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Silveira FM, Schuch LF, Pereira-Prado V, Molina-Frechero N, Lopez-Verdin S, Gómez Palacio-Gastélum M, Arocena M, Niklander S, Sicco E, Bologna-Molina R. Hypoxia-inducible factor-1α at the invasive tumor front in oral squamous cell carcinoma. World J Exp Med 2025; 15:102175. [DOI: 10.5493/wjem.v15.i2.102175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition, leading to aggressive tumor progression.
AIM To characterize the expression of hypoxia-inducible factor 1-alpha (HIF-1α) at the invasive tumor front (ITF) in comparison to tumor islands (TI) in oral squamous cell carcinoma (OSCC) and to explore its relationship with E-cadherin and Vimentin expression.
METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa (NOM) were included in this study. The ITF was identified based on the region and immune expression of AE1/AE3. Immunohistochemistry was performed to assess the expression of HIF-1α, Vimentin, and E-cadherin. The immunostaining was analyzed using an immunoreactive score, and the results were illustrated using immunofluorescence.
RESULTS HIF-1α expression was significantly higher in the TI region compared to the ITF region (P = 0.0134). Additionally, a significant difference was observed between TI and NOM (P = 0.0115). In the ITF regions, HIF-1α expression showed a significant correlation with Vimentin expression, with higher levels of HIF-1α associated with increased Vimentin expression (P = 0.017).
CONCLUSION Based on the results of this study, HIF-1α appears to play a distinct role in OSCC tumor progression, underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC. Further research is needed to better understand their impact on OSCC prognosis.
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Affiliation(s)
- Felipe Martins Silveira
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Lauren Frenzel Schuch
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Vanesa Pereira-Prado
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Nelly Molina-Frechero
- Division of Biological and Health Sciences, Autonomous Metropolitan University, Coyoacan 04960, Mexico
| | - Sandra Lopez-Verdin
- Health Science Center, Research Institute of Dentistry, Universidad de Guadalajara, Guadalajara 44100, Jalisco, Mexico
| | | | - Miguel Arocena
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, Montevideo 11600, Uruguay
| | - Sven Niklander
- Unit of Oral Pathology and Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar 2520000, Chile
| | - Estefania Sicco
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Ronell Bologna-Molina
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
- Department of Research, Universidad Juarez del Estado de Durango, Durango 34000, Mexico
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2
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St-Cyr G, Daniel L, Giguère H, Birtch R, Ilkow CS, Tai LH. Therapeutic limitations of oncolytic VSVd51-mediated miR-199a-5p delivery in triple negative breast cancer models. Sci Rep 2025; 15:16634. [PMID: 40360587 PMCID: PMC12075832 DOI: 10.1038/s41598-025-01584-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 05/07/2025] [Indexed: 05/15/2025] Open
Abstract
Triple-negative breast cancer (TNBC) metastasis is driven, in part, by the epithelial-to-mesenchymal transition (EMT), a process critical for cancer cell migration and invasion. Current treatment options, including immunotherapies and targeted therapies, demonstrate limited efficacy in this aggressive disease, underscoring the need for innovative therapeutic approaches. Here, we present a novel approach integrating oncolytic virotherapy with RNA interference by engineering two variants of vesicular stomatitis virus (VSVd51) expressing pri- or pre-miR-199a-5p, a microRNA implicated in the regulation of EMT. We demonstrate that both viral constructs are functional and capable of overexpressing mature miR-199a-5p. In the human TNBC cell line MDA-MB-231, both viral variants inhibited the expression of ZEB1, a transcription factor central to EMT. However, in the mouse TNBC cell line 4T1, miR-199a-5p delivered via VSVd51 failed to disrupt EMT-related gene expression. In vivo testing of VSVd51-pre-miR-199 in the syngeneic BALB/c-4T1 mouse model revealed no significant survival benefits or reduction in tumor growth, even when coupled with primary tumor resection. Additional in vivo testing in immunodeficient mice using the MDA-MB-231 xenograft model showed no effect on tumor reduction. Our study highlights the challenges of integrating miRNA-based strategies with oncolytic viruses in a cancer context-specific manner and underscores the importance of vector selection and tumor model compatibility for therapeutic synergy.
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Affiliation(s)
- Guillaume St-Cyr
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 rue Jean-Mignault, Sherbrooke, Québec, J1E 4 K8, Canada
- Centre de Recherche du Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Lauren Daniel
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 rue Jean-Mignault, Sherbrooke, Québec, J1E 4 K8, Canada
- Centre de Recherche du Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Hugo Giguère
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 rue Jean-Mignault, Sherbrooke, Québec, J1E 4 K8, Canada
- Centre de Recherche du Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Rayanna Birtch
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Carolina S Ilkow
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, 3201 rue Jean-Mignault, Sherbrooke, Québec, J1E 4 K8, Canada.
- Centre de Recherche du Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, QC, Canada.
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3
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Mimpen JY, Baldwin MJ, Paul C, Ramos-Mucci L, Kurjan A, Cohen CJ, Sharma S, Chevalier Florquin MSN, Hulley PA, McMaster J, Titchener A, Martin A, Costa ML, Gwilym SE, Cribbs AP, Snelling SJB. Exploring cellular changes in ruptured human quadriceps tendons at single-cell resolution. J Physiol 2025. [PMID: 40232153 DOI: 10.1113/jp287812] [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: 10/04/2024] [Accepted: 02/21/2025] [Indexed: 04/16/2025] Open
Abstract
Tendon ruptures in humans have often been studied during the chronic phase of injury, particularly in the context of rotator cuff disease. However, the early response to acute tendon ruptures remains less investigated. Quadriceps tendons, which require prompt surgical treatment, offer a model to investigate this early response. Therefore, this study aimed to explore the early cellular changes in ruptured compared to healthy human quadriceps tendons. Quadriceps tendon samples were collected from patients undergoing fracture repair (healthy) or tendon repair surgery (collected 7-8 days post-injury). Nuclei were isolated for single-nucleus RNA sequencing, and comprehensive transcriptomic analysis was conducted. The transcriptomes of 12,808 nuclei (7268 from healthy and 5540 from ruptured quadriceps tendons) were profiled, revealing 12 major cell types and several cell subtypes and states. Rupture samples showed increased expression of genes related to extracellular matrix organisation and cell cycle signalling, and a decrease in expression of genes in lipid metabolism pathways. These changes were predominantly driven by gene expression changes in the fibroblast, vascular endothelial cell (VEC), mural cell, and macrophage populations: fibroblasts shift to an activated phenotype upon rupture and there is an increase in the proportion of capillary and dividing VECs. A diverse immune environment was observed, with a shift from homeostatic to activated macrophages following rupture. Cell-cell interactions increased in number and diversity in rupture, and primarily involved fibroblast and VEC populations. Collectively, this transcriptomic analysis suggests that fibroblasts and endothelial cells are key orchestrators of the early injury response within ruptured quadriceps tendon. KEY POINTS: Tendon ruptures in humans have regularly been studied during the chronic phase of injury, but less is known about the early injury response after acute tendon ruptures. This study explored the early cellular changes in ruptured compared to healthy human quadriceps tendons at single-cell resolution. Fibroblasts and endothelial cells seem to be the key orchestrators of the early injury response within ruptured quadriceps tendon. Therefore, these cell types are obvious targets for interventions to enhance tendon healing. Overall, this study highlights that the development of more effective therapeutic options for tendon injury requires better understanding of the cellular, extracellular, and mechanical landscape of tendon tissue.
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Affiliation(s)
- Jolet Y Mimpen
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Mathew J Baldwin
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Claudia Paul
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Lorenzo Ramos-Mucci
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Alina Kurjan
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Carla J Cohen
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Shreeya Sharma
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | | | - Philippa A Hulley
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - John McMaster
- Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | | | | | - Matthew L Costa
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Stephen E Gwilym
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Oxford University Hospital NHS Foundation Trust, Oxford, UK
| | - Adam P Cribbs
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Oxford Centre for Translational Myeloma Research University of Oxford, Oxford, UK
| | - Sarah J B Snelling
- The Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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Mushtaq A, Li L, A A, Grøndahl L. Chitosan-Based Nanoparticles for Twist1 Knockdown in 4T1 Cells. Macromol Biosci 2025:e2400627. [PMID: 40205959 DOI: 10.1002/mabi.202400627] [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: 12/15/2024] [Revised: 03/17/2025] [Indexed: 04/11/2025]
Abstract
Bone metastasized breast cancer reduces the quality of life and median survival. Targeted delivery of twist1-siRNA using nanoparticles (NPs) is a promising strategy to overcome current limitations in treating such metastatic breast cancers. This research evaluates two types of chitosan (CHI)-based NPs for the delivery of twist1-siRNA. Alendronate conjugated PEG functionalized chitosan (ALD-PEG-CHI) NPs are developed for active targeting while PEG functionalized CHI (mPEG-CHI) NPs are fabricated for passive targeting. The size of twist1-siRNA-loaded NPs is below 70 nm and the zeta potential is near neutral for both types of NPs. Based on gel retardation assay, complete encapsulation of twist1-siRNA is achieved in both NP systems. The ALD-PEG-CHI-siRNA and mPEG-CHI-siRNA NPs display serum protection for 6 and 4 h, respectively, compared to the immediate degradation of naked twist1-siRNA. The NPs can knockdown twist1 in 4T1 cells as demonstrated through protein expression as well as by phenotypic change in directional cell migration by wound healing assay. Overall, these in vitro results illustrate the potential of the NPs as an effective therapeutic system for bone metastasized breast cancer.
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Affiliation(s)
- Asim Mushtaq
- School of Chemistry and Molecular Biosciences, The University of Queensland, Cooper Road, Brisbane, Queensland, 4072, Australia
| | - Li Li
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Corner of College and Cooper Road, Brisbane, Queensland, 4072, Australia
| | - Anitha A
- School of Chemistry and Molecular Biosciences, The University of Queensland, Cooper Road, Brisbane, Queensland, 4072, Australia
| | - Lisbeth Grøndahl
- School of Chemistry and Molecular Biosciences, The University of Queensland, Cooper Road, Brisbane, Queensland, 4072, Australia
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Corner of College and Cooper Road, Brisbane, Queensland, 4072, Australia
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5
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Huimin W, Xin W, Shan Y, Junwang Z, Jing W, Yuan W, Qingtong L, Xiaohui L, Jia Y, Lili Y. Lactate promotes the epithelial-mesenchymal transition of liver cancer cells via TWIST1 lactylation. Exp Cell Res 2025; 447:114474. [PMID: 39993459 DOI: 10.1016/j.yexcr.2025.114474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/15/2025] [Accepted: 02/16/2025] [Indexed: 02/26/2025]
Abstract
Elevated lactate levels increase the risk of liver cancer progression. However, the mechanisms by which lactate promotes liver cancer progression remain poorly understood. Epithelial-mesenchymal transition (EMT), characterized by the loss of epithelial cells polarity and cell-cell adhesion, leading to the acquisition of mesenchymal-like phenotypes, is widely recognized as a key contributor to liver cancer progression. TWIST1 (Twist Family BHLH Transcription Factor 1) plays a central role in inducing EMT. Here, we investigated the role of lactate in promoting EMT in liver cancer and the underlying regulatory mechanisms. High levels of lactate significantly promoted EMT progression in liver cancer cells. Mechanistically, lactate-induced lactylation of TWIST1 in vivo and in vitro. Mutation assay confirmed that Lysine 33 (K33) is the major site of TWIST1 lactylation. Moreover, cell fractionation & luciferase reporter assay results identified that TWIST1-K33R mutant impaired the EMT process via inhibiting nuclear import and the transcriptional activity. Thus, our findings provide novel insights into the regulatory role of lactate in EMT in liver cancer pathogenesis. Additionally, targeting of lactate-driven lactylation of TWIST1 may boost the therapeutic strategy for liver cancer.
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Affiliation(s)
- Wang Huimin
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wu Xin
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Yu Shan
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Zhang Junwang
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wen Jing
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Wang Yuan
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Liu Qingtong
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Li Xiaohui
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China
| | - Yao Jia
- Department of Gastroenterology, Shanxi Bethune Hospital, No.99 Longcheng Road, Taiyuan, 030032, China
| | - Yuan Lili
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Taiyuan, 030000, China.
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6
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Pei S, Zhang D, Li Z, Liu J, Li Z, Chen J, Xie Z. The Role of the Fox Gene in Breast Cancer Progression. Int J Mol Sci 2025; 26:1415. [PMID: 40003882 PMCID: PMC11855465 DOI: 10.3390/ijms26041415] [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: 11/26/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future.
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Affiliation(s)
- Shaoxuan Pei
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Dechun Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhuohan Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jinkai Liu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Ziyi Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jianrui Chen
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhenzhen Xie
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
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7
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Ma J, Chen Y, Song J, Ruan Q, Li L, Luo L. Establishment and application of a zebrafish model of Werner syndrome identifies sapanisertib as a potential antiaging drug. Proc Natl Acad Sci U S A 2025; 122:e2413719122. [PMID: 39883840 PMCID: PMC11804616 DOI: 10.1073/pnas.2413719122] [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: 07/09/2024] [Accepted: 01/03/2025] [Indexed: 02/01/2025] Open
Abstract
Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named meteor (met), harboring a mutation in the Werner syndrome RecQ-like helicase (wrn) gene. Loss of wrn leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration. Therefore, we conducted a screening of antiaging drugs using the met mutant and revealed that sapanisertib effectively ameliorated most of the aging phenotypes of the mutant. Mechanistically, the geroprotective effects of sapanisertib may be attributed to inhibition of mTORC1/2. Furthermore, sapanisertib also attenuated chronological aging in wild-type aged zebrafish and replicative-senescence in human foreskin fibroblasts. Taken together, our study introduces a unique and efficient model for large-scale antiaging drug screening in vertebrates and suggests sapanisertib as a potential therapeutic option for treating premature aging and promoting healthy aging.
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Affiliation(s)
- Jianlong Ma
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai200438, China
| | - Yang Chen
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing400715, China
| | - Jingmei Song
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing400715, China
| | - Qingfeng Ruan
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing400715, China
| | - Lianghui Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing400715, China
| | - Lingfei Luo
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai200438, China
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing400715, China
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8
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Nara M, Kurosawa M, Itsumi M, Morisaki H, Fukamachi H, Okahashi N, Suzuki N, Kuwata H. Experimental Murine Periodontitis Increases Salivary Gland IgA-Producing B Cells Following Oral Dysbiosis. Microbiol Immunol 2025; 69:114-127. [PMID: 39709535 PMCID: PMC11789210 DOI: 10.1111/1348-0421.13191] [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: 09/17/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 12/23/2024]
Abstract
The oral microbiome is closely involved in the maintenance of host health and the development of systemic diseases. The salivary glands play an essential role in homeostasis in the oral cavity. Here, we investigated the effects of periodontal inflammation on salivary gland function and the oral microbiome. In experimental periodontitis model mice, an increase in IgA⁺ cells in the salivary glands were observed 1 week after treatment. Alteration of the oral microbiome was also induced in this model. Gene expression analysis of the salivary glands showed changes in the expression of genes related to B-cell maturation and plasma cell differentiation and an increase in the expression of genes related to macrophage activation upon experimental periodontitis induction. Furthermore, the relationship between disruption of oral microflora and salivary gland function was examined using a cohousing model in which experimental periodontitis model mice and untreated mice were reared in the same cage. We found that cohoused normal mice underwent alteration of the oral microbiome, with increases in IgA⁺ cells and macrophages in the salivary glands. In summary, our results suggest that, in the oral cavity, there is a close link between oral bacterial flora and immune cells in the salivary glands. Our results also show that localized inflammation disrupts the homeostasis in the oral cavity, inducing pathological conditions such as dysbiosis. Our study suggests the importance of the interaction among local oral inflammation, salivary gland function, and oral microflora, and provides new insights into the mechanisms by which oral health is maintained.
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Affiliation(s)
- Mai Nara
- Department of Conservative Dentistry, Division of EndodontologyShowa University Graduate School of DentistryOta‐kuTokyoJapan
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Mie Kurosawa
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Momoe Itsumi
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Hirobumi Morisaki
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Haruka Fukamachi
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Nobuo Okahashi
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
| | - Noriyuki Suzuki
- Department of Conservative Dentistry, Division of EndodontologyShowa University Graduate School of DentistryOta‐kuTokyoJapan
| | - Hirotaka Kuwata
- Department of Oral Microbiology and ImmunologyShowa University Graduate School of DentistryShinagawa‐kuTokyoJapan
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9
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Roy A, Sudhamalla B. ATAD2 and TWIST1 Interaction Promotes MYC Activation in Colorectal Carcinoma. Biochemistry 2025; 64:114-126. [PMID: 39686835 DOI: 10.1021/acs.biochem.4c00360] [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: 12/18/2024]
Abstract
ATPase family AAA domain-containing protein 2 (ATAD2) is significantly up-regulated in many cancer types and contributes to poor patient outcomes. ATAD2 exhibits a multidomain architecture comprising an N-terminal acidic domain, two AAA+ ATPase domains, a bromodomain, and a C-terminal domain. The AAA+ ATPase domain facilitates protein oligomerization and ATP binding, while the bromodomain recognizes acetylated lysine in histones and nonhistone proteins. ATAD2 involvement in cancer extends across multiple signaling pathways, such as Rb-E2F1, PI3K/AKT, and TGF-β1/Smad3, which promotes cell proliferation and cancer progression. Herein, we report that ATAD2 directly interacts with TWIST1, and both N-terminal regions of proteins mediate the interaction. Immunofluorescence experiments suggested that ATAD2 and TWIST1 primarily colocalize in the nucleus. Notably, our qPCR results revealed the functional significance of ATAD2-TWIST1 interaction by demonstrating their synergistic effect on the transcriptional activation of MYC in colorectal carcinoma cell lines. Moreover, the ChIP-qPCR result further indicates that ATAD2 and TWIST1 significantly localize in the promoter of the MYC gene. In addition, analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data suggests a correlation between ATAD2, TWIST1, and MYC overexpression and poor survival rates in colorectal carcinoma. Lastly, the overexpression of ATAD2 and TWIST1 enhances cell proliferation, emphasizing their role in colorectal carcinoma progression through MYC activation. Together, these results suggest that ATAD2 is a crucial factor in TWIST1-dependent MYC gene activation, resulting in an active ATAD2-TWIST1-MYC axis that contributes to colon cancer cell proliferation.
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Affiliation(s)
- Anirban Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
| | - Babu Sudhamalla
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
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10
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Wang H, Gao Y, Guo F, Zhou P, Ma Z, Chi K, Ye J, Sun H, He X, Shi B, Wang Y, Han Z. ERβ-regulated circATP2B1/miR-204-3p/TWIST1 positive feedback loop facilitates epithelial to mesenchymal transition in clear cell renal cell carcinoma. Transl Oncol 2025; 51:102213. [PMID: 39586165 PMCID: PMC11626627 DOI: 10.1016/j.tranon.2024.102213] [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: 05/08/2024] [Revised: 11/14/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Our previous studies have shown that estrogen receptor beta (ERβ) can promote the progression of clear cell renal cell carcinoma (ccRCC) by downregulating the expression of circATP2B1 and miR-204-3p. Here, we found that ERβ might promote the epithelial-mesenchymal transition(EMT) of ccRCC by modulating the circATP2B1/miR-204-3p/TWIST1(Twist family basic helix-loop-helix transcription factor 1) signaling pathway. METHODS We utilized bioinformatics analysis to determine the clinical significance of TWIST1 in ccRCC. The expression of TWIST1 in ccRCC tissues and cells was examined using immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting assay. Chromatin Immunoprecipitation assay were conducted to validate the relationship between ERβ and TWIST1. Luciferase reporter gene assays were employed to validate the binding targets of TWIST1 and miR-204-3p. The role of TWIST1 in ccRCC was studied through in vitro and in vivo experiments. Transwell assays and wound healing assays were used to assess the impact of TWIST1 on the invasive and migratory abilities of ccRCC cells. RESULTS Mechanism analysis revealed that miR-204-3p can inhibit TWIST1 by targeting its 3' untranslated region. Additionally, TWIST1 can promote ERβ transcription by directly binding to transcription factor binding site in the ERβ promoter region, forming a positive feedback loop. These in vitro data were further validated in an in vivo mouse model. Importantly, analysis of data from the TCGA-KIRC database further confirmed the above in vitro/in vivo findings. CONCLUSIONS Together, our results suggest that ERβ/circATP2B1/miR-204-3p/TWIST1 can promote EMT by forming a positive feedback loop, thus promoting the progression of ccRCC. Targeting this newly identified signaling pathway may more effectively control the progression of ccRCC.
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Affiliation(s)
- Hu Wang
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Department of Urology, The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing 314033, China
| | - Yilong Gao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fengran Guo
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Pengfei Zhou
- Zhengding County People's Hospital, Shijiazhuang, China
| | - Ziyang Ma
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Kui Chi
- Department of Vascular surgery, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Jiaqing Ye
- Department of Clinical laboratory, the Third Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Hao Sun
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Xingyu He
- Department of Pathology, Hebei Medical University, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China
| | - Bei Shi
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Yaxuan Wang
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
| | - Zhenwei Han
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
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11
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Yang XD, Haga CL, Phinney DG. Signaling Dynamics in Osteogenesis: Unraveling Therapeutic Targets for Bone Generation. Curr Drug Targets 2025; 26:350-366. [PMID: 39791147 DOI: 10.2174/0113894501359782241216082049] [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: 10/08/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 01/12/2025]
Abstract
Diseases affecting bone encompass a spectrum of disorders, from prevalent conditions such as osteoporosis and Paget's disease, collectively impacting millions, to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs, such as bisphosphonates, synthetic hormones, and antibodies, are utilized in the treatment of bone diseases, their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems. Consequently, the selection of an appropriate target is a complicated process despite the significant demand for novel medications to address bone diseases. Research has shown the role of various cell signaling pathways, including Wnt, PTHR1, CASR, BMPRs, OSCAR, and TWIST1, in the regulation of osteogenesis, bone remodeling, and homeostasis. Disruptions in bone homeostasis can result in decreased bone density and the onset of osteoporosis. There remains a need for the development of drugs that can enhance bone remodeling with improved side effects profiles. The exploration of promising targets to stimulate bone formation has the potential to significantly advance the field of bone-related medical care, thereby improving the quality of life for millions. Additionally, a deeper understanding of anabolic and catabolic pathway mechanisms could enable future studies to explore synergistic effects between unrelated pathways. Herein, we explore potential drug targets that may be exploited therapeutically using small molecule agonists or antagonists to promote bone remodeling and discuss their advantages and limitations.
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Affiliation(s)
- Xue D Yang
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL33458, USA
| | - Christopher L Haga
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL33458, USA
| | - Donald G Phinney
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL33458, USA
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12
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Tu M, Ge B, Li J, Pan Y, Zhao B, Han J, Wu J, Zhang K, Liu G, Hou M, Yue M, Han X, Sun T, An Y. Emerging biological functions of Twist1 in cell differentiation. Dev Dyn 2025; 254:8-25. [PMID: 39254141 DOI: 10.1002/dvdy.736] [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: 04/09/2024] [Revised: 08/03/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
Twist1 is required for embryonic development and expresses after birth in mesenchymal stem cells derived from mesoderm, where it governs mesenchymal cell development. As a well-known regulator of epithelial-mesenchymal transition or embryonic organogenesis, Twist1 is important in a variety of developmental systems, including mesoderm formation, neurogenesis, myogenesis, cranial neural crest cell migration, and differentiation. In this review, we first highlight the physiological significance of Twist1 in cell differentiation, including osteogenic, chondrogenic, and myogenic differentiation, and then detail its probable molecular processes and signaling pathways. On this premise, we summarize the significance of Twist1 in distinct developmental disorders and diseases to provide a reference for studies on cell differentiation/development-related diseases.
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Affiliation(s)
- Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Bingqian Ge
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiali Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yanbing Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jialin Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Kaifeng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Guangchao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Mengwen Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Man Yue
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
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Sun D, Song Y, Gao W, Lin B, Wang B, Yang X, Li S, Jin Y, Zhang J. DNA-templated nanosheets for enhanced chemodynamic therapy and gene therapy to inhibit tumor recurrence and metastasis. Int J Pharm 2024; 667:124910. [PMID: 39500474 DOI: 10.1016/j.ijpharm.2024.124910] [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: 06/23/2024] [Revised: 10/13/2024] [Accepted: 11/01/2024] [Indexed: 11/10/2024]
Abstract
Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO2) that combine the functions of Mn2+-mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO2 nanosheets respond effectively to the TME, releasing Mn2+ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn2+ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO2 nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H2O2 into O2. This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence and metastasis.
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Affiliation(s)
- Danna Sun
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, China
| | - Yuwei Song
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
| | - Wenyan Gao
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
| | - Boyang Lin
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
| | - Bei Wang
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
| | - Xinjian Yang
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, China
| | - Shaochun Li
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
| | - Yi Jin
- College of Basic Medical Science, Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China.
| | - Jinchao Zhang
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, China.
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14
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Lovisa S, Vetrano S. TWISTed fibroblasts: New drivers of intestinal fibrosis in Crohn's disease. Heliyon 2024; 10:e40604. [PMID: 39654763 PMCID: PMC11626011 DOI: 10.1016/j.heliyon.2024.e40604] [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: 08/14/2024] [Revised: 11/06/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024] Open
Abstract
Fibrosis is the pathological consequence of chronic inflammation. In Crohn's disease (CD), fibrostenotic complications occur with 50-70 % frequency as a failure to properly repair the tissue damage. Intestinal stenosis requires surgical intervention and relapses in most patients. Mesenchymal cells encompassed of heterogeneous cell subsets orchestrate this complex process. The lack of a full characterization of the stromal diversity and function in CD has consequently slowed the development of anti-fibrotic targets. Two recent studies align together demonstrating FAP+TWIST1+ fibroblasts as the primary mesenchymal population driving intestinal fibrosis in CD. Genetic and pharmacological targeting of Twist1 in mouse models proved the functional role of Fap+Twist1+ fibroblasts and indicate the use of the Twist1 inhibitor harmine as a potential therapeutic strategy to revert fibrosis.
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Affiliation(s)
- Sara Lovisa
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Stefania Vetrano
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
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15
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Dhiman S, Panigrahi I, Sharma M, Chaudhry C, Garg M. TWIST1 Gene Variants Cause Craniosynostosis with Limb Abnormalities in Asian Patients. J Pediatr Genet 2024; 13:258-262. [PMID: 39502847 PMCID: PMC11534420 DOI: 10.1055/s-0043-1771527] [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: 08/23/2022] [Accepted: 06/25/2023] [Indexed: 11/08/2024]
Abstract
The TWIST1 gene codes for a highly conserved transcription factor in a basic helix-loop-helix transcription factors family. The pattern of inheritance is autosomal dominant in Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, and Sweeney-Cox syndrome. Major features of these syndromes include coronal synostosis, vision problems, and deafness, and facial features include hypertelorism, low-set ears, arched eyebrows, beaked nose, maxillary hypoplasia, and other dysmorphisms including broad great toes, clinodactyly, brachydactyly, and cutaneous syndactyly. TWIST1 (bHLH) transcription factor regulates the formation of head and limbs in the embryo. We describe three families affected with craniosynostosis in whom a sporadic TWIST1 variant was identified on whole exome sequencing, chromosomal microarray, and Sanger sequencing.
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Affiliation(s)
| | | | - Maryada Sharma
- Department of Otorhinolaryngology, PGIMER, Chandigarh, India
| | | | - Mahak Garg
- Department of Pediatrics, PGIMER, Chandigarh, India
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16
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Liu Y, Xiao H, Zeng H, Xiang Y. Beyond tumor‑associated macrophages involved in spheroid formation and dissemination: Novel insights for ovarian cancer therapy (Review). Int J Oncol 2024; 65:117. [PMID: 39513610 PMCID: PMC11575928 DOI: 10.3892/ijo.2024.5705] [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: 05/24/2024] [Accepted: 10/22/2024] [Indexed: 11/15/2024] Open
Abstract
Ovarian cancer (OC) is the most common and deadly malignant tumor of the female reproductive system. When OC cells detach from the primary tumor and enter the ascitic microenvironment, they are present as individual cells or multicellular spheroids in ascites. These spheroids, composed of cancer and non‑malignant cells, are metastatic units and play a crucial role in the progression of OC. However, little is known about the mechanism of spheroid formation and dissemination. Tumor‑associated macrophages (TAMs) in the center of spheroids are key in spheroid formation and metastasis and provide a potential target for OC therapy. The present review summarizes the key biological features of spheroids, focusing on the role of TAMs in spheroid formation, survival and peritoneal metastasis, and the strategies targeting TAMs to provide new insights in treating OC.
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Affiliation(s)
- Yuchen Liu
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Haoyue Xiao
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Hai Zeng
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
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17
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Xu C, Fu X, Qin H, Yao K. Traversing the epigenetic landscape: DNA methylation from retina to brain in development and disease. Front Cell Neurosci 2024; 18:1499719. [PMID: 39678047 PMCID: PMC11637887 DOI: 10.3389/fncel.2024.1499719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024] Open
Abstract
DNA methylation plays a crucial role in development, aging, degeneration of various tissues and dedifferentiated cells. This review explores the multifaceted impact of DNA methylation on the retina and brain during development and pathological processes. First, we investigate the role of DNA methylation in retinal development, and then focus on retinal diseases, detailing the changes in DNA methylation patterns in diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. Since the retina is considered an extension of the brain, its unique structure allows it to exhibit similar immune response mechanisms to the brain. We further extend our exploration from the retina to the brain, examining the role of DNA methylation in brain development and its associated diseases, such as Alzheimer's disease (AD) and Huntington's disease (HD) to better understand the mechanistic links between retinal and brain diseases, and explore the possibility of communication between the visual system and the central nervous system (CNS) from an epigenetic perspective. Additionally, we discuss neurodevelopmental brain diseases, including schizophrenia (SZ), autism spectrum disorder (ASD), and intellectual disability (ID), focus on how DNA methylation affects neuronal development, synaptic plasticity, and cognitive function, providing insights into the molecular mechanisms underlying neurodevelopmental disorders.
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Affiliation(s)
- Chunxiu Xu
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Xuefei Fu
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Huan Qin
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Kai Yao
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
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18
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Pranter R, Feiner N. Spatiotemporal distribution of neural crest cells in the common wall lizard Podarcis muralis. Dev Dyn 2024. [PMID: 39560189 DOI: 10.1002/dvdy.758] [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: 05/24/2024] [Revised: 08/23/2024] [Accepted: 10/06/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Neural crest cells (NCCs) are migratory embryonic stem cells that give rise to a diverse set of cell types. Here we describe the dynamic distribution of NCCs in developing embryos of the common wall lizard Podarcis muralis inferred from 10 markers. Our aim is to provide insights into the NCC development of lacertid lizards and to infer evolutionary modifications by comparisons to other tetrapods. RESULTS NCC migration is ongoing at oviposition, following three streams in the head and multiple in the trunk. From 21ss, we observe expression patterns indicating the beginning of differentiation toward mesenchymal and neuronal fates. By 35ss, migration is restricted to caudal levels, and fully differentiated chromaffin cells are observed. CONCLUSIONS We find that some markers show patterns that differ from other tetrapods. For example, the antibody HNK-1 labels three NCC streams from the hindbrain while some comparable reptile studies describe four. However, the information emerging from all markers combined shows that the overall spatiotemporal distribution of NCCs in the common wall lizard is largely conserved with that of other tetrapods. Our study highlights the dynamic nature of seemingly canonical marker genes and provides the first description of spatiotemporal NCC dynamics in a lacertid lizard.
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Affiliation(s)
- Robin Pranter
- Department of Biology, Lund University, Lund, Sweden
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19
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Sun L, Liu L, Jiang J, Liu K, Zhu J, Wu L, Lu X, Huang Z, Yuan Y, Crowley SD, Mao H, Xing C, Ren J. Transcription factor Twist1 drives fibroblast activation to promote kidney fibrosis via signaling proteins Prrx1/TNC. Kidney Int 2024; 106:840-855. [PMID: 39181396 DOI: 10.1016/j.kint.2024.07.028] [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: 11/30/2023] [Revised: 07/12/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024]
Abstract
The transcription factor Twist1 plays a vital role in normal development in many tissue systems and continues to be important throughout life. However, inappropriate Twist1 activity has been associated with kidney injury and fibrosis, though the underlying mechanisms involved remain incomplete. Here, we explored the role of Twist1 in regulating fibroblast behaviors and the development kidney fibrosis. Initially Twist1 protein and activity was found to be markedly increased within interstitial myofibroblasts in fibrotic kidneys in both humans and rodents. Treatment of rat kidney interstitial fibroblasts with transforming growth factor-β1 (a profibrotic factor) also induced Twist1 expression in vitro. Gain- and loss-of-function experiments supported that Twist1 signaling was responsible for transforming growth factor-β1-induced fibroblast activation and fetal bovine serum-induced fibroblast proliferation. Mechanistically, Twist1 protein promoted kidney fibroblast activation by driving the expression of downstream signaling proteins, Prrx1 and Tnc. Twist1 directly enhanced binding to the promoter of Prrx1 but not TNC, whereas the promoter of TNC was directly bound by Prrx1. Finally, mice with fibroblast-specific deletion of Twist1 exhibited less Prrx1 and TNC protein abundance, interstitial extracellular matrix deposition and kidney inflammation in both the unilateral ureteral obstruction and ischemic-reperfusion injury-induced-kidney fibrotic models. Inhibition of Twist1 signaling with Harmine, a β-carboline alkaloid, improved extracellular matrix deposition in both injury models. Thus, our results suggest that Twist1 signaling promotes the activation and proliferation of kidney fibroblasts, contributing to the development of interstitial fibrosis, offering a potential therapeutic target for chronic kidney disease.
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Affiliation(s)
- Lianqin Sun
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lishan Liu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Juanjuan Jiang
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Kang Liu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jingfeng Zhu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lin Wu
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaohan Lu
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Zhimin Huang
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yanggang Yuan
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Steven D Crowley
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Durham VA Medical Center, Durham, North Carolina, USA
| | - Huijuan Mao
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Changying Xing
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Jiafa Ren
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Tolue Ghasaban F, Moghbeli M. Long non-coding RNAs as the pivotal regulators of epithelial mesenchymal transition through WNT/β-catenin signaling pathway in tumor cells. Pathol Res Pract 2024; 263:155683. [PMID: 39471528 DOI: 10.1016/j.prp.2024.155683] [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: 07/03/2024] [Accepted: 10/25/2024] [Indexed: 11/01/2024]
Abstract
Tumor cell invasion is considered as one of the main therapeutic challenges in cancer patients, which leads to distant metastasis and reduced prognosis. Therefore, investigation of the factors involved in tumor cell invasion improves the therapeutic methods to reduce tumor metastasis. Epithelial-mesenchymal transition (EMT) process has a pivotal role in tumor cell invasion and metastasis, during which tumor cells gain the invasive ability by losing epithelial characteristics and acquiring mesenchymal characteristics. WNT/β-catenin signaling pathway has a key role in tumor cell invasion by regulation of EMT process. Long non-coding RNAs (lncRNAs) have also an important role in EMT process through the regulation of WNT/β-catenin pathway. Deregulation of lncRNAs is associated with tumor metastasis in different tumor types. Therefore, in the present review, we investigated the role of lncRNAs in EMT process and tumor cell invasion through the regulation of WNT/β-catenin pathway. It has been reported that lncRNAs mainly induced the EMT process and tumor cell invasion through the activation of WNT/β-catenin pathway. LncRNAs that regulate the WNT/β-catenin mediated EMT process can be introduced as the prognostic markers as well as suitable therapeutic targets to reduce the tumor metastasis in cancer patients.
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Affiliation(s)
- Faezeh Tolue Ghasaban
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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21
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Gu C, Tang Q, Li L, Chen Y. Optimization and Implication of Adipose-Derived Stem Cells in Craniofacial Bone Regeneration and Repair. Bioengineering (Basel) 2024; 11:1100. [PMID: 39593759 PMCID: PMC11592193 DOI: 10.3390/bioengineering11111100] [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: 09/14/2024] [Revised: 10/17/2024] [Accepted: 10/27/2024] [Indexed: 11/28/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) have emerged as a promising resource for craniofacial bone regeneration due to their high abundance and easy accessibility, significant osteogenic potential, versatile applications, and potential for personalized medicine, which underscore their importance in this field. This article reviews the current progress of preclinical studies that describe the careful selection of specific ADSC subpopulations, key signaling pathways involved, and usage of various strategies to enhance the osteogenic potential of ADSCs. Additionally, clinical case reports regarding the application of ADSCs in the repair of calvarial defects, cranio-maxillofacial defects, and alveolar bone defects are also discussed.
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Affiliation(s)
- Cong Gu
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
| | - Qinghuang Tang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA
| | - Liwen Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
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22
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Upadhyay A, Bakkalci D, Micalet A, Butler M, Bergin M, Moeendarbary E, Loizidou M, Cheema U. Dense Collagen I as a Biomimetic Material to Track Matrix Remodelling in Renal Carcinomas. ACS OMEGA 2024; 9:41419-41432. [PMID: 39398183 PMCID: PMC11465592 DOI: 10.1021/acsomega.4c04442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/15/2024]
Abstract
Aims: Renal tissue is a dynamic biophysical microenvironment, regulating healthy function and influencing tumor development. Matrix remodelling is an iterative process and aberrant tissue repair is prominent in kidney fibrosis and cancer. Biomimetic 3D models recapitulating the collagen composition and mechanical fidelity of native renal tissue were developed to investigate cell-matrix interactions in renal carcinomas. Methods: Collagen I and laminin hydrogels were engineered with renal cancer cells (ACHN and 786-O), which underwent plastic compression to generate dense matrices. Mechanical properties were determined using shear rheology and qPCR determined the gene expression of matrix markers. Results: The shear modulus and phase angle of acellular dense collagen I gels (474 Pa and 10.7) are similar to human kidney samples (1410 Pa and 10.5). After 21 days, 786-O cells softened the dense matrix (∼155 Pa), with collagen IV downregulation and upregulation of matrix metalloproteinases (MMP7 and MMP8). ACHN cells were found to be less invasive and stiffened the matrix to ∼1.25 kPa, with gene upregulation of collagen IV and the cross-linking enzyme LOX. Conclusions: Renal cancer cells remodel their biophysical environment, altering the material properties of tissue stroma in 3D models. These models can generate physiologically relevant stiffness to investigate the different matrix remodelling mechanisms utilized by cancer cells.
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Affiliation(s)
- Anuja Upadhyay
- UCL
Centre for 3D Models of Health and Disease, Division of Surgery and
Interventional Science, University College
London, Charles Bell House, 43-45 Foley Street, W1W 7TS London, United Kingdom
| | - Deniz Bakkalci
- UCL
Centre for 3D Models of Health and Disease, Division of Surgery and
Interventional Science, University College
London, Charles Bell House, 43-45 Foley Street, W1W 7TS London, United Kingdom
| | - Auxtine Micalet
- UCL
Centre for 3D Models of Health and Disease, Division of Surgery and
Interventional Science, University College
London, Charles Bell House, 43-45 Foley Street, W1W 7TS London, United Kingdom
- Department
of Mechanical Engineering, Roberts Building, University College London, WC1E 6BT London, United Kingdom
| | - Matt Butler
- UCB
Pharma, 216 Bath Road, SL1 3WE Slough, United Kingdom
| | | | - Emad Moeendarbary
- Department
of Mechanical Engineering, Roberts Building, University College London, WC1E 6BT London, United Kingdom
| | - Marilena Loizidou
- Division
of Surgery and Interventional Science, University
College London, Royal
Free Campus, Rowland Hill Street, NW3
2PF London, United
Kingdom
| | - Umber Cheema
- UCL
Centre for 3D Models of Health and Disease, Division of Surgery and
Interventional Science, University College
London, Charles Bell House, 43-45 Foley Street, W1W 7TS London, United Kingdom
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23
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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24
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Geister E, Ard D, Patel H, Findley A, DeSouza G, Martin L, Knox H, Gavara N, Lugea A, Sabbatini ME. The Role of Twist1 in Chronic Pancreatitis-Associated Pancreatic Stellate Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1879-1897. [PMID: 39032603 PMCID: PMC11423762 DOI: 10.1016/j.ajpath.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/18/2024] [Accepted: 06/28/2024] [Indexed: 07/23/2024]
Abstract
In healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Luciferase assay indicated that Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induced rigid ECM production and MMP-9 transcription in an NF-κB-dependent mechanism that selectively displayed proteolytic activity toward type I/III collagen.
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Affiliation(s)
- Emma Geister
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Dalton Ard
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Heer Patel
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Alyssa Findley
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Godfrey DeSouza
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Lyndsay Martin
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Henry Knox
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Natasha Gavara
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Aurelia Lugea
- Cedars-Sinai Medical Center, Los Angeles, California
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25
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Valbuena R, Nigam A, Tycko J, Suzuki P, Spees K, Aradhana, Arana S, Du P, Patel RA, Bintu L, Kundaje A, Bassik MC. Prediction and design of transcriptional repressor domains with large-scale mutational scans and deep learning. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.21.614253. [PMID: 39386603 PMCID: PMC11463546 DOI: 10.1101/2024.09.21.614253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Regulatory proteins have evolved diverse repressor domains (RDs) to enable precise context-specific repression of transcription. However, our understanding of how sequence variation impacts the functional activity of RDs is limited. To address this gap, we generated a high-throughput mutational scanning dataset measuring the repressor activity of 115,000 variant sequences spanning more than 50 RDs in human cells. We identified thousands of clinical variants with loss or gain of repressor function, including TWIST1 HLH variants associated with Saethre-Chotzen syndrome and MECP2 domain variants associated with Rett syndrome. We also leveraged these data to annotate short linear interacting motifs (SLiMs) that are critical for repression in disordered RDs. Then, we designed a deep learning model called TENet ( T ranscriptional E ffector Net work) that integrates sequence, structure and biochemical representations of sequence variants to accurately predict repressor activity. We systematically tested generalization within and across domains with varying homology using the mutational scanning dataset. Finally, we employed TENet within a directed evolution sequence editing framework to tune the activity of both structured and disordered RDs and experimentally test thousands of designs. Our work highlights critical considerations for future dataset design and model training strategies to improve functional variant prioritization and precision design of synthetic regulatory proteins.
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26
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Tang WB, Wang WH, Lee HJ, Zhou J, Yu XB, Zhou Q, Cho S, Kim K. δ-catenin promotes Twist1 stabilization in prostate cancer through ubiquitination modification. Am J Cancer Res 2024; 14:3773-3788. [PMID: 39267672 PMCID: PMC11387878 DOI: 10.62347/aljt8663] [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: 05/08/2024] [Accepted: 08/06/2024] [Indexed: 09/15/2024] Open
Abstract
Prostate cancer generally has a high long-term survival rate; however, metastatic prostate cancer remains largely incurable despite intensive multimodal therapy. Recent research has identified δ-catenin, a member of the catenin family, as playing a crucial role in the progression of prostate cancer. Nonetheless, the extent to which δ-catenin influences transcription factors associated with epithelial-mesenchymal transition (EMT) has not been thoroughly explored. This study aims to investigate the hypothesis that δ-catenin enhances the stability of Twist1, thereby promoting the migratory and invasive capabilities of prostate cancer cells. Clinical data indicate a strong correlation between δ-catenin and Twist1 expression levels. Western blot analysis confirmed that δ-catenin stabilizes Twist1 and induces ectopic expression. Additionally, δ-catenin was found to reduce Twist1 phosphorylation by inhibiting GSK-3β activity. Immunoprecipitation analysis suggested that δ-catenin exerts its effect by competing with Twist1 for binding to ubiquitin (Ub). These results highlight the role of δ-catenin in the ubiquitination modification of Twist1, suggesting that the combined presence of δ-catenin and Twist1 could serve as a biomarker for tumor progression in prostate cancer.
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Affiliation(s)
- Wei-Bo Tang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University Gwangju 61186, Korea
- School of Pharmaceutical Science, Wenzhou Medical University Wenzhou 325000, Zhejiang, China
| | - Wen-Hang Wang
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University Wenzhou 325035, Zhejiang, China
| | - Hyoung Jae Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University Gwangju 61186, Korea
| | - Jie Zhou
- School of Pharmaceutical Science, Wenzhou Medical University Wenzhou 325000, Zhejiang, China
| | - Xu-Ben Yu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University Gwangju 61186, Korea
| | - Quan Zhou
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University Gwangju 61186, Korea
| | - Sayeon Cho
- College of Pharmacy, Chung-Ang University Seoul 06974, Korea
| | - Kwonseop Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University Gwangju 61186, Korea
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27
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Alfahed A. Deregulation of TWIST1 expression by promoter methylation in gastrointestinal cancers. Saudi J Biol Sci 2024; 31:103842. [PMID: 39479535 PMCID: PMC11385410 DOI: 10.1016/j.sjbs.2023.103842] [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: 08/24/2023] [Revised: 10/03/2023] [Accepted: 10/15/2023] [Indexed: 11/02/2024] Open
Abstract
TWIST1, a basic helix-loop-helix transcription factor with versatile roles in cancer, is frequently deregulated in cancers, through established pathway perturbations. However. the significance of TWIST1 methylation in the deregulation of TWIST1 in gastrointestinal cancers is not fully clear. This study hypothesized that TWIST1 promoter methylation deregulates TWIST1 expression independent of established deregulators such as the WNT, TGFB, NOTCH and miRNA pathways. To prove this hypothesis, colon, gastric and rectal cancer genomic data comprising gene expression, DNA methylation, and miRNA data were retrieved from the Cancer Genome Atlas cohorts which are publicly available in cancer genomic databases, the Genome Data Commons and the cBioportal.org. About 217 variables comprising expression levels of genes of the WNT, TGFB, NOTCH and miRNA signalling pathways, as well as the beta values of 17 TWIST1 methylation loci were subjected to Principal Component Regression Analysis, and then standard Linear Regression Analysis. The results showed that TWIST1 methylation is a predictor of TWIST1 expression in the gastrointestinal cancers, independent of WNT, TGFB, and NOTCH signalling and miRNA deregulation. The results also showed that different TWIST1 methylation loci may deregulate TWIST1 expression in different cancer types. The inference that can be drawn from this study is that TWIST1 DNA methylation is an important TWIST1 deregulation mechanism in colon, rectal and gastric cancers.
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Affiliation(s)
- Abdulaziz Alfahed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudia Arabia
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28
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Zhu W, Ding Y, Huang W, Guo N, Ren Q, Wang N, Ma X. Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia. Br J Haematol 2024; 205:568-579. [PMID: 38877874 DOI: 10.1111/bjh.19591] [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: 01/04/2024] [Accepted: 05/30/2024] [Indexed: 08/10/2024]
Abstract
MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.
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Affiliation(s)
- Wenqi Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yiyi Ding
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Wanling Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Nini Guo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Nan Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Xiaotong Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
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29
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Nasimi Shad A, Akhlaghipour I, Alshakarchi HI, Saburi E, Moghbeli M. Role of microRNA-363 during tumor progression and invasion. J Physiol Biochem 2024; 80:481-499. [PMID: 38691273 DOI: 10.1007/s13105-024-01022-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
Recent progresses in diagnostic and therapeutic methods have significantly improved prognosis in cancer patients. However, cancer is still considered as one of the main causes of human deaths in the world. Late diagnosis in advanced tumor stages can reduce the effectiveness of treatment methods and increase mortality rate of cancer patients. Therefore, investigating the molecular mechanisms of tumor progression can help to introduce the early diagnostic markers in these patients. MicroRNA (miRNAs) has an important role in regulation of pathophysiological cellular processes. Due to their high stability in body fluids, they are always used as the non-invasive markers in cancer patients. Since, miR-363 deregulation has been reported in a wide range of cancers, we discussed the role of miR-363 during tumor progression and metastasis. It has been reported that miR-363 has mainly a tumor suppressor function through the regulation of transcription factors, apoptosis, cell cycle, and structural proteins. MiR-363 also affected the tumor progression via regulation of various signaling pathways such as WNT, MAPK, TGF-β, NOTCH, and PI3K/AKT. Therefore, miR-363 can be introduced as a probable therapeutic target as well as a non-invasive diagnostic marker in cancer patients.
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Affiliation(s)
- Arya Nasimi Shad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hawraa Ibrahim Alshakarchi
- Al-Zahra Center for Medical and Pharmaceutical Research Sciences (ZCMRS), Al-Zahraa University for Women, Karbala, Iraq
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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30
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Cong L, Shi J, Zhao J, Li K, Dai D, Zhang B, Zhao W. Huaier inhibits cholangiocarcinoma cells through the twist1/FBP1/Wnt/β-catenin axis. Mol Biol Rep 2024; 51:842. [PMID: 39042261 DOI: 10.1007/s11033-024-09738-5] [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: 02/02/2024] [Accepted: 06/18/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND Although Huaier granules can be used as prospective anti-cholangiocarcinoma drugs, the mechanism of action of Huaier granules in cholangiocarcinoma is not clear. The anti-cholangiocarcinoma effect of Huaier granules was validated in cell line research. In vitro experiments were conducted to investigate the signalling pathways affected by Huaier in CCA cells. METHODS AND RESULTS Real-time quantitative PCR (RT‒qPCR) and Western blot analysis were performed to analyse gene expression in CCA cells. MTT assays, scratch tests, and Transwell assays were used to explore the effects on the proliferation and metastasis of CCA cells. Chromatin immunoprecipitation assays were performed to reveal the potential underlying mechanisms involved. Twist1 was upregulated in human CCA tissues. In addition, its expression levels were negatively related to FBP1 expression levels. Mechanistically, Twist1 can bind to the region of the FBP1 promoter to reduce its expression. Huaier plays an indispensable role in suppressing Twist1 expression to inhibit the Twist1/FBP1/Wnt/β-catenin axis. Then, we verified the effect of Huaier in vitro. CONCLUSIONS These findings suggested that Huaier granules were capable of inhibiting CCA development through regulating the Twist1/FBP1/Wnt/β-catenin signalling axis and provided a novel orientation for the development of novel anti-CCA drugs.
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Affiliation(s)
- Liyuan Cong
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China
| | - Jian Shi
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China
| | - Jing Zhao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Kun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China
| | - Dongdong Dai
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China
| | - Bingyuan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China
| | - Wei Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao, 266003, People's Republic of China.
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Sun KY, Bai X, Chen S, Bao S, Zhang C, Kapoor M, Backman J, Joseph T, Maxwell E, Mitra G, Gorovits A, Mansfield A, Boutkov B, Gokhale S, Habegger L, Marcketta A, Locke AE, Ganel L, Hawes A, Kessler MD, Sharma D, Staples J, Bovijn J, Gelfman S, Di Gioia A, Rajagopal VM, Lopez A, Varela JR, Alegre-Díaz J, Berumen J, Tapia-Conyer R, Kuri-Morales P, Torres J, Emberson J, Collins R, Cantor M, Thornton T, Kang HM, Overton JD, Shuldiner AR, Cremona ML, Nafde M, Baras A, Abecasis G, Marchini J, Reid JG, Salerno W, Balasubramanian S. A deep catalogue of protein-coding variation in 983,578 individuals. Nature 2024; 631:583-592. [PMID: 38768635 PMCID: PMC11254753 DOI: 10.1038/s41586-024-07556-0] [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: 06/19/2023] [Accepted: 05/10/2024] [Indexed: 05/22/2024]
Abstract
Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.
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Affiliation(s)
| | | | - Siying Chen
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Suying Bao
- Regeneron Genetics Center, Tarrytown, NY, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Liron Ganel
- Regeneron Genetics Center, Tarrytown, NY, USA
| | | | | | | | | | | | | | | | | | | | | | - Jesús Alegre-Díaz
- Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Jaime Berumen
- Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Roberto Tapia-Conyer
- Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Pablo Kuri-Morales
- Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
- Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico
| | - Jason Torres
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Jonathan Emberson
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Rory Collins
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | | | | | | | | | | | | | - Mona Nafde
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Aris Baras
- Regeneron Genetics Center, Tarrytown, NY, USA
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Zeng Z, Li Y, Zhou H, Li M, Ye J, Li D, Zhu Y, Zhang Y, Zhang X, Deng Y, Li J, Gu L, Wu J. System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening. BMC Cancer 2024; 24:773. [PMID: 38937694 PMCID: PMC11209979 DOI: 10.1186/s12885-024-12549-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 06/21/2024] [Indexed: 06/29/2024] Open
Abstract
OBJECTIVE Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function. METHODS In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis. RESULTS After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma. CONCLUSIONS Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.
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Affiliation(s)
- Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yina Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Heng Zhou
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Mingyang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Juan Ye
- Department of Pharmacy, Huazhong University of Science and Technology Hospital, Wuhan, Hubei, China
| | - Dan Li
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yuxi Zhu
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA
| | - Yonggang Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xu Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yunchao Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Juan Li
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Lijuan Gu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
| | - Jie Wu
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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Yu X, Xu J. TWIST1 Drives Cytotoxic CD8+ T-Cell Exhaustion through Transcriptional Activation of CD274 (PD-L1) Expression in Breast Cancer Cells. Cancers (Basel) 2024; 16:1973. [PMID: 38893094 PMCID: PMC11171171 DOI: 10.3390/cancers16111973] [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: 04/12/2024] [Revised: 05/15/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to transcriptionally activate PD-L1 expression, which significantly accelerates the exhaustion and death of the cytotoxic CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or inhibition of PD-L1 significantly enhances the tumor antigen-specific CD8+ T cells to suppress the growth of breast cancer cells. These results demonstrate that TWIST1 directly induces PD-L1 expression in ERα-negative breast cancer cells to promote immune evasion. Targeting TWIST1, BRD8, and/or PD-L1 in ERα-negative breast cancer cells with TWIST1 expression may sensitize CD8+ T-cell-mediated immunotherapy.
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Affiliation(s)
- Xiaobin Yu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA;
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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Zhang G, Hou S, Li S, Wang Y, Cui W. Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review). Int J Oncol 2024; 64:48. [PMID: 38488027 PMCID: PMC11000535 DOI: 10.3892/ijo.2024.5636] [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: 08/01/2023] [Accepted: 02/29/2024] [Indexed: 03/19/2024] Open
Abstract
Since its discovery, the role of the transcription factor, signal transducer and activator of transcription 3 (STAT3), in both normal physiology and the pathology of numerous diseases, including cancer, has been extensively studied. STAT3 is aberrantly activated in different types of cancer, fulfilling a critical role in cancer progression. The biological process, epithelial‑mesenchymal transition (EMT), is indispensable for embryonic morphogenesis. During the development of cancer, EMT is hijacked to confer motility, tumor cell stemness, drug resistance and adaptation to changes in the microenvironment. The aim of the present review was to outline recent advances in knowledge of the role of STAT3 in EMT, which may contribute to the understanding of the function of STAT3 in EMT in various types of cancer. Delineating the underlying mechanisms associated with the STAT3‑EMT signaling axis may generate novel diagnostic and therapeutic options for cancer treatment.
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Affiliation(s)
- Guoan Zhang
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Sen Hou
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Shuyue Li
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Yequan Wang
- Department of Forensic Genetics, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
| | - Wen Cui
- Department of Forensic Pathology, Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Forensic Science Center of Jining Medical University, Jining, Shandong 272067, P.R. China
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35
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Khan AQ, Hasan A, Mir SS, Rashid K, Uddin S, Steinhoff M. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin Cancer Biol 2024; 100:1-16. [PMID: 38503384 DOI: 10.1016/j.semcancer.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow 226026, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Khalid Rashid
- Department of Urology,Feinberg School of Medicine, Northwestern University, 303 E Superior Street, Chicago, IL 60611, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India; Laboratory Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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Kong L, Jin X. Dysregulation of deubiquitination in breast cancer. Gene 2024; 902:148175. [PMID: 38242375 DOI: 10.1016/j.gene.2024.148175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/04/2023] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
Breast cancer (BC) is a highly frequent malignant tumor that poses a serious threat to women's health and has different molecular subtypes, histological subtypes, and biological features, which act by activating oncogenic factors and suppressing cancer inhibitors. The ubiquitin-proteasome system (UPS) is the main process contributing to protein degradation, and deubiquitinases (DUBs) are reverse enzymes that counteract this process. There is growing evidence that dysregulation of DUBs is involved in the occurrence of BC. Herein, we review recent research findings in BC-associated DUBs, describe their nature, classification, and functions, and discuss the potential mechanisms of DUB-related dysregulation in BC. Furthermore, we present the successful treatment of malignant cancer with DUB inhibitors, as well as analyzing the status of targeting aberrant DUBs in BC.
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Affiliation(s)
- Lili Kong
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China.
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37
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Sasagawa S, Kumai J, Wakamatsu T, Yui Y. Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma. CANCER INNOVATION 2024; 3:e113. [PMID: 38946933 PMCID: PMC11212284 DOI: 10.1002/cai2.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/14/2023] [Accepted: 12/22/2023] [Indexed: 07/02/2024]
Abstract
Background Synovial sarcoma (SS) is an SS18-SSX fusion gene-driven soft tissue sarcoma with mesenchymal characteristics, associated with a poor prognosis due to frequent metastasis to a distant organ, such as the lung. Histone deacetylase (HDAC) inhibitors (HDACis) are arising as potent molecular targeted drugs, as HDACi treatment disrupts the SS oncoprotein complex, which includes HDACs, in addition to general HDACi effects. To provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells, we examined cellular responses to HDACi treatment in combination with two-dimensional (2D) and 3D culture conditions. Methods Using several SS cell lines, biochemical and cell biological assays were performed with romidepsin, an HDAC1/2 selective inhibitor. SN38 was concomitantly used as an ameliorant drug with romidepsin treatment. Cytostasis, apoptosis induction, and MHC class I polypeptide-related sequence A/B (MICA/B) induction were monitored to evaluate the drug efficacy. In addition to the conventional 2D culture condition, spheroid culture was adopted to evaluate the influence of cell-mass microenvironment on chemoresistance. Results By monitoring the cellular behavior with romidepsin and/or SN38 in SS cells, we observed that responsiveness is diverse in each cell line. In the apoptotic inducible cells, co-treatment with SN38 enhanced cell death. In nonapoptotic inducible cells, cytostasis and MICA/B induction were observed, and SN38 improved MICA/B induction further. As a novel efficacy of SN38, we revealed TWIST1 suppression in SS cells. In the spheroid (3D) condition, romidepsin efficacy was severely restricted in TWIST1-positive cells. We demonstrated that TWIST1 downregulation restored romidepsin efficacy even in spheroid form, and concomitant SN38 treatment along with romidepsin reproduced the reaction. Conclusions The current study demonstrated the benefits and concerns of using HDACi for SS treatment in 2D and 3D culture conditions and provided molecular evidence that concomitant treatment with SN38 can overcome drug resistance to HDACi by suppressing TWIST1 expression.
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Affiliation(s)
- Satoru Sasagawa
- Molecular Biology Laboratory, Research InstituteNozaki Tokushukai HospitalDaitoOsakaJapan
| | - Jun Kumai
- Sarcoma Treatment Laboratory, Research InstituteNozaki Tokushukai HospitalDaitoOsakaJapan
| | - Toru Wakamatsu
- Department of Musculoskeletal Oncology ServiceOsaka International Cancer InstituteOsakaJapan
| | - Yoshihiro Yui
- Sarcoma Treatment Laboratory, Research InstituteNozaki Tokushukai HospitalDaitoOsakaJapan
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38
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Mikheeva SA, Funk CC, Horner PJ, Rostomily RC, Mikheev AM. Novel TCF4:TCF12 heterodimer inhibits glioblastoma growth. Mol Oncol 2024; 18:517-527. [PMID: 37507199 PMCID: PMC10920085 DOI: 10.1002/1878-0261.13496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/15/2023] [Accepted: 07/24/2023] [Indexed: 07/30/2023] Open
Abstract
TWIST1 (TW) is a pro-oncogenic basic helix-loop-helix (bHLH) transcription factor and promotes the hallmark features of malignancy (e.g., cell invasion, cancer cell stemness, and treatment resistance), which contribute to poor prognoses of glioblastoma (GBM). We previously reported that specific TW dimerization motifs regulate unique cellular phenotypes in GBM. For example, the TW:E12 heterodimer increases periostin (POSTN) expression and promotes cell invasion. TW dimer-specific transcriptional regulation requires binding to the regulatory E-box consensus sequences, but alternative bHLH dimers that balance TW dimer activity in regulating pro-oncogenic TW target genes are unknown. We leveraged the ENCODE DNase I hypersensitivity data to identify E-box sites and tethered TW:E12 and TW:TW proteins to validate dimer binding to E-boxes in vitro. Subsequently, TW knockdown revealed a novel TCF4:TCF12 bHLH dimer occupying the same TW E-box site that, when expressed as a tethered TCF4:TCF12 dimer, markedly repressed POSTN expression and extended animal survival. These observations support TCF4:TCF12 as a novel dimer with tumor-suppressor activity in GBM that functions in part through displacement of and/or competitive inhibition of pro-oncogenic TW dimers at E-box sites.
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Affiliation(s)
- Svetlana A. Mikheeva
- Department of Neurosurgery, Center for NeuroregenerationHouston Methodist Research InstituteTexasUSA
| | - Cory C. Funk
- Institute for Systems BiologySeattleWashingtonUSA
| | - Philip J. Horner
- Department of Neurosurgery, Center for NeuroregenerationHouston Methodist Research InstituteTexasUSA
- Department of NeurosurgeryUniversity of WashingtonSeattleWashingtonUSA
- Institute for Stem Cell and Regenerative MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Robert C. Rostomily
- Department of Neurosurgery, Center for NeuroregenerationHouston Methodist Research InstituteTexasUSA
- Department of NeurosurgeryUniversity of WashingtonSeattleWashingtonUSA
- Institute for Stem Cell and Regenerative MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Andrei M. Mikheev
- Department of Neurosurgery, Center for NeuroregenerationHouston Methodist Research InstituteTexasUSA
- Department of NeurosurgeryUniversity of WashingtonSeattleWashingtonUSA
- Institute for Stem Cell and Regenerative MedicineUniversity of WashingtonSeattleWashingtonUSA
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Yang F, Akhtar MN, Zhang D, El-Mayta R, Shin J, Dorsey JF, Zhang L, Xu X, Guo W, Bagley SJ, Fuchs SY, Koumenis C, Lathia JD, Mitchell MJ, Gong Y, Fan Y. An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma. SCIENCE ADVANCES 2024; 10:eadj4678. [PMID: 38416830 PMCID: PMC10901371 DOI: 10.1126/sciadv.adj4678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 01/25/2024] [Indexed: 03/01/2024]
Abstract
Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.
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Affiliation(s)
- Fan Yang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Md Naushad Akhtar
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Duo Zhang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rakan El-Mayta
- Department of Bioengineering, University of Pennsylvania School of Engineering and Applied Science, Philadelphia, PA 19104, USA
| | - Junyoung Shin
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jay F. Dorsey
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lin Zhang
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xiaowei Xu
- Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Wei Guo
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Stephen J. Bagley
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Serge Y Fuchs
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Constantinos Koumenis
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Justin D. Lathia
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Michael J. Mitchell
- Department of Bioengineering, University of Pennsylvania School of Engineering and Applied Science, Philadelphia, PA 19104, USA
| | - Yanqing Gong
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
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40
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Huang L, Woods CM, Dharmawardana N, Michael MZ, Ooi EH. The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review. Front Oncol 2024; 14:1358854. [PMID: 38454932 PMCID: PMC10917904 DOI: 10.3389/fonc.2024.1358854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
This scoping review identifies the mechanistic pathways of metformin when used to treat head and neck cancer cells, in the pre-clinical setting. Understanding the underlying mechanisms will inform future experimental designs exploring metformin as a potential adjuvant for head and neck cancer. This scoping review was conducted according to the Joanna-Briggs Institute framework. A structured search identified 1288 studies, of which 52 studies fulfilled the eligibility screen. The studies are presented in themes addressing hallmarks of cancer. Most of the studies demonstrated encouraging anti-proliferative effects in vitro and reduced tumor weight and volume in animal models. However, a few studies have cautioned the use of metformin which supported cancer cell growth under certain conditions.
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Affiliation(s)
- Lucy Huang
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Otolaryngology Head and Neck Surgery, Flinders Medical Centre, Adelaide, SA, Australia
| | - Charmaine M. Woods
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Otolaryngology Head and Neck Surgery, Flinders Medical Centre, Adelaide, SA, Australia
| | - Nuwan Dharmawardana
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Otolaryngology Head and Neck Surgery, Flinders Medical Centre, Adelaide, SA, Australia
| | - Michael Z. Michael
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Adelaide, SA, Australia
| | - Eng Hooi Ooi
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Department of Otolaryngology Head and Neck Surgery, Flinders Medical Centre, Adelaide, SA, Australia
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Patil K, Sher G, Kuttikrishnan S, Moton S, Alam M, Buddenkotte J, Ahmad A, Steinhoff M, Uddin S. The cross-talk between miRNAs and JAK/STAT pathway in cutaneous T cell lymphoma: Emphasis on therapeutic opportunities. Semin Cell Dev Biol 2024; 154:239-249. [PMID: 36216715 DOI: 10.1016/j.semcdb.2022.09.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 02/25/2023]
Abstract
Mycosis Fungoides (MF) and Sézary Syndrome (SS) belong to a wide spectrum of T cell lymphoproliferative disorders collectively termed cutaneous T cell lymphomas (CTCL). CTCLs represent an archetype of heterogeneous and dynamically variable lymphoproliferative neoplasms typified by distinct clinical, histological, immunophenotypic, and genetic features. Owing to its complex dynamics, the pathogenesis of CTCL remains elusive. However, in recent years, progress in CTCL classification combined with next-generation sequencing analyses has broadened the genetic and epigenetic spectrum of clearly defined CTCL entities such as MF and SS. Several large-scale genome studies have identified the polygenic nature of CTCL and unveiled an idiosyncratic mutational landscape involving genetic aberrations, epigenetic alterations, cell cycle dysregulation, apoptosis, and the constitutive activation of T cell/NF-κB/JAK-STAT signaling pathways. In this review, we summarize the evolving insights on how the intrinsic epigenetic events driven by dysregulated miRNAs, including the oncogenic and tumor-suppressive miRNAs, influence the pathogenesis of MF and SS. We also focus on the interplay between the JAK/STAT pathway and miRNAs in CTCL as well as the significance of the miRNA/STAT axis as a relevant pathogenetic mechanism underlying CTCL initiation and progression. Based on these biologic insights, the current status and recent progress on novel therapies with a strong biological rationale, including miRNA-targeted molecules and JAK/STAT-targeted therapy for CTCL management, are discussed.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Gulab Sher
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Safwan Moton
- College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33200, USA
| | - Majid Alam
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Joerg Buddenkotte
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Weill Cornell Medicine-Qatar, Medical School, Doha 24144, Qatar; Dept. of Dermatology, Weill Cornell Medicine-New York 10065, New York, USA.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar.
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Acloque H, Yang J, Theveneau E. Epithelial-to-mesenchymal plasticity from development to disease: An introduction to the special issue. Genesis 2024; 62:e23581. [PMID: 38098257 PMCID: PMC11021161 DOI: 10.1002/dvg.23581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 12/17/2023]
Abstract
Epithelial-Mesenchymal Transition (EMT) refers to the ability of cells to switch between epithelial and mesenchymal states, playing critical roles in embryonic development, wound healing, fibrosis, and cancer metastasis. Here, we discuss some examples that challenge the use of specific markers to define EMT, noting that their expression may not always correspond to the expected epithelial or mesenchymal identity. In concordance with recent development in the field, we emphasize the importance of generalizing the use of the term Epithelial-Mesenchymal Plasticity (EMP), to better capture the diverse and context-dependent nature of the bidirectional journey that cells can undertake between the E and M phenotypes. We highlight the usefulness of studying a wide range of physiological EMT scenarios, stress the value of the dynamic of expression of EMP regulators and advocate, whenever possible, for more systematic functional assays to assess cellular states.
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Affiliation(s)
- Hervé Acloque
- INRAE, AgroParisTech, GABI, Université Paris Saclay, Jouy en Josas, France
| | - Jing Yang
- Department of Pharmacology and of Pediatrics, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, California, USA
| | - Eric Theveneau
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France
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Liao C, Liu Y, Lin Y, Wang J, Zhou T, Weng W. Mesenchymal Stem Cell-conditioned Medium Protecting Renal Tubular Epithelial Cells by Inhibiting Hypoxia-inducible Factor-1α and Nuclear Receptor Coactivator-1. Curr Stem Cell Res Ther 2024; 19:1369-1381. [PMID: 37817516 DOI: 10.2174/011574888x247652230928064627] [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: 02/28/2023] [Revised: 08/09/2023] [Accepted: 08/24/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) is characterized by inflammatory infiltration and damage and death of renal tubular epithelial cells (RTECs), in which hypoxia plays an important role. Deferoxamine (DFO) is a well-accepted chemical hypoxia-mimetic agent. Mesenchymal stem cell-conditioned medium (MSC-CM) can reduce local inflammation and repair tissue. In this study, we explored the effect and molecular mechanism of MSC-CM-mediated protection of RTECs under DFO-induced hypoxia. METHODS Rat renal proximal tubule NRK-52E cells were treated with different concentrations of DFO for 24 hours, followed by evaluation of RTEC injury, using a Cell Counting Kit-8 (CCK-8) to detect cell viability and western blotting to evaluate the expression of transforming growth factor- beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), and hypoxia-inducible factor-1 alpha (HIF-1α) in NRK-52E cells. Then, three groups of NRK-52E cells were used in experiments, including normal control (NC), 25 μM DFO, and 25 μM DFO + MSC-CM. MSC-CM was obtained from the human umbilical cord. MSC-CM was used to culture cells for 12 hours before DFO treatment, then fresh MSC-CM and 25 μM DFO were added, and cells were cultured for another 24 hours before analysis. RESULTS Western blotting and cellular immunofluorescence staining showed culture of NRK-52E cells in 25 μM DFO for 24 hours induced HIF-1α and nuclear receptor coactivator-1 (NCoA-1), simulating hypoxia. MSC-CM could inhibit the DFO-induced up-regulation of α-SMA, TGF-β1, HIF-1α and NCoA-1. CONCLUSION Our results suggest that MSC-CM has a protective effect on RTECs by down-regulating HIF-1α and NCoA-1, which may be the harmful factors in renal injury.
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Affiliation(s)
- Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Yiping Liu
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Yongda Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Jiali Wang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Wenjuan Weng
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
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Qin LN, Zhang H, Li QQ, Wu T, Cheng SB, Wang KW, Shi Y, Ren HR, Xing XW, Yang C, Sun T. Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma. Theranostics 2024; 14:436-450. [PMID: 38164156 PMCID: PMC10750215 DOI: 10.7150/thno.90322] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/17/2023] [Indexed: 01/03/2024] Open
Abstract
Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.
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Affiliation(s)
- Lu-ning Qin
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Heng Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Qing-qing Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Ting Wu
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Shan-bin Cheng
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Kai-wen Wang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Yue Shi
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Hao-ran Ren
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Xue-wu Xing
- Department of Orthopedics, Tianjin First Central Hospital, Tianjin, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Tao Sun
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
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Rohner PT, Hu Y, Moczek AP. Utilizing geometric morphometrics to investigate gene function during organ growth: Insights through the study of beetle horn shape allometry. Evol Dev 2024; 26:e12464. [PMID: 38041612 DOI: 10.1111/ede.12464] [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: 12/21/2022] [Revised: 10/05/2023] [Accepted: 11/15/2023] [Indexed: 12/03/2023]
Abstract
Static allometry is a major component of morphological variation. Much of the literature on the development of allometry investigates how functional perturbations of diverse pathways affect the relationship between trait size and body size. Often, this is done with the explicit objective to identify developmental mechanisms that enable the sensing of organ size and the regulation of relative growth. However, changes in relative trait size can also be brought about by a range of other distinctly different developmental processes, such as changes in patterning or tissue folding, yet standard univariate biometric approaches are usually unable to distinguish among alternative explanations. Here, we utilize geometric morphometrics to investigate the degree to which functional genetic manipulations known to affect the size of dung beetle horns also recapitulate the effect of horn shape allometry. We reasoned that the knockdown phenotypes of pathways governing relative growth should closely resemble shape variation induced by natural allometric variation. In contrast, we predicted that if genes primarily affect alternative developmental processes, knockdown effects should align poorly with shape allometry. We find that the knockdown effects of several genes (e.g., doublesex, Foxo) indeed closely aligned with shape allometry, indicating that their corresponding pathways may indeed function primarily in the regulation of relative trait growth. In contrast, other knockdown effects (e.g., Distal-less, dachs) failed to align with allometry, implicating these pathways in potentially scaling-independent processes. Our findings moderate the interpretation of studies focusing on trait length and highlight the usefulness of multivariate approaches to study allometry and phenotypic plasticity.
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Affiliation(s)
- Patrick T Rohner
- Department of Biology, Indiana University, Bloomington, Indiana, USA
- Department of Ecology, Behavior, and Evolution, University of California San Diego, La Jolla, California, USA
| | - Yonggang Hu
- Department of Biology, Indiana University, Bloomington, Indiana, USA
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China
| | - Armin P Moczek
- Department of Biology, Indiana University, Bloomington, Indiana, USA
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Lee SM, Cho J, Choi S, Kim DH, Ryu JW, Kim I, Woo DC, Sung YH, Jeong JY, Baek IJ, Pack CG, Rho JK, Lee SW, Ha CH. HDAC5-mediated exosomal Maspin and miR-151a-3p as biomarkers for enhancing radiation treatment sensitivity in hepatocellular carcinoma. Biomater Res 2023; 27:134. [PMID: 38102691 PMCID: PMC10725039 DOI: 10.1186/s40824-023-00467-7] [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: 09/18/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Tumor-derived exosomes are critical elements of the cell-cell communication response to various stimuli. This study aims to reveal that the histone deacetylase 5 (HDAC5) and p53 interaction upon radiation in hepatocellular carcinoma intricately regulates the secretion and composition of exosomes. METHODS We observed that HDAC5 and p53 expression were significantly increased by 2 Gy and 4 Gy radiation exposure in HCC. Normal- and radiation-derived exosomes released by HepG2 were purified to investigate the exosomal components. RESULTS We found that in the radiation-derived exosome, exosomal Maspin was notably increased. Maspin is known as an anti-angiogenic gene. The expression of Maspin was regulated at the cellular level by HDAC5, and it was elaborately regulated and released in the exosome. Radiation-derived exosome treatment caused significant inhibition of angiogenesis in HUVECs and mouse aortic tissues. Meanwhile, we confirmed that miR-151a-3p was significantly reduced in the radiation-derived exosome through exosomal miRNA sequencing, and three HCC-specific exosomal miRNAs were also decreased. In particular, miR-151a-3p induced an anti-apoptotic response by inhibiting p53, and it was shown to induce EMT and promote tumor growth by regulating p53-related tumor progression genes. In the HCC xenograft model, radiation-induced exosome injection significantly reduced angiogenesis and tumor size. CONCLUSIONS Our present findings demonstrated HDAC5 is a vital gene of the p53-mediated release of exosomes resulting in tumor suppression through anti-cancer exosomal components in response to radiation. Finally, we highlight the important role of exosomal Maspin and mi-151a-3p as a biomarker in enhancing radiation treatment sensitivity. Therapeutic potential of HDAC5 through p53-mediated exosome modulation in radiation treatment of hepatocellular carcinoma.
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Affiliation(s)
- Seung Min Lee
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Jeongin Cho
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Sujin Choi
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Dong Ha Kim
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Je-Won Ryu
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Inki Kim
- Department of Pharmacology, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Cheol Woo
- Department of Biomedical Engineering, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Hoon Sung
- Department of Cell and Genetic Engineering, Asan Medical Center, Asan Institute for Life Sciences University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin-Yong Jeong
- Department of Microbiology, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Jeoung Baek
- Department of Cell and Genetic Engineering, Asan Medical Center, Asan Institute for Life Sciences University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chan-Gi Pack
- Department of Biomedical Engineering, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin Kyung Rho
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Sang-Wook Lee
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
| | - Chang Hoon Ha
- Department of Biochemistry and Molecular Biology and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
- Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
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Kim JY, Hong N, Park S, Ham SW, Kim EJ, Kim SO, Jang J, Kim Y, Kim JK, Kim SC, Park JW, Kim H. Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion. Cell Death Dis 2023; 14:822. [PMID: 38092725 PMCID: PMC10719344 DOI: 10.1038/s41419-023-06356-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 11/25/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells.
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Affiliation(s)
- Jung Yun Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Nayoung Hong
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Sehyeon Park
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Seok Won Ham
- MEDIFIC Inc., Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea
| | - Eun-Jung Kim
- MEDIFIC Inc., Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea
| | - Sung-Ok Kim
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, 24252, Republic of Korea
| | - Junseok Jang
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Yoonji Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Jun-Kyum Kim
- MEDIFIC Inc., Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea
| | - Sung-Chan Kim
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, 24252, Republic of Korea
| | - Jong-Whi Park
- Department of Life Sciences, Gachon University, Incheon, 21999, Republic of Korea.
| | - Hyunggee Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
- Institute of Animal Molecular Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
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Xu J, Guo R, Wen N, Li L, Yi Y, Chen J, He Z, Yang J, Xiao ZXJ, Niu M. FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis. PLoS Biol 2023; 21:e3002446. [PMID: 38134227 PMCID: PMC10745200 DOI: 10.1371/journal.pbio.3002446] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
Tumor metastasis is the major cause of breast cancer morbidity and mortality. It has been reported that the F-box protein FBXO3 functions as an E3 ubiquitin ligase in regulating various biological processes, including host autoimmune, antiviral innate immunity, and inflammatory response. However, the role of FBXO3 in tumor metastasis remains elusive. We have previously shown that ΔNp63α is a common inhibitory target in oncogene-induced cell motility and tumor metastasis. In this study, we show that FBXO3 plays a vital role in PI3K-mediated breast cancer metastasis independent of its E3 ligase activity and ΔNp63α in breast cancer cells and in mouse. FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis. Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation. Furthermore, p110αH1047R facilitates the phosphorylation and stabilization of FBXO3 in an ERK1-dependent manner. Knockdown of either FBXO3 or USP4 leads to significant inhibition of PI3K-induced breast cancer metastasis. Clinically, elevated expression of p110α/FBXO3/USP4/Twist1 is associated with poor overall survival (OS) and recurrence-free survival (RFS) of breast cancer patients. Taken together, this study reveals that the FBXO3-USP4-Twist1 axis is pivotal in PI3K-mediated breast tumor metastasis and that FBXO3/USP4 may be potential therapeutic targets for breast cancer treatment.
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Affiliation(s)
- Jing Xu
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Rongtian Guo
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Nasi Wen
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Luping Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yong Yi
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Jingzhen Chen
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zongyu He
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Jian Yang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Zhi-Xiong Jim Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Mengmeng Niu
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
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Sun L, Ji S, Xie X, Si L, Liu S, Lin Y, Wang Y, Song Z, Fang N, An Y, Yang J. Deciphering the interaction between Twist1 and PPARγ during adipocyte differentiation. Cell Death Dis 2023; 14:764. [PMID: 37996425 PMCID: PMC10667345 DOI: 10.1038/s41419-023-06283-0] [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: 07/04/2023] [Revised: 11/01/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023]
Abstract
Obesity, a worldwide epidemic in recent years, is mainly due to the uncontrolled development of adipose tissues, which includes adipocyte hypertrophy and hyperplasia. Adipocyte differentiation is a process involving multiple transcription factor cascades, and the exact mechanism has not yet been defined. As a bHLH transcription factor, Twist1 exerts its activity by forming homo- or heterodimers with other factors. In this study, we showed Twist1 restricts adipogenesis through PPARγ. Expression of various differentiation markers (including PPARγ and adiponectin) and triglyceride-containing lipid droplets were decreased with overexpression of Twist1. Pathway enrichment analysis of RNA-seq data showed that differentially expressed genes (DEGs) caused by Twist1 overexpression were significantly related to lipolysis and PPARγ signaling. This implicates that Twist1 plays important regulatory roles in these processes. ChIP and dual luciferase assays showed that Twist1 could bind either PPARγ or adiponectin promoter to repress their respective transcription or directly to PPARγ protein to regulate its transcriptional activity. Furthermore, Twist1 directly interacted RXRα, which usually forms heterodimer with PPARγ to regulate adipogenesis. Taken together, our results suggest that Twist1 is an inhibitory modulator of adipogenesis and its function is likely through direct interaction with PPARγ protein or its gene promoter.
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Affiliation(s)
- Leilei Sun
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada
| | - Shaoping Ji
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Xuan Xie
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
| | - Lei Si
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Shaohao Liu
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Yao Lin
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Yahui Wang
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Zhenhua Song
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Na Fang
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China
| | - Yang An
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
- Department of Biochemistry and Molecular Biology, Cell Signal Transduction Laboratory, School of Basic Medical Science, Bioinformatics Center, Henan University, Kaifeng, 475004, China.
| | - Jian Yang
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
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50
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Yu X, He T, Tong Z, Liao L, Huang S, Fakhouri WD, Edwards DP, Xu J. Molecular mechanisms of TWIST1-regulated transcription in EMT and cancer metastasis. EMBO Rep 2023; 24:e56902. [PMID: 37680145 PMCID: PMC10626429 DOI: 10.15252/embr.202356902] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/09/2023] Open
Abstract
TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to TWIST1-activated genes, resulting in decreasing TWIST1-activated target gene expression and cancer metastasis. Both TWIST1/NuRD and TWIST1/TIP60-Com complexes are required for TWIST1 to promote EMT, proliferation, and metastasis at full capacity. Therefore, the diacetylation status of TWIST1-K73/76 dictates whether TWIST1 interacts either with NuRD to repress epithelial genes, or with TIP60-Com to activate mesenchymal genes and MYC. Since BRD8 is essential for TWIST1-acK73/76 and TIP60-Com interaction, targeting BRD8 could be a means to inhibit TWIST1-activated gene expression.
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Affiliation(s)
- Xiaobin Yu
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Tao He
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Present address:
Institute for Cancer MedicineSouthwest Medical UniversitySichuanChina
| | - Zhangwei Tong
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Lan Liao
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Dan L. Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTXUSA
| | - Shixia Huang
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Dan L. Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTXUSA
| | - Walid D Fakhouri
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of DentistryUniversity of Texas Health Science Center at HoustonHoustonTXUSA
| | - Dean P Edwards
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Dan L. Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTXUSA
| | - Jianming Xu
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Dan L. Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTXUSA
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