Mejia
- Departamento de Bioquímica, Facultad de MedicinaUniversidad Nacional Autónoma de México (UNAM)Mexico CityMexico
| | | | - Gabriela Fonseca Camarillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránClínica de Enfermedad Inflamatoria IntestinalCiudad de MéxicoMexico
| | - Jesús Kazuo Yamamoto‐Furusho
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránClínica de Enfermedad Inflamatoria IntestinalCiudad de MéxicoMexico
| | | | | | | | - Martha Robles‐Flores
- Departamento de Bioquímica, Facultad de MedicinaUniversidad Nacional Autónoma de México (UNAM)Mexico CityMexico
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28
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Zhong ZT, Wang XY, Pan Y, Zhou K, Chen JH, Gao YQ, Dai B, Zhou ZL, Wang RQ. AMPK: An energy sensor for non-small cell lung cancer progression and treatment. Pharmacol Res 2025; 212:107592. [PMID: 39805353 DOI: 10.1016/j.phrs.2025.107592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/23/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Lung cancer (LC) is the leading cause of cancer-related morbidity and mortality in China, with non-small cell lung cancer (NSCLC) accounting for 85 % of the overall lung cancer cases. AMP-activated protein kinase (AMPK) is a key regulator of energy balance and homeostasis, and its dysregulation is a common feature in various malignancies, particularly in NSCLC with mutations in Liver kinase B1 (LKB1). Studies have shown that the AMPK signalling pathway has a dual role in NSCLC progression, both inhibiting and promoting the progression of malignant tumours. Therefore, drugs targeting the AMPK signalling pathway may hold significant promise for therapeutic application in NSCLC. This review aims to examine the manifestations and mechanisms by which AMPK and its associated signalling molecules influence NSCLC progression and treatment. Firstly, we discuss the critical importance of AMPK within the mutational context of NSCLC. Secondly, we summarise the drugs and related substances that modulate the AMPK signalling pathway in NSCLC and evaluate the evidence from preclinical studies on combination AMPK-targeted therapies to address the issue of drug resistance in NSCLC under current clinical treatments. In summary, this paper highlights the critical importance of developing AMPK-targeted drugs to enhance therapeutic efficacy in NSCLC, as well as the potential for applying these drugs in clinical therapy to overcome drug resistance.
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Affiliation(s)
- Zhi-Ting Zhong
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Xu-Yan Wang
- Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China
| | - Ying Pan
- Department of Oncology, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China
| | - Ke Zhou
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China
| | - Jing-Hui Chen
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China
| | - Yu-Qi Gao
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China
| | - Bo Dai
- Department of Cardiology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan City, Guangdong Province 528200, China.
| | - Zhi-Ling Zhou
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China.
| | - Rui-Qi Wang
- Department of Pharmacy, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China.
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29
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Lyu Y, Li Q, Xie S, Zhao Z, Ma L, Wu Z, Bao W, Cai Y, Liu H, He H, Xie K, Gao F, Yang Y, Wu P, He P, Wang K, Dai X, Wu H, Lan T, Cheng C. Synergistic Ultrasound-Activable Artificial Enzyme and Precision Gene Therapy to Suppress Redox Homeostasis and Malignant Phenotypes for Controllably Combating Hepatocellular Carcinoma. J Am Chem Soc 2025; 147:2350-2368. [PMID: 39723916 DOI: 10.1021/jacs.4c10997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most lethal malignant tumors. Multimodal therapeutics with synergistic effects for treating HCC have attracted increasing attention, for instance, designing biocompatible porphyrin-based nanomedicines for enzyme-mimetic and ultrasound (US)-activable reactive oxygen species (ROS) generation. Despite the promise, the landscape of such advancements remains sparse. Here, we propose the de novo design of a π-conjugated, osmium (Os)-coordinated polyporphyrin (P-Por-Os) nanovesicle to serve as an ultrasound-activable artificial enzyme for synergistic therapies to suppress redox homeostasis and malignant phenotypes for controllably combating HCC. Our findings reveal that the P-Por-Os with US showed superior, multifaceted, and controllable ROS-generating activities. This system not only subverts the redox balance within HCC cells but also achieves precise and controlled tumor ablation at remarkably low concentrations, as evidenced across cellular assays and animal models. In the liver orthotopic model, US not only activates the artificial enzyme to catalyze ROS but also facilitates remote-controlled ablation of HCC through precise US positioning. Moreover, the P-Por-Os + US can assist the precision gene therapy by knocking down the ROS resistance factor, MT2A, and down-regulating its downstream oncogene IGFBP2 to attenuate ROS resistance, proliferation, and migration of HCC efficiently. We suggest that the design of this ultrasound-activable artificial enzyme presents a promising avenue for the engineering of innovative tumoricidal materials, offering a synergistic therapeutic approach with high biosecurity for HCC treatment.
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Affiliation(s)
- Yinghao Lyu
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qian Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
| | - Sinan Xie
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhenyang Zhao
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
| | - Lang Ma
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhe Wu
- Tianfu Jincheng Laboratory, City of Future Medicine, Chengdu 610093, China
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 641400, China
| | - Wen Bao
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 641400, China
| | - Yunshi Cai
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Liu
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Haorong He
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kunlin Xie
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fengwei Gao
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ying Yang
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Pu Wu
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Penghui He
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kaipeng Wang
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinye Dai
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hong Wu
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tian Lan
- Department of General Surgery, Liver Transplant Center, Transplant Center, Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chong Cheng
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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30
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Maharati A, Rajabloo Y, Moghbeli M. Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells. Heliyon 2025; 11:e41483. [PMID: 39834411 PMCID: PMC11743095 DOI: 10.1016/j.heliyon.2024.e41483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/22/2025] Open
Abstract
Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yasamin Rajabloo
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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31
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Tatlı Doğan H, Doğan M, Kahraman S, Çanakçı D, Şendur MAN, Tahtacı M, Erdoğan F. Impact of HIF-1α, LOX and ITGA5 Synergistic Interaction in the Tumor Microenvironment on Colorectal Cancer Prognosis. Diagnostics (Basel) 2025; 15:184. [PMID: 39857068 PMCID: PMC11764385 DOI: 10.3390/diagnostics15020184] [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: 12/09/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
Background: As colorectal cancers are histopathologically and molecularly highly heterogeneous tumors, it is necessary to consider the tumor's microenvironment as well as its cellular characteristics in order to determine the biological behavior of the tumor. This study included 100 patients who underwent resection for colorectal cancer. We aimed to investigate the relationships between the expression status of the HIF-1α, LOX and ITGA5 proteins and clinicopathologic parameters. Methods: HIF-1α, LOX and ITGA5 antibodies were applied immunohistochemically to tissue microarrays prepared from tumor samples. Expression status in the tumor microenvironment were evaluated using a combined scoring system based on staining intensity and the percentage of positively stained cells. Nuclear HIF-1α expression in tumor cells was quantified, with >1% considered positive. The staining of HIF-1α, ITGA5 and LOX was analyzed in relation to prognostic and molecular features. Results: The staining of HIF-1α, ITGA5 and LOX in the tumor microenvironment demonstrated a positive correlation with one another and with HIF-1α and LOX expression in tumor cells. In patients with KRAS, NRAS or BRAF mutation and the moderate to strong expression of all three of these proteins in the tumor microenvironment, the number of metastatic lymph nodes was higher than in other patients. Stage IV patients with the moderate to strong expression of HIF-1α, ITGA5 or LOX in the microenvironment had lower progression-free survival than those with weak expression (p < 0.05). In addition, female gender; moderate to strong HIF-1α, LOX and ITGA5 stromal expression; and metastatic first line chemotherapy only were found to be independently associated with an increased risk of progression. Conclusions: These markers may be useful in predicting treatment responses and may also guide the development of alternative or combined treatments that specifically target molecules such as HIF and LOX. Our study should be supported by more comprehensive studies addressing the tumor stroma and its prognostic importance.
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Affiliation(s)
- Hayriye Tatlı Doğan
- Department of Pathology, Faculty of Medicine, Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
| | - Mehmet Doğan
- Department of Pathology, Faculty of Medicine, Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
| | - Seda Kahraman
- Department of Medical Oncology, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
| | - Doğukan Çanakçı
- Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
| | | | - Mustafa Tahtacı
- Department of Gastroenterology, Faculty of Medicine, Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
| | - Fazlı Erdoğan
- Department of Pathology, Faculty of Medicine, Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06800, Turkey
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32
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Chen HJ. Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer. J Exp Med 2025; 222:e20241581. [PMID: 39585349 PMCID: PMC11602549 DOI: 10.1084/jem.20241581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.
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Affiliation(s)
- Huanhuan Joyce Chen
- The Pritzker School of Molecular Engineering, Cummings Life Science Center, The University of Chicago, Chicago, IL, USA
- The Ben May Department for Cancer Research, Cummings Life Science Center, The University of Chicago, Chicago, IL, USA
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33
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Zhang J, Yao M, Xia S, Zeng F, Liu Q. Systematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: implications for cellular adaptation and therapeutic strategies in cancer. Cell Mol Biol Lett 2025; 30:2. [PMID: 39757165 DOI: 10.1186/s11658-024-00682-7] [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: 09/27/2024] [Accepted: 12/19/2024] [Indexed: 01/07/2025] Open
Abstract
Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1's regulatory mechanism and paves the way for future research and therapeutic development.
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Affiliation(s)
- Jiayi Zhang
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
- School of Clinical Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Mingxuan Yao
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Shiting Xia
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
| | - Fancai Zeng
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
| | - Qiuyu Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
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34
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Puik JR, Le C, Kazemier G, Oprea-Lager DE, Swijnenburg RJ, Giovannetti E, Griffioen AW, Huijbers EJ. Prostate-specific membrane antigen as target for vasculature-directed therapeutic strategies in solid tumors. Crit Rev Oncol Hematol 2025; 205:104556. [PMID: 39551117 DOI: 10.1016/j.critrevonc.2024.104556] [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: 07/19/2024] [Revised: 10/21/2024] [Accepted: 11/07/2024] [Indexed: 11/19/2024] Open
Abstract
Prostate-specific membrane antigen (PSMA) is one of the few biomarkers which has been successfully translated to the clinic as theranostic biomarker for patients with prostate cancer. In the context of prostate cancer, PSMA is overexpressed on the cell membrane of tumor cells, making it a viable target for interventions with urea-based small molecule inhibitors or antibodies conjugated to radioactive isotopes. Interestingly, in several non-prostatic cancers, expression of PSMA appears to be associated with the tumor neovasculature. This offers novel therapeutic opportunities for treatments targeting the vasculature in non-prostatic cancers. In this review, we discuss PSMA and its potential as target for vasculature-directed therapeutic approaches, including radioligand therapy, fusion protein vaccination and CAR T-cell therapy.
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Affiliation(s)
- Jisce R Puik
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Surgery, De Boelelaan 1117, Amsterdam, the Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands
| | - Chung Le
- Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Geert Kazemier
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Surgery, De Boelelaan 1117, Amsterdam, the Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands
| | - Daniela E Oprea-Lager
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, De Boelelaan 1117, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Surgery, De Boelelaan 1117, Amsterdam, the Netherlands; Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands
| | - Elisa Giovannetti
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands; Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC), Fondazione Pisana per la Scienza, University of Pisa, Pisa, Italy.
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; CimCure BV, Plesmanlaan 125, Amsterdam, the Netherlands
| | - Elisabeth Jm Huijbers
- Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; CimCure BV, Plesmanlaan 125, Amsterdam, the Netherlands
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35
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Das A, Sonar S, Kalele K, Subramaniyan V. Fruit exosomes: a sustainable green cancer therapeutic. SUSTAINABLE FOOD TECHNOLOGY 2025; 3:145-160. [DOI: 10.1039/d4fb00281d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2024]
Abstract
Fruit exosomes are the source of natural cancer therapeutic tools.
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Affiliation(s)
- Asmit Das
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Swarup Sonar
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Ketki Kalele
- Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
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36
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Nishizawa H, Funasaki S, Ma W, Kubota Y, Watanabe K, Arima Y, Kuroda S, Ito T, Furuya M, Motoshima T, Nishiyama A, Mehanna S, Satou Y, Hasumi H, Jikuya R, Makiyama K, Tamura T, Oike Y, Tanaka Y, Suda T, Schmidt LS, Linehan WM, Baba M, Kamba T. HIF1α Plays a Crucial Role in the Development of TFE3-Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis. Genes Cells 2025; 30:e13195. [PMID: 39807625 PMCID: PMC11729263 DOI: 10.1111/gtc.13195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.
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Grants
- JP21K19721 Japan Society for the Promotion of Science
- HHSN261201500003C NCI NIH HHS
- JP24K09315 Japan Society for the Promotion of Science
- JP 24K02578 Japan Society for the Promotion of Science
- JPMXP0618217493 Ministry of Education, Culture, Sports, Science and Technology
- JP20K09560 Japan Society for the Promotion of Science
- JPMXP0622717006 Ministry of Education, Culture, Sports, Science and Technology
- JP21K09374 Japan Society for the Promotion of Science
- JP23K24474 Japan Society for the Promotion of Science
- JP21K06000 Japan Society for the Promotion of Science
- HHSN261201500003I NCI NIH HHS
- JP23K27589 Japan Society for the Promotion of Science
- JPMXP0723833149 Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology
- National Cancer Institute
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Affiliation(s)
- Hidekazu Nishizawa
- Department of Urology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Shintaro Funasaki
- Divison of Molecular and Vascular Biology, IRDAKumamoto UniversityKumamotoJapan
| | - Wenjuan Ma
- Cambridge Stem Cell Institute, University of CambridgeCambridgeUK
| | - Yoshiaki Kubota
- Department of AnatomyInstitute for Advanced Medical Research and Keio University School of MedicineTokyoJapan
| | | | - Yuichiro Arima
- Developmental Cardiology Laboratory, International Research Center for Medical Science (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Shoichiro Kuroda
- Department of Urology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Takaaki Ito
- Department of Medical TechnologyKumamoto Health Science University Faculty of Health SciencesKumamotoJapan
| | - Mitsuko Furuya
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Takanobu Motoshima
- Department of Urology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Akira Nishiyama
- Department of ImmunologyYokohama City University Graduate School of MedicineKanagawaJapan
| | - Sally Mehanna
- Biotechnology Department, Faculty of Nanotechnology for Postgraduate Studies, Cairo UniversityAd DoqiEgypt
| | - Yorifumi Satou
- Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus InfectionKumamoto UniversityKumamotoJapan
| | - Hisashi Hasumi
- Department of UrologyYokohama City University Graduate School of MedicineKanagawaJapan
| | - Ryosuke Jikuya
- Department of UrologyYokohama City University Graduate School of MedicineKanagawaJapan
| | - Kazuhide Makiyama
- Department of UrologyYokohama City University Graduate School of MedicineKanagawaJapan
| | - Tomohiko Tamura
- Department of ImmunologyYokohama City University Graduate School of MedicineKanagawaJapan
- Advanced Medical Research CenterYokohama City UniversityKanagawaJapan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Toshio Suda
- Laboratory of Stem Cell Regulation, International Research Center for Medical Science (IRCMS)Kumamoto UniversityKumamotoJapan
| | - Laura S. Schmidt
- Urologic Oncology BranchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
- Basic Science Program, Frederick National Laboratory for Cancer ResearchNational Cancer InstituteFrederickMarylandUSA
| | - W. Marston Linehan
- Urologic Oncology BranchNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Masaya Baba
- Department of Urology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Tomomi Kamba
- Department of Urology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
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Zhou Z, Cai S, Zhou X, Zhao W, Sun J, Zhou Z, Yang Z, Li W, Wang Z, Zou H, Fu H, Wang X, Khoo BL, Yang M. Circulating Tumor Cells Culture: Methods, Challenges, and Clinical Applications. SMALL METHODS 2024:e2401026. [PMID: 39726345 DOI: 10.1002/smtd.202401026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/10/2024] [Indexed: 12/28/2024]
Abstract
Circulating tumor cells (CTCs) play a pivotal role in cancer metastasis and hold considerable potential for clinical diagnosis, therapeutic monitoring, and prognostic evaluation. Nevertheless, the limited quantity of CTCs in liquid biopsy samples poses challenges for comprehensive downstream analysis. In vitro culture of CTCs can effectively address the issue of insufficient CTC numbers. Furthermore, research based on CTC cell lines serves as a valuable complement to traditional cancer cell line-based research. While numerous reports exist on CTC in vitro culture and even the establishment of CTC cell lines, the methods used vary, leading to disparate culture outcomes. This review presents the developmental history and current status of CTC in vitro culture research. Additionally, the culture strategies applied in different methods and analyzed the impact of various steps on culture outcomes are compared. Overall, the review indicates that while the short-term culture of CTCs is relatively straightforward, long-term culture success has been achieved for various specific cancer types but still faces challenges. Further optimization of efficient and widely applicable culture strategies is needed. Additionally, ongoing applications of CTC in vitro culture are summarized, highlighting the potential of expanded CTCs for drug susceptibility testing and as therapeutic tools in personalized treatment.
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Affiliation(s)
- Zhengdong Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Songhua Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Xiaoyu Zhou
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
| | - Wei Zhao
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Jiayu Sun
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhihang Zhou
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zihan Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Wenxiu Li
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Zhe Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Heng Zou
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Huayang Fu
- Cellomics (Shenzhen) Limited, Shenzhen, 518118, China
| | - Xicheng Wang
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Bee Luan Khoo
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, 999077, China
| | - Mengsu Yang
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Futian Research Institute, Shenzhen, 518057, China
- Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
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Diseri A, Stravodimos G, Argyriou A, Spyroulias GA, Leonidas DD, Liakos P. Expression, purification, and biophysical analysis of a part of the C-terminal domain of human hypoxia inducible factor-2α (HIF-2α). Biochem Biophys Res Commun 2024; 739:150965. [PMID: 39556935 DOI: 10.1016/j.bbrc.2024.150965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/24/2024] [Accepted: 11/06/2024] [Indexed: 11/20/2024]
Abstract
Hypoxia inducible factor 2α (HIF-2α) is a member of the basic helix-loop-helix(bHLH)-Per-Arnt-Sim (PAS) family of transcription factors. It is overexpressed in several cancers, associated with poor prognosis of the patients and resistance to treatment. Here, we study the residues 366-704 of the C-terminal end of human HIF-2α, which contains the N-transcriptional activation domain (NTAD), the oxygen-dependent degradation domain (ODD), and a part of the inhibitory domain (IH). An efficient protocol was developed to produce the 366-704 domain of human HIF-2α protein. Subsequently, we analyzed its biophysical characteristics using circular dichroism spectroscopy and size exclusion chromatography showing that the protein forms an antiparallel beta sheet conformation, and a computational model of the HIF-2α structure was produced. Our data offer new structural information for the unique biological properties of HIF-2α.
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Affiliation(s)
- Aikaterini Diseri
- Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - George Stravodimos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | | | | | - Demetres D Leonidas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Panagiotis Liakos
- Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece.
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Liu WJ, Wang L, Sun FL, Zhou FM, Zhang RK, Liu J, Zhao M, Wang LH, Qin YR, Zhao YQ, Qiu JG, Jiang BH. Hexavalent chromium induced metabolic reprogramming, carcinogenesis and tumor progression through PDK1 upregulation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 288:117341. [PMID: 39550876 DOI: 10.1016/j.ecoenv.2024.117341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/06/2024] [Accepted: 11/10/2024] [Indexed: 11/19/2024]
Abstract
Lung cancer is the leading factor of cancer-related death in the worldwide. Hexavalent chromium [Cr(VI)] is a potential carcinogen for inducing lung cancers. To understand new mechanism of Cr(VI)-induced tumorigenesis and cancer development, we identified that PDK1 expression levels were greatly increased in chromium-transformed cells (Cr-T) compared to the parental BEAS-2B (B2B) cells by proteomic profiling and Western blotting; PDK1 levels were also induced in lung cancer cell lines and in lung samples of mice exposed to Cr(VI). Cr(VI) increased Warburg effect, cell migration, proliferation and colony formation through PDK1 upregulation. To identify the mechanism of PDK1 induction, we performed miRNA-seq analysis of Cr-T and B2B cells, and found miR-493 levels was significantly suppressed by Cr(VI). PDK1 was induced by miR-493 suppression, and was a direct target of miR-493. Interestingly, we also found HIF-1α was directly targeting by miR-493 and was induced by miR-493 downregulation. HIF-1α expression levels were upregulated in lung samples of mice with Cr(VI)-exposure. PDK1 was induced by HIF-1α, showing miR-493 suppression can directly induce PDK1 as well as through HIF-1α induction. MiR-493 overexpression was sufficient to suppress tumor growth, PDK1 and HIF-1α expression in vivo. We also showed that levels of miR-493 suppression, HIF-1α and PDK1 elevations were strongly correlated with poor prognosis of lung cancer subjects. These results demonstrate both HIF-1α and PDK1 expression are induced by Cr(VI)-mediated miR-493 suppression, and MiR-493/HIF-1α/PDK1 axis is a new pathway in Cr(VI)-inducing carcinogenesis and tumor growth.
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Affiliation(s)
- Wen-Jing Liu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Lin Wang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Fan-Li Sun
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Feng-Mei Zhou
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Rui-Ke Zhang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Jie Liu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Min Zhao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Li-Hong Wang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Yan-Ru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan China
| | - Yan-Qiu Zhao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Jian-Ge Qiu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China.
| | - Bing-Hua Jiang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China.
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Wei W, Qu ZL, Lei L, Zhang P. TREM2-mediated Macrophage Glycolysis Promotes Skin Wound Angiogenesis via the Akt/mTOR/HIF-1α Signaling Axis. Curr Med Sci 2024; 44:1280-1292. [PMID: 39672999 DOI: 10.1007/s11596-024-2946-3] [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: 08/20/2024] [Accepted: 09/30/2024] [Indexed: 12/15/2024]
Abstract
OBJECTIVE The trigger receptor expressed on myeloid cells-2 (TREM2) pathway in myeloid cells is a key disease-inducing immune signaling hub that is essential for detecting tissue damage and limiting its pathological spread. However, the role and potential mechanisms of TREM2 in wound repair remain unclear. The purpose of this study was to determine the role and mechanism of TREM2 in skin wound healing in mice. METHODS Immunofluorescence staining was used to determine the expression and cellular localization of TREM2 and test the effects of TREM2 knockout on angiogenesis, glycolysis, and lactylation in skin tissue. Western blotting was used to analyze the expression of the Akt/mTOR/HIF-1α signaling pathway in the wounded skin tissues of wild-type (WT) and TREM2 knockout mice. A coimmunoprecipitation assay was used to determine whether HIF-1α, which mediates angiogenesis, is modified by lactylation. RESULTS The number of TREM2+ macrophages was increased, and TREM2+ macrophages mediated angiogenesis after skin injury. TREM2 promoted glycolysis and lactylation in macrophages during wound healing. Mechanistically, TREM2 promoted macrophage glycolysis and angiogenesis in wounded skin tissues by activating the Akt/mTOR/HIF-1α signaling pathway. HIF-1α colocalized with Klac to mediate lactylation in macrophages, and lactate could stabilize the expression of the HIF-1α protein through lactylation. Lactate treatment ameliorated the impaired angiogenesis and delayed wound healing in wounded skin in TREM2 knockout mice. CONCLUSION TREM2+ macrophage-mediated glycolysis can promote angiogenesis and wound healing. Our findings provide an effective strategy and target for promoting skin wound healing.
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Affiliation(s)
- Wei Wei
- Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Key Laboratory of Skin Infection and Immunity, Wuhan No. 1 Hospital, Wuhan, 430022, China
| | - Zi-Lu Qu
- Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Key Laboratory of Skin Infection and Immunity, Wuhan No. 1 Hospital, Wuhan, 430022, China
| | - Li Lei
- Department of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210000, China
| | - Ping Zhang
- Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Provincial Key Laboratory of Skin Infection and Immunity, Wuhan No. 1 Hospital, Wuhan, 430022, China.
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Li Z, Huang H, Zhao Z, Ma W, Mao H, Liu F, Yang Y, Wang D, Lu Z. Development and Validation of a Nomogram Based on DCE-MRI Radiomics for Predicting Hypoxia-Inducible Factor 1α Expression in Locally Advanced Rectal Cancer. Acad Radiol 2024; 31:4923-4933. [PMID: 38816315 DOI: 10.1016/j.acra.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 06/01/2024]
Abstract
RATIONALE AND OBJECTIVES The expression levels of hypoxia-inducible factor 1 alpha (HIF-1α) have been identified as a pivotal marker, correlating with treatment response in patients with locally advanced rectal cancer (LARC). This study aimed to develop and validate a nomogram based on dynamic contrast-enhanced MRI (DCE-MRI) radiomics and clinical features for predicting the expression of HIF-1α in patients with LARC. MATERIALS AND METHODS A total of 102 patients diagnosed with locally advanced rectal cancer were divided into training (n = 71) and validation (n = 31) cohorts. The expression statuses of HIF-1α were histopathologically classified, categorizing patients into high and low expression groups. The intraclass correlation coefficient (ICC), minimum redundancy maximum relevance (mRMR), and the least absolute shrinkage and selection operator (LASSO) were employed for feature selection to construct a radiomics signature and calculate the radiomics score (Rad-score). Univariate and multivariate analyses of clinical features and Rad-score were applied, and the clinical model and the nomogram were constructed. The predictive performance of the nomogram incorporating clinical features and Rad-score was assessed using Receiver Operating Characteristics (ROC) curves, decision curve analysis (DCA), and calibration curves. RESULTS Seven radiomics features from DCE-MRI were used to build the radiomics signature. The nomogram incorporating CEA, Ki-67 and Rad-score had the highest AUC values in the training cohort and in the validation cohort (AUC: 0.918 and 0.920). Decision curve analysis showed that the nomogram outperformed the clinical model and radiomics signature in terms of clinical utility. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. CONCLUSION The nomogram based on DCE-MRI radiomics and clinical features showed favorable predictive efficacy and might be useful for preoperatively discriminating the expression of HIF-1α.
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Affiliation(s)
- Zhiheng Li
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Huizhen Huang
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Zhenhua Zhao
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Weili Ma
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Haijia Mao
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Fang Liu
- Department of Pathology, Shaoxing People's Hospital, Shaoxing, China
| | - Ye Yang
- Department of Pathology, Shaoxing People's Hospital, Shaoxing, China
| | - Dandan Wang
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China
| | - Zengxin Lu
- Department of Radiology, Shaoxing People's Hospital, Shaoxing, China.
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Zhang J, Zhao Y, Liang R, Zhou X, Wang Z, Yang C, Gao L, Zheng Y, Shao H, Su Y, Cui W, Jia L, Yang J, Wu C, Wang L. DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer. Acta Pharm Sin B 2024; 14:5219-5234. [PMID: 39807333 PMCID: PMC11725086 DOI: 10.1016/j.apsb.2024.08.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/18/2024] [Accepted: 07/26/2024] [Indexed: 01/16/2025] Open
Abstract
DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.
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Affiliation(s)
- Jiayu Zhang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yingxi Zhao
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ruijuan Liang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xue Zhou
- Department of Biochemistry and Molecular Biology, School of Medical Devices, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhonghua Wang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Cheng Yang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Lingyue Gao
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yonghao Zheng
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hui Shao
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yang Su
- Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Wei Cui
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Lina Jia
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jingyu Yang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Chunfu Wu
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Lihui Wang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
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Aburahess S, Li L, Hussain A, Obeidat M, Alavi P, Azad AK, Jahroudi N, Ballermann BJ. Hypoxia-induced TIMAP upregulation in endothelial cells and TIMAP-dependent tumor angiogenesis. Am J Physiol Cell Physiol 2024; 327:C1359-C1372. [PMID: 39344413 DOI: 10.1152/ajpcell.00054.2024] [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: 01/26/2024] [Revised: 09/13/2024] [Accepted: 09/15/2024] [Indexed: 10/01/2024]
Abstract
TGFβ-inhibited membrane associated protein (TIMAP), the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1-mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of bone morphogenetic factor 9 (BMP9), hypoxia, and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the SMAD1/5/8 pathway. Angiogenic growth factors, including VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating SMAD1/5/8 pathway activation, but also through SMAD1/5/8-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared with wild-type littermates. These findings indicate that TIMAP plays a critical proangiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the SMAD1/5/8 pathway and through the elaboration of angiogenic growth factors by tumor cells.NEW & NOTEWORTHY The protein phosphatase 1 regulatory subunit TGFβ-inhibited membrane associated protein (TIMAP), known to activate AKT in endothelial cells (EC), was shown here to be repressed by bone morphogenetic factor 9 (BMP9). Hypoxia and angiogenic growth factors induced TIMAP expression by inhibiting the BMP9 pathway. In a mouse breast cancer model, TIMAP deletion inhibited tumor angiogenesis and tumor growth. Therefore, the proangiogenic functions of TIMAP are induced by hypoxia and angiogenic growth factors.
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Affiliation(s)
- Salah Aburahess
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Laiji Li
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Aashiq Hussain
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Marya Obeidat
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Parnian Alavi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Abul K Azad
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Schwartzman JD, McCall M, Ghattas Y, Pugazhendhi AS, Wei F, Ngo C, Ruiz J, Seal S, Coathup MJ. Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies. Biomaterials 2024; 311:122683. [PMID: 38954959 DOI: 10.1016/j.biomaterials.2024.122683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/09/2024] [Accepted: 06/23/2024] [Indexed: 07/04/2024]
Abstract
The repair of large bone defects due to trauma, disease, and infection can be exceptionally challenging in the elderly. Despite best clinical practice, bone regeneration within contemporary, surgically implanted synthetic scaffolds is often problematic, inconsistent, and insufficient where additional osteobiological support is required to restore bone. Emergent smart multifunctional biomaterials may drive important and dynamic cellular crosstalk that directly targets, signals, stimulates, and promotes an innate bone repair response following age-related biological decline and when in the presence of disease or infection. However, their role remains largely undetermined. By highlighting their mechanism/s and mode/s of action, this review spotlights smart technologies that favorably align in their conceivable ability to directly target and enhance bone repair and thus are highly promising for future discovery for use in the elderly. The four degrees of interactive scaffold smartness are presented, with a focus on bioactive, bioresponsive, and the yet-to-be-developed autonomous scaffold activity. Further, cell- and biomolecular-assisted approaches were excluded, allowing for contemporary examination of the capabilities, demands, vision, and future requisites of next-generation biomaterial-induced technologies only. Data strongly supports that smart scaffolds hold significant promise in the promotion of bone repair in patients with a reduced osteobiological response. Importantly, many techniques have yet to be tested in preclinical models of aging. Thus, greater clarity on their proficiency to counteract the many unresolved challenges within the scope of aging bone is highly warranted and is arguably the next frontier in the field. This review demonstrates that the use of multifunctional smart synthetic scaffolds with an engineered strategy to circumvent the biological insufficiencies associated with aging bone is a viable route for achieving next-generation therapeutic success in the elderly population.
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Affiliation(s)
| | - Max McCall
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Yasmine Ghattas
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Abinaya Sindu Pugazhendhi
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Fei Wei
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Christopher Ngo
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Jonathan Ruiz
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Sudipta Seal
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA; Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), Materials Science and Engineering, College of Medicine, University of Central Florida, USA, Orlando, FL
| | - Melanie J Coathup
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA.
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Ma XY, Li MY, Jin KH, Han ZY, Gao YL, Jin XJ, Zhao YQ, Piao HR. Design, Synthesis, and Hypoxia-Inducible Factor-1α Inhibitory Activity Evaluation of Panaxadiol Derivatives Containing a Thiazole Moiety. Chem Biodivers 2024; 21:e202401542. [PMID: 39193815 DOI: 10.1002/cbdv.202401542] [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: 06/25/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 08/29/2024]
Abstract
The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor. Consequently, we hypothesized that the introduction of a thiazole functional group in PD was likely to improve the biological potency. Here, three series of PD derivatives containing a thiazole moiety were synthesized, including (a) sulfonyl-containing thiazole derivatives (5 a-l), (b) urea-containing thiazole derivatives (7 a-i), and (c) thiourea-containing thiazole derivatives (9 a-i), and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. The results showed that about 1/3 of the target compounds showed moderate or strong HIF-1α inhibitory activity, among which compounds 5 d and 7 b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 μM. Molecular docking experiments were also performed to investigate the structure-activity relationship. Compounds 5 d and 7 b can be used as leads for further study and development of novel antitumor drugs.
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Affiliation(s)
- Xin-Yu Ma
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Ming-Yue Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Kai-Han Jin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Zhen-Yuan Han
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Yuan-Liang Gao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Xue-Jun Jin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Yu-Qing Zhao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
| | - Hu-Ri Piao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, 133000, China
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46
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Procházková K, Uhlík J. Influence of Hypoxia on the Airway Epithelium. Physiol Res 2024; 73:S557. [PMID: 39589303 PMCID: PMC11627265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 06/26/2024] [Indexed: 11/27/2024] Open
Abstract
The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction. Keywords: Secretory cells, Motile cilia, Epithelial barrier, Oxygenation, Obstructive respiratory diseases.
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Affiliation(s)
- K Procházková
- Department of Histology and Embryology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
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Ummarino A, Calà N, Allavena P. Extrinsic and Cell-Intrinsic Stress in the Immune Tumor Micro-Environment. Int J Mol Sci 2024; 25:12403. [PMID: 39596467 PMCID: PMC11594858 DOI: 10.3390/ijms252212403] [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: 10/06/2024] [Revised: 11/08/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
In continuously progressive tumor tissues, the causes of cellular stress are multiple: metabolic alterations, nutrient deprivation, chronic inflammation and hypoxia. To survive, tumor cells activate the stress response program, a highly conserved molecular reprogramming proposed to cope with challenges in a hostile environment. Not only cancer cells are affected, but stress responses in tumors also have a profound impact on their normal cellular counterparts: fibroblasts, endothelial cells and infiltrating immune cells. In recent years, there has been a growing interest in the interaction between cancer and immune cells, especially in difficult conditions of cellular stress. A growing literature indicates that knowledge of the molecular pathways activated in tumor and immune cells under stress conditions may offer new insights for possible therapeutic interventions. Counter-regulating the stress caused by the presence of a growing tumor can therefore be a weapon to limit disease progression. Here, we review the main pathways activated in cellular stress responses with a focus on immune cells present in the tumor microenvironment.
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Affiliation(s)
- Aldo Ummarino
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Nicholas Calà
- Etromapmacs Pole, Agorà Biomedical Sciences, 71010 Foggia, Italy;
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Ren W, Liang H, Sun J, Cheng Z, Liu W, Wu Y, Shi Y, Zhou Z, Chen C. TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis. Cell Death Dis 2024; 15:821. [PMID: 39532855 PMCID: PMC11557851 DOI: 10.1038/s41419-024-07223-2] [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: 07/02/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown. In this study, we demonstrated that TNFAIP2 promotes TNBC angiogenesis by activating the Rac1-ERK-AP1-HIF1α signaling axis. Under hypoxia, TNFAIP2 activates Rac1 and ERK sequentially. Following that, ERK activates the AP-1 (c-Jun/Fra1) transcription factor. By employing chromatin immunoprecipitation and luciferase reporter assays, we showed that AP-1 directly interacts with the HIF1α gene promoter, thereby enhancing its transcription. The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.
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MESH Headings
- Humans
- Animals
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- rac1 GTP-Binding Protein/metabolism
- rac1 GTP-Binding Protein/genetics
- Female
- Cell Line, Tumor
- Mice, Nude
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/pathology
- Triple Negative Breast Neoplasms/metabolism
- Triple Negative Breast Neoplasms/drug therapy
- Mice
- Signal Transduction
- Transcription Factor AP-1/metabolism
- Pyrimidinones/pharmacology
- Pyridines/pharmacology
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Transcription, Genetic/drug effects
- Pyridones/pharmacology
- Mice, Inbred BALB C
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Nitriles/pharmacology
- MAP Kinase Signaling System/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Angiogenesis
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Affiliation(s)
- Wenlong Ren
- School of Life Science, University of Science & Technology of China, Hefei, Anhui, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Huichun Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jian Sun
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Zhuo Cheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Wenjing Liu
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Yingying Wu
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yujie Shi
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, China.
| | - Zhongmei Zhou
- The School of Continuing Education, Kunming Medical University, Kunming, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, ChinaAcademy of Biomedical Engineering, Kunming Medical University, Kunming, China.
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Li Y, Zhu R, He X, Song Y, Fan T, Ma J, Xiang G, Ma X. Discovery of potent hypoxia-inducible factor-1α (HIF-1α) degraders by proteolysis targeting chimera (PROTAC). Bioorg Chem 2024; 153:107943. [PMID: 39536629 DOI: 10.1016/j.bioorg.2024.107943] [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: 08/21/2024] [Revised: 10/16/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
Under hypoxic conditions in tumor cells, HIF-1α is unable to bind to VHL E3 ligase due to the blocked hydroxylation reaction, resulting in impaired degradation and intracellular accumulation. Mounting evidences show a close association between HIF-1α overexpression and drug resistance, treatment failure, and increased mortality. To address HIF-1α overexpression, we innovatively introduced an E3 ligase ligand to the HIF-1α inhibitor IDF-11774 using the PROTACs strategy, aiming to reactivate the degradative pathway impeded under hypoxia, and thereby achieve the degradation of HIF-1α protein under hypoxia. Western blotting analyses demonstrated that most of our designed PROTACs effectively degraded HIF-1α. Among these, compounds C3 and V2 exhibited excellent anti-proliferation activity on MDA-MB-231 cells with IC50 values of 48.98 μM and 7.54 μM, respectively. Both compounds induced protein degradation in a concentration-dependent manner, achieving degradation rates up to 80 %. Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment strategy against solid tumors.
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Affiliation(s)
- Yuying Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ruixue Zhu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xuelian He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yanjia Song
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting Fan
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junhui Ma
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guangya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Pharmacy, Tongren Polytechnic College, Tongren Guizhou 554300, China.
| | - Xiang Ma
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Pharmacy, Tongren Polytechnic College, Tongren Guizhou 554300, China.
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50
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Muscogiuri G, Barrea L, Bettini S, El Ghoch M, Katsiki N, Tolvanen L, Verde L, Colao A, Busetto L, Yumuk VD, Hassapidou M, on behalf of EASO Nutrition Working Group. European Association for the Study of Obesity (EASO) Position Statement on Medical Nutrition Therapy for the Management of Individuals with Overweight or Obesity and Cancer. Obes Facts 2024; 18:86-105. [PMID: 39433024 PMCID: PMC12017763 DOI: 10.1159/000542155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 10/09/2024] [Indexed: 10/23/2024] Open
Abstract
Obesity, a prevalent and multifactorial disease, is linked to a range of metabolic abnormalities, including insulin resistance, dyslipidemia, and chronic inflammation. These imbalances not only contribute to cardiometabolic diseases but also play a significant role in cancer pathogenesis. The rising prevalence of obesity underscores the need to investigate dietary strategies for effective weight management for individuals with overweight or obesity and cancer. This European Society for the Study of Obesity (EASO) position statement aimed to summarize current evidence on the role of obesity in cancer and to provide insights on the major nutritional interventions, including the Mediterranean diet (MedDiet), the ketogenic diet (KD), and the intermittent fasting (IF), that should be adopted to manage individuals with overweight or obesity and cancer. The MedDiet, characterized by high consumption of plant-based foods and moderate intake of olive oil, fish, and nuts, has been associated with a reduced cancer risk. The KD and the IF are emerging dietary interventions with potential benefits for weight loss and metabolic health. KD, by inducing ketosis, and IF, through periodic fasting cycles, may offer anticancer effects by modifying tumor metabolism and improving insulin sensitivity. Despite the promising results, current evidence on these dietary approaches in cancer management in individuals with overweight or obesity is limited and inconsistent, with challenges including variability in adherence and the need for personalized dietary plans.
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Affiliation(s)
- Giovanna Muscogiuri
- Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Centro Italiano per la cura e il Benessere del Paziente con Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Cattedra Unesco “Educazione Alla Salute E Allo Sviluppo Sostenibile”, University Federico II, Naples, Italy
| | - Luigi Barrea
- Centro Italiano per la cura e il Benessere del Paziente con Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Department of Wellbeing, Nutrition and Sport, Pegaso Telematic University, Centro Direzionale Isola F2, Naples, Italy
| | - Silvia Bettini
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, Padova, Italy
| | - Marwan El Ghoch
- Center for the Study of Metabolism, Body Composition and Lifestyle, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Niki Katsiki
- School of Medicine, European University Cyprus, Nicosia, Cyprus
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece
| | - Liisa Tolvanen
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Obesity, Academic Specialist Center, Stockholm Health Care Services, Stockholm, Sweden
- ESDN Obesity of EFAD, Naarden, The Netherlands
| | - Ludovica Verde
- Centro Italiano per la cura e il Benessere del Paziente con Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Annamaria Colao
- Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Centro Italiano per la cura e il Benessere del Paziente con Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Cattedra Unesco “Educazione Alla Salute E Allo Sviluppo Sostenibile”, University Federico II, Naples, Italy
| | - Luca Busetto
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, Padova, Italy
| | - Volkan Demirhan Yumuk
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Fatih, Istanbul, Turkey
- European Association for the Study of Obesity-Collaborating Center for Obesity Management, Istanbul, Turkey
| | - Maria Hassapidou
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece
- ESDN Obesity of EFAD, Naarden, The Netherlands
| | - on behalf of EASO Nutrition Working Group
- Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Centro Italiano per la cura e il Benessere del Paziente con Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e Andrologia, Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
- Cattedra Unesco “Educazione Alla Salute E Allo Sviluppo Sostenibile”, University Federico II, Naples, Italy
- Department of Wellbeing, Nutrition and Sport, Pegaso Telematic University, Centro Direzionale Isola F2, Naples, Italy
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, Padova, Italy
- Center for the Study of Metabolism, Body Composition and Lifestyle, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
- School of Medicine, European University Cyprus, Nicosia, Cyprus
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Obesity, Academic Specialist Center, Stockholm Health Care Services, Stockholm, Sweden
- ESDN Obesity of EFAD, Naarden, The Netherlands
- Department of Public Health, University of Naples Federico II, Naples, Italy
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Fatih, Istanbul, Turkey
- European Association for the Study of Obesity-Collaborating Center for Obesity Management, Istanbul, Turkey
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