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Hashemolhosseini S, Gessler L. Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction. Neural Regen Res 2025; 20:2464-2479. [PMID: 39248171 PMCID: PMC11801303 DOI: 10.4103/nrr.nrr-d-24-00417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/04/2024] [Accepted: 08/05/2024] [Indexed: 09/10/2024] Open
Abstract
Skeletal muscles are essential for locomotion, posture, and metabolic regulation. To understand physiological processes, exercise adaptation, and muscle-related disorders, it is critical to understand the molecular pathways that underlie skeletal muscle function. The process of muscle contraction, orchestrated by a complex interplay of molecular events, is at the core of skeletal muscle function. Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction. Within muscle fibers, calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force. Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling. The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis. Myogenic regulators coordinate the differentiation of myoblasts into mature muscle fibers. Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability. Several muscle-related diseases, including congenital myasthenic disorders, sarcopenia, muscular dystrophies, and metabolic myopathies, are underpinned by dysregulated molecular pathways in skeletal muscle. Therapeutic interventions aimed at preserving muscle mass and function, enhancing regeneration, and improving metabolic health hold promise by targeting specific molecular pathways. Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway, a critical regulator of myogenesis, muscle regeneration, and metabolic function, and the Hippo signaling pathway. In recent years, more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers, and at the neuromuscular junction. In fact, research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers. In this review, we will summarize and discuss the data on these two pathways, focusing on their concerted action next to their contribution to skeletal muscle biology. However, an in-depth discussion of the non-canonical Wnt pathway, the fibro/adipogenic precursors, or the mechanosensory aspects of these pathways is not the focus of this review.
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Affiliation(s)
- Said Hashemolhosseini
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Lea Gessler
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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2
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Guo X, Yang L, Wang Y, Yuan M, Zhang W, He X, Wang Q. Wnt2bb signaling promotes pharyngeal chondrogenic precursor proliferation and chondrocyte maturation by activating Yap expression in zebrafish. J Genet Genomics 2025; 52:220-230. [PMID: 39566725 DOI: 10.1016/j.jgg.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/22/2024]
Abstract
Pharyngeal cartilage morphogenesis is crucial for the formation of craniofacial structures. Cranial neural crest cells are specified at the neural plate border, migrate to pharyngeal arches, and differentiate into pharyngeal chondrocytes, which subsequently flatten, elongate, and stack like coins during maturation. Although the developmental processes prior to chondrocyte maturation have been extensively studied, their subsequent changes in morphology and organization remain largely elusive. Here, we show that wnt2bb is expressed in the pharyngeal ectoderm adjacent to the chondrogenic precursor cells in zebrafish. Inactivation of Wnt2bb leads to a reduction in nuclear β-catenin, which impairs chondrogenic precursor proliferation and disrupts chondrocyte morphogenesis and organization, eventually causing a severe shrinkage of pharyngeal cartilages. Moreover, the decrease of β-catenin in wnt2bb-/- mutants is accompanied by the reduction of Yap expression. Reactivation of Yap can restore the proliferation of chondrocyte progenitors as well as the proper size, shape, and stacking of pharyngeal chondrocytes. Our findings suggest that Wnt/β-catenin signaling promotes Yap expression to regulate pharyngeal cartilage formation in zebrafish.
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Affiliation(s)
- Xiaojuan Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Liping Yang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Yujie Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Mengna Yuan
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
| | - Wenqing Zhang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Xinyu He
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
| | - Qiang Wang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Innovation Centre of Ministry of Education for Development and Diseases, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
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3
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Ajongbolo AO, Langhans SA. YAP/TAZ-associated cell signaling - at the crossroads of cancer and neurodevelopmental disorders. Front Cell Dev Biol 2025; 13:1522705. [PMID: 39936032 PMCID: PMC11810912 DOI: 10.3389/fcell.2025.1522705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
YAP/TAZ (Yes-associated protein/paralog transcriptional co-activator with PDZ-binding domain) are transcriptional cofactors that are the key and major downstream effectors of the Hippo signaling pathway. Both are known to play a crucial role in defining cellular outcomes, including cell differentiation, cell proliferation, and apoptosis. Aside from the canonical Hippo signaling cascade with the key components MST1/2 (mammalian STE20-like kinase 1/2), SAV1 (Salvador homologue 1), MOB1A/B (Mps one binder kinase activator 1A/B) and LATS1/2 (large tumor suppressor kinase 1/2) upstream of YAP/TAZ, YAP/TAZ activation is also influenced by numerous other signaling pathways. Such non-canonical regulation of YAP/TAZ includes well-known growth factor signaling pathways such as the epidermal growth factor receptor (EGFR)/ErbB family, Notch, and Wnt signaling as well as cell-cell adhesion, cell-matrix interactions and mechanical cues from a cell's microenvironment. This puts YAP/TAZ at the center of a complex signaling network capable of regulating developmental processes and tissue regeneration. On the other hand, dysregulation of YAP/TAZ signaling has been implicated in numerous diseases including various cancers and neurodevelopmental disorders. Indeed, in recent years, parallels between cancer development and neurodevelopmental disorders have become apparent with YAP/TAZ signaling being one of these pathways. This review discusses the role of YAP/TAZ in brain development, cancer and neurodevelopmental disorders with a special focus on the interconnection in the role of YAP/TAZ in these different conditions.
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Affiliation(s)
- Aderonke O. Ajongbolo
- Division of Neurology and Nemours Biomedical Research, Nemours Children’s Health, Wilmington, DE, United States
- Biological Sciences Graduate Program, University of Delaware, Newark, DE, United States
| | - Sigrid A. Langhans
- Division of Neurology and Nemours Biomedical Research, Nemours Children’s Health, Wilmington, DE, United States
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Fan L, Guo X, Washington MK, Shi J, Ness RM, Liu Q, Wen W, Huang S, Liu X, Cai Q, Zheng W, Coffey RJ, Shrubsole MJ, Su T. Yes-associated protein plays oncogenic roles in human sporadic colorectal adenomas. Carcinogenesis 2025; 46:bgaf007. [PMID: 39977302 PMCID: PMC11923420 DOI: 10.1093/carcin/bgaf007] [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: 09/06/2024] [Revised: 02/04/2025] [Accepted: 02/18/2025] [Indexed: 02/22/2025] Open
Abstract
The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r = 0.53, P < .0001) and nuclear β-catenin (r = 0.26, P = .0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P = .05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR = 12.62, 95% CI = 4.57-34.86, P trend < .001), which persisted after adjusting for covariates and biomarkers (OR = 12.31, 95% CI = 3.78-40.10, P trend < .0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced versus nonadvanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR = 16.82, 95% CI = 4.41-64.08, P < .0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.
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Affiliation(s)
- Lei Fan
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
| | - Xingyi Guo
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Mary K Washington
- Department of Pathology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Jiajun Shi
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Reid M Ness
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Qi Liu
- Center for Quantitative Sciences and Department of Biostatistics, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Shuya Huang
- Department of Breast Surgery, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, Shandong 250031, China
| | - Xiao Liu
- Center for Quantitative Sciences and Department of Biostatistics, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Robert J Coffey
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
- Cell and Development Biology, Vanderbilt University, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Martha J Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Timothy Su
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
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Furutake Y, Yamaguchi K, Yamanoi K, Kitamura S, Takamatsu S, Taki M, Ukita M, Hosoe Y, Murakami R, Abiko K, Horie A, Hamanishi J, Baba T, Matsumura N, Mandai M. YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma. Mol Cancer Ther 2024; 23:1652-1665. [PMID: 38958503 DOI: 10.1158/1535-7163.mct-24-0145] [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: 03/06/2024] [Revised: 05/16/2024] [Accepted: 06/28/2024] [Indexed: 07/04/2024]
Abstract
Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.
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MESH Headings
- Ferroptosis
- Humans
- Female
- Animals
- Mice
- Ovarian Neoplasms/pathology
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/genetics
- Prognosis
- YAP-Signaling Proteins/metabolism
- Acyltransferases
- Adenocarcinoma, Clear Cell/metabolism
- Adenocarcinoma, Clear Cell/pathology
- Adenocarcinoma, Clear Cell/drug therapy
- Adenocarcinoma, Clear Cell/genetics
- Cell Line, Tumor
- Transcription Factors/metabolism
- Xenograft Model Antitumor Assays
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Gene Expression Regulation, Neoplastic
- Mice, Nude
- Cell Proliferation
- Drug Resistance, Neoplasm
- Signal Transduction
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Affiliation(s)
- Yoko Furutake
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Yamaguchi
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Koji Yamanoi
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Sachiko Kitamura
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Shiro Takamatsu
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Mana Taki
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Masayo Ukita
- Department of Obstetrics and Gynecology, Shizuoka General Hospital, Shizuoka, Japan
| | - Yuko Hosoe
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Ryusuke Murakami
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Kaoru Abiko
- Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Akihito Horie
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Junzo Hamanishi
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Tsukasa Baba
- Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Noriomi Matsumura
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
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6
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Ghosh R, Herberg S. The role of YAP/TAZ mechanosignaling in trabecular meshwork and Schlemm's canal cell dysfunction. Vision Res 2024; 224:108477. [PMID: 39208753 PMCID: PMC11470804 DOI: 10.1016/j.visres.2024.108477] [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: 06/01/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
This focused review highlights the importance of yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ) mechanosignaling in human trabecular meshwork and Schlemm's canal cells in response to glaucoma-associated extracellular matrix stiffening and cyclic mechanical stretch, as well as biochemical pathway modulators (with signaling crosstalk) including transforming growth factor beta 2, glucocorticoids, Wnt, lysophosphatidic acid, vascular endothelial growth factor, and oxidative stress. We provide a comprehensive overview of relevant literature from the last decade, highlight intriguing research avenues with translational potential, and close with an outlook on future directions.
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Affiliation(s)
- Rajanya Ghosh
- Department of Ophthalmology and Visual Sciences, Center for Vision Research, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Samuel Herberg
- Department of Ophthalmology and Visual Sciences, Center for Vision Research, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; BioInspired Institute, Syracuse University, Syracuse, NY 13244, USA; Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY 13244, USA.
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Mohammadpour S, Torshizi Esfahani A, Sarpash S, Vakili F, Zafarjafarzadeh N, Mashaollahi A, Pardakhtchi A, Nazemalhosseini-Mojarad E. Hippo Signaling Pathway in Colorectal Cancer: Modulation by Various Signals and Therapeutic Potential. Anal Cell Pathol (Amst) 2024; 2024:5767535. [PMID: 39431199 PMCID: PMC11489006 DOI: 10.1155/2024/5767535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 07/07/2024] [Accepted: 08/19/2024] [Indexed: 10/22/2024] Open
Abstract
Colorectal cancer (CRC) stands as a significant global health issue, marked by elevated occurrence and mortality statistics. Despite the availability of various treatments, including chemotherapy, radiotherapy, and targeted therapy, CRC cells often exhibit resistance to these interventions. As a result, it is imperative to identify the disease at an earlier stage and enhance the response to treatment by acquiring a deeper comprehension of the processes driving tumor formation, aggressiveness, metastasis, and resistance to therapy. The Hippo pathway plays a critical role in facilitating the initiation of tumorigenesis and frequently experiences disruption within CRC because of genetic mutations and modified expression in its fundamental constituents. Targeting upstream regulators or core Hippo pathway components may provide innovative therapeutic strategies for modulating Hippo signaling dysfunction in CRC. To advance novel therapeutic techniques for CRC, it is imperative to grasp the involvement of the Hippo pathway in CRC and its interaction with alternate signaling pathways, noncoding RNAs, gut microbiota, and the immune microenvironment. This review seeks to illuminate the function and control of the Hippo pathway in CRC, ultimately aiming to unearth innovative therapeutic methodologies for addressing this ailment.
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Affiliation(s)
- Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Torshizi Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - SeyedKasra Sarpash
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Vakili
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nikta Zafarjafarzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhesam Mashaollahi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ali Pardakhtchi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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Gan X, Feng Y, Liu Y, Lin X, Yu X, Rong X, Han Q. Identification of zinc finger MIZ-type containing 2 as an oncoprotein enhancing NAD-dependent protein deacetylase sirtuin-1 deacetylase activity to regulate Wnt and Hippo pathways in non-small-cell lung cancer. Cell Mol Biol Lett 2024; 29:122. [PMID: 39266996 PMCID: PMC11391738 DOI: 10.1186/s11658-024-00636-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 08/19/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors. METHODS ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways. RESULTS ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified. CONCLUSIONS ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.
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Affiliation(s)
- Xueting Gan
- Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China
| | - Yuheng Feng
- Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China
| | - Yang Liu
- Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China
| | - Xuyong Lin
- Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China
| | - Xinmiao Yu
- Department of Surgical Oncology and Breast Surgery, the First Hospital of China Medical University, Shenyang. No. 155 Nanjing North Street, Heping Area, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Xuezhu Rong
- Department of Pathology, the First Hospital of China Medical University. No, 155 Nanjing North Street, Heping Area, Shenyang, 110001, Liaoning Province, People's Republic of China.
| | - Qiang Han
- Department of Pathology, Shenbei New Area, College of Basic Medical Sciences and the First Hospital of China Medical University. No, 77 Puhe Road, Shenyang, 110122, Liaoning Province, People's Republic of China.
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9
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Hantusch B, Kenner L, Stanulović VS, Hoogenkamp M, Brown G. Targeting Androgen, Thyroid Hormone, and Vitamin A and D Receptors to Treat Prostate Cancer. Int J Mol Sci 2024; 25:9245. [PMID: 39273194 PMCID: PMC11394715 DOI: 10.3390/ijms25179245] [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: 07/11/2024] [Revised: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR), upon ligand binding and homodimerization, shuttles from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXRs) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and androgen deprivation alone or with chemotherapy is the standard therapy for PCa. RARγ activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TRβ support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.
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Affiliation(s)
- Brigitte Hantusch
- Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1010 Vienna, Austria;
- Comprehensive Cancer Center, Medical University Vienna, 1090 Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1010 Vienna, Austria;
- Comprehensive Cancer Center, Medical University Vienna, 1090 Vienna, Austria
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
- Christian Doppler Laboratory for Applied Metabolomics, Medical University Vienna, 1090 Vienna, Austria
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| | - Vesna S. Stanulović
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; (V.S.S.); (M.H.)
| | - Maarten Hoogenkamp
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; (V.S.S.); (M.H.)
| | - Geoffrey Brown
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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10
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Nakako Y, Hasegawa K, Fujii S, Kami Y, Sakamoto T, Sakamoto M, Moriyama M, Kurppa KJ, Heikinheimo K, Yoshiura K, Kawano S, Kiyoshima T. Wnt/β-catenin-YAP axis in the pathogenesis of primary intraosseous carcinoma NOS, deriving from odontogenic keratocyst. Pathol Res Pract 2024; 260:155420. [PMID: 38908335 DOI: 10.1016/j.prp.2024.155420] [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: 03/18/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
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Affiliation(s)
- Yusuke Nakako
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kana Hasegawa
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Dento-craniofacial Development and Regeneration Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.
| | - Yukiko Kami
- Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Taiki Sakamoto
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Mizuki Sakamoto
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masafumi Moriyama
- Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kari J Kurppa
- Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
| | - Kristiina Heikinheimo
- Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku and Turku University Hospital, 20520, Finland
| | - Kazunori Yoshiura
- Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Shintaro Kawano
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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11
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Taylor J, Dubois F, Bergot E, Levallet G. Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review). Int J Oncol 2024; 65:68. [PMID: 38785155 PMCID: PMC11155713 DOI: 10.3892/ijo.2024.5656] [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: 11/21/2023] [Accepted: 03/04/2024] [Indexed: 05/25/2024] Open
Abstract
The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5‑30 mm, or whole‑brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial‑to‑mesenchymal transition, overexpression of programmed cell death‑ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes‑associated protein‑1, on cerebral metastases originating from lung cancer.
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Affiliation(s)
- Jasmine Taylor
- University of Caen Normandy, National Center for Scientific Research, Normandy University, Unit of Imaging and Therapeutic Strategies for Cancers and Cerebral Tissues (ISTCT)-UMR6030, GIP CYCERON, F-14074 Caen, France
| | - Fatéméh Dubois
- University of Caen Normandy, National Center for Scientific Research, Normandy University, Unit of Imaging and Therapeutic Strategies for Cancers and Cerebral Tissues (ISTCT)-UMR6030, GIP CYCERON, F-14074 Caen, France
- Departments of Pathology, and Thoracic Oncology, Caen University Hospital, F-14033 Caen, France
| | - Emmanuel Bergot
- University of Caen Normandy, National Center for Scientific Research, Normandy University, Unit of Imaging and Therapeutic Strategies for Cancers and Cerebral Tissues (ISTCT)-UMR6030, GIP CYCERON, F-14074 Caen, France
- Departments of Pneumology and Thoracic Oncology, Caen University Hospital, F-14033 Caen, France
| | - Guénaëlle Levallet
- University of Caen Normandy, National Center for Scientific Research, Normandy University, Unit of Imaging and Therapeutic Strategies for Cancers and Cerebral Tissues (ISTCT)-UMR6030, GIP CYCERON, F-14074 Caen, France
- Departments of Pathology, and Thoracic Oncology, Caen University Hospital, F-14033 Caen, France
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12
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King CM, Ding W, Eshelman MA, Yochum GS. TCF7L1 regulates colorectal cancer cell migration by repressing GAS1 expression. Sci Rep 2024; 14:12477. [PMID: 38816533 PMCID: PMC11139868 DOI: 10.1038/s41598-024-63346-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/28/2024] [Indexed: 06/01/2024] Open
Abstract
Dysregulated Wnt/β-catenin signaling is a common feature of colorectal cancer (CRC). The T-cell factor/lymphoid enhancer factor (TCF/LEF; hereafter, TCF) family of transcription factors are critical regulators of Wnt/β-catenin target gene expression. Of the four TCF family members, TCF7L1 predominantly functions as a transcriptional repressor. Although TCF7L1 has been ascribed an oncogenic role in CRC, only a few target genes whose expression it regulates have been characterized in this cancer. Through transcriptome analyses of TCF7L1 regulated genes, we noted enrichment for those associated with cellular migration. By silencing and overexpressing TCF7L1 in CRC cell lines, we demonstrated that TCF7L1 promoted migration, invasion, and adhesion. We localized TCF7L1 binding across the CRC genome and overlapped enriched regions with transcriptome data to identify candidate target genes. The growth arrest-specific 1 (GAS1) gene was among these and we demonstrated that GAS1 is a critical mediator of TCF7L1-dependent CRC cell migratory phenotypes. Together, these findings uncover a novel role for TCF7L1 in repressing GAS1 expression to enhance migration and invasion of CRC cells.
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Affiliation(s)
- Carli M King
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Wei Ding
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Melanie A Eshelman
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Gregory S Yochum
- Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
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13
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Slaninová V, Heron-Milhavet L, Robin M, Jeanson L, Aissanou A, Kantar D, Tosi D, Bréhélin L, Gongora C, Djiane A. The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells. BMC Cancer 2024; 24:587. [PMID: 38741073 PMCID: PMC11092100 DOI: 10.1186/s12885-024-12316-4] [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: 09/25/2023] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.
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Affiliation(s)
- Věra Slaninová
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | | | - Mathilde Robin
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- LIRMM, Univ Montpellier, Inserm, CNRS, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | - Laura Jeanson
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Adam Aissanou
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diala Kantar
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diego Tosi
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | | | - Céline Gongora
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
| | - Alexandre Djiane
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France.
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
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14
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Zhang H, Yin M, Hu Y, Jiang M, Lu M, Wu Y. Prognostic analysis of Yes-associated protein 1 in patients with colorectal cancer. A systematic review and meta-analysis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:148-156. [PMID: 36177818 DOI: 10.17235/reed.2022.8472/2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
BACKGROUND colorectal cancer (CRC) is the most common carcinoma worldwide, but a lack of effective prognostic markers limits clinical diagnosis and treatment. Yes-associated protein 1 (YAP1) is an effector of the HIPPO-pathway, which plays a critical role in cancer development and prognosis, including CRC. However, previous reports have suggested that it plays a dual role in CRC. METHODS a meta-analysis using RevMan 5.4 and Stata 14.0 was performed to evaluate the relationship between YAP1 and clinical outcomes of CRC, after searching for eligible studies in the PubMed, Web of Science and Embase databases. Online datasets GEPIA and LOGpc were also used to calculate survival results and for comparison with the meta-analysis results. Besides, "DESeq" packages were used for the expression analysis of YAP1 from the TCGA dataset. RESULTS YAP1 was overexpressed in the cancer tissues when compared to normal tissues in patients with CRC from the TCGA database (p = 0.000164) and GEPIA database. A total of 10 studies involving 2305 patients from the literature were selected. Pooled HR indicated that overexpression of YAP1 was associated with poor clinical outcomes (HR = 1.70, 95 % CI: 1.28-2.26, p = 0.0003). Subgroup analysis showed a clear correlation between overexpression of YAP1 and worse survival rate in Chinese patients (HR = 1.94, 95 % CI: 1.40-2.69, p = 0.0001), nuclear YAP1 overexpression (HR = 2.07, 95 % CI: 1.29-3.31, p = 0.003), 60 months of follow-up (HR = 1.89, 95 % CI: 1.30-2.73, p = 0.0008), IHC test (HR = 1.65, 95 % CI: 1.17-2.33, p = 0.005), IHC combined with other tests (HR = 1.77, 95 % CI: 1.13-2.77, p = 0.01) and multivariate analysis (HR = 1.70, 95 % CI: 1.24-2.31, p = 0.0009). Nevertheless, disease-free survival (DFS) showed no significant results in the patients with CRC in our meta-analysis (HR = 1.38, 95 % CI: 0.51-3.75, p = 0.52) as well as in the GEPIA and LOGpc databases. Meanwhile, YAP1 overexpression was also significantly associated with worse overall survival (OS) in GSE17536, GSE40967, GSE29623 and GSE71187. CONCLUSION YAP1 overexpression is common in CRC tissues. Overexpression of YAP1 in CRC patients, particularly in the nucleus, might be related to shorter OS, maybe in the early stages. YAP1 could serve as a potential predictor of poor prognosis in CRC.
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Affiliation(s)
- Hui Zhang
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | | | - Yu Hu
- Wuhan Mental Health Center, Tongji Medical College of Huazhong University,
| | - Mingming Jiang
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | - Mingliang Lu
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | - Yajuan Wu
- Radiotherapy, The Second Chest Radiotherapy Ward of Shanxi Cancer Hospital, china
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15
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Ding R, Chen Y, Shi X, Li Y, Yu Y, Sun Z, Duan J. Size-dependent toxicity of polystyrene microplastics on the gastrointestinal tract: Oxidative stress related-DNA damage and potential carcinogenicity. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 912:169514. [PMID: 38135073 DOI: 10.1016/j.scitotenv.2023.169514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/16/2023] [Accepted: 12/17/2023] [Indexed: 12/24/2023]
Abstract
Microplastics (MPs) and nanoplastics (NPs) have been generally regarded as emerging pollutants and received worldwide attention in recent years. Water and food consumption are the primary pathways for human exposure to MPs/NPs, thus gastrointestinal tracts may be susceptible to their toxicity. Although the recent report has indicated the presence of MPs/NPs in multiple human organs, little is known about their gastric effects. Therefore, this study focused on the adverse effects of polystyrene microplastics (PS-MPs) on gastric epithelium in vivo and in vitro. Surface-enhanced Raman spectroscopy (SERS) revealed the distribution of PS-MPs was associated with their particle sizes, and predominantly concentrated in gastric tissues. Gastric barrier injury and mitochondrial damage were observed in rats after exposure to PS-MPs. Compared with the larger ones, polystyrene nanoplastics (PS-NPs) more significantly reduced the activity of antioxidant enzymes while enhancing the level of MDA, 8-OhdG and γ-H2AX. Meanwhile, PS-MPs caused upregulation of β-catenin/YAP through redox-dependent regulation of nucleoredoxin (NXN) and dishevelled (Dvl). These findings supported the size-dependent effects of PS-MPs on oxidative stress and DNA damage. Moreover, the redox-dependent activation of the β-catenin/YAP cascade suggested a novel toxic mechanism for PS-MPs and implied the potential carcinogenic effects.
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Affiliation(s)
- Ruiyang Ding
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Yueyue Chen
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Xuemin Shi
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Yang Yu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
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16
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Shin E, Kwon Y, Jung E, Kim YJ, Kim C, Hong S, Kim J. TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions. Proc Natl Acad Sci U S A 2024; 121:e2314346121. [PMID: 38315837 PMCID: PMC10873613 DOI: 10.1073/pnas.2314346121] [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: 08/29/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPβ1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.
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Affiliation(s)
- Eunbie Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Yongsoo Kwon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Eunji Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Yong Joon Kim
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul03722, South Korea
| | - Changgon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Semyeong Hong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Joon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
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17
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Li Y, Zheng Z, Xiao L, Chen Y, Liu X, Long D, Chai L, Li Y, Tan C. Dinaciclib exerts a tumor-suppressing effect via β-catenin/YAP axis in pancreatic ductal adenocarcinoma. Anticancer Drugs 2024; 35:140-154. [PMID: 37694833 DOI: 10.1097/cad.0000000000001545] [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: 09/12/2023]
Abstract
Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing β-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating β-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.
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Affiliation(s)
- Yichen Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University
| | - Zhenjiang Zheng
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University
| | - Li Xiao
- Department of Traditional Chinese Medicine, Chengdu Third People's Hospital
| | - Yonghua Chen
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University
| | - Xubao Liu
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University
| | - Dan Long
- Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Diseaserelated Molecular Network, West China Hospital, Sichuan University
| | - Li Chai
- Research Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yi Li
- Research Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Chunlu Tan
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University
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18
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Tai Y, Shang J. Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma. Front Endocrinol (Lausanne) 2024; 14:1260701. [PMID: 38269250 PMCID: PMC10806569 DOI: 10.3389/fendo.2023.1260701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 12/20/2023] [Indexed: 01/26/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
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Affiliation(s)
- Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jiwen Shang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Department of Ambulatory Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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19
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Doxtater K, Tripathi MK, Sekhri R, Hafeez BB, Khan S, Zafar N, Behrman SW, Yallapu MM, Jaggi M, Chauhan SC. MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway. Life Sci Alliance 2023; 6:e202301975. [PMID: 37793774 PMCID: PMC10551643 DOI: 10.26508/lsa.202301975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
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Affiliation(s)
- Kyle Doxtater
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Radhika Sekhri
- Department of Pathology, Montefiore Medical Center College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Nadeem Zafar
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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20
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Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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21
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Liu Y, Lei P, Samuel RZ, Kashyap AM, Groth T, Bshara W, Neelamegham S, Andreadis ST. Cadherin-11 increases tumor cell proliferation and metastatic potential via Wnt pathway activation. Mol Oncol 2023; 17:2056-2073. [PMID: 37558205 PMCID: PMC10552893 DOI: 10.1002/1878-0261.13507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 06/23/2023] [Accepted: 07/08/2023] [Indexed: 08/11/2023] Open
Abstract
During epithelial-mesenchymal transition (EMT) in cancer progression, tumor cells switch cadherin profile from E-cadherin to cadherin-11 (CDH11), which is accompanied by increased invasiveness and metastatic activity. However, the mechanism through which CDH11 may affect tumor growth and metastasis remains elusive. Here, we report that CDH11 was highly expressed in multiple human tumors and was localized on the membrane, in the cytoplasm and, surprisingly, also in the nucleus. Interestingly, β-catenin remained bound to carboxy-terminal fragments (CTFs) of CDH11, the products of CDH11 cleavage, and co-localized with CTFs in the nucleus in the majority of breast cancer samples. Binding of β-catenin to CTFs preserved β-catenin activity, whereas inhibiting CDH11 cleavage led to β-catenin phosphorylation and diminished Wnt signaling, similar to CDH11 knockout. Our data elucidate a previously unknown role of CDH11, which serves to stabilize β-catenin in the cytoplasm and facilitates its translocation to the nucleus, resulting in activation of Wnt signaling, with subsequent increased proliferation, migration and invasion potential.
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Affiliation(s)
- Yayu Liu
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Pedro Lei
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Ronel Z. Samuel
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Anagha M. Kashyap
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Theodore Groth
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Wiam Bshara
- Roswell Park Comprehensive Cancer Center Pathology Resource NetworkBuffaloNYUSA
| | - Sriram Neelamegham
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- Department of Biomedical Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- New York State Center of Excellence in Bioinformatics and Life SciencesBuffaloNYUSA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Stelios T. Andreadis
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- Department of Biomedical Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- New York State Center of Excellence in Bioinformatics and Life SciencesBuffaloNYUSA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at BuffaloThe State University of New YorkAmherstNYUSA
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22
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Li C, Furth EE, Rustgi AK, Klein PS. When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex. Cells 2023; 12:2256. [PMID: 37759479 PMCID: PMC10528086 DOI: 10.3390/cells12182256] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.
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Affiliation(s)
- Chenchen Li
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA
| | - Peter S. Klein
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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23
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Benton D, Chernoff J. TRIMming away colon cancer: TRIM21-mediated ubiquitination as an activator of the Hippo tumor suppressor pathway. Cell Chem Biol 2023; 30:699-701. [PMID: 37478825 DOI: 10.1016/j.chembiol.2023.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 07/23/2023]
Abstract
In this issue of Cell Chemical Biology, Liu et al.1 identify TRIM21-mediated ubiquitination of the Hippo pathway kinase MST2, promoting its dimerization and activation. The antidepressant Vilazodone was found to bind to TRIM21, enhancing its activity toward MST2, increasing Hippo activation, and reducing colorectal cancer metastasis.
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Affiliation(s)
- Dorothy Benton
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Jonathan Chernoff
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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24
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Chen B, Jin W. A comprehensive review of stroke-related signaling pathways and treatment in western medicine and traditional Chinese medicine. Front Neurosci 2023; 17:1200061. [PMID: 37351420 PMCID: PMC10282194 DOI: 10.3389/fnins.2023.1200061] [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: 04/04/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
This review provides insight into the complex network of signaling pathways and mechanisms involved in stroke pathophysiology. It summarizes the historical progress of stroke-related signaling pathways, identifying potential interactions between them and emphasizing that stroke is a complex network disease. Of particular interest are the Hippo signaling pathway and ferroptosis signaling pathway, which remain understudied areas of research, and are therefore a focus of the review. The involvement of multiple signaling pathways, including Sonic Hedgehog (SHH), nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), hypoxia-inducible factor-1α (HIF-1α), PI3K/AKT, JAK/STAT, and AMPK in pathophysiological mechanisms such as oxidative stress and apoptosis, highlights the complexity of stroke. The review also delves into the details of traditional Chinese medicine (TCM) therapies such as Rehmanniae and Astragalus, providing an analysis of the recent status of western medicine in the treatment of stroke and the advantages and disadvantages of TCM and western medicine in stroke treatment. The review proposes that since stroke is a network disease, TCM has the potential and advantages of a multi-target and multi-pathway mechanism of action in the treatment of stroke. Therefore, it is suggested that future research should explore more treasures of TCM and develop new therapies from the perspective of stroke as a network disease.
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Affiliation(s)
- Binhao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
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25
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Nabatchian F, Davoudi M, Ashtiani M, Davoudi N, Afrisham R. Hydroalcoholic Extract of Achillea Wilhelmsii Decreases the Expressions
of Hippo Signaling Pathway-Associated Oncogenes in the A549 Lung
Cancer Cell Line. CURRENT CHEMICAL BIOLOGY 2023; 17:140-146. [DOI: 10.2174/2212796817666230214100146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 11/19/2022] [Accepted: 12/29/2022] [Indexed: 05/17/2025]
Abstract
Background:
Achillea wilhelmsii used in traditional Iranian medicine to treat a variety of
disorders, has been proven to contribute to some signaling pathways in cancers. Evidence suggests
that the Hippo pathway, which regulates organ size, is altered in a few conditions like lung cancer. In
this regard, this study aimed to evaluate the effect of the hydroalcoholic extract of this plant on the viability
and mRNA expression of some Hippo signaling pathway-associated oncogenes and suppressors
in A549 lung cancer cell lines.
Methods:
Hydroalcoholic extract was prepared using a Soxhlet extractor and its antiproliferative activity
was studied by MTT assay. Then, the mRNA expressions of "large tumour suppressor kinases 1
and 2" (LATS1 and LATS2), "Yes1 Associated Transcriptional Regulator" (YAP1), and "Transcriptional
co‑activator with PDZ‑binding motif" (TAZ) were measured using real-time PCR.
Results:
According to MTT, the viability was decreased significantly after 24 h treatment with A. wilhelmsii
at the concentrations of 800-1000 μg/ml and after 48 h treatment at the concentration of 400-
1000 μg/ml. While the mRNA levels of LATS1, TAZ, and YAP1 decreased significantly compared to
untreated cells at the concentration of 200 μg/ml after 48 h treatment. However, the mRNA expression
of LATS2 did not change.
Conclusion:
Our findings showed that hydroalcoholic extract of A. wilhelmsii inhibited the viability of
lung cancer cells as well as it could decrease the expression of both oncogenes in the Hippo pathway.
However, it had suppressing effects on LATS1, which should be considered in further studies.
conclusion:
Hydroalcoholic extract of A. wilhelmsii might inhibit proliferation of lung cancer cells as well as it could decrease the expression of both oncogenes in them. However, it had suppressing effects on LATS1, which should be considered in further studies.
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Affiliation(s)
- Fariba Nabatchian
- Department of Medical Laboratory Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran,
Iran
| | - Maryam Davoudi
- Department of Medical Laboratory Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran,
Iran
| | - Mojtaba Ashtiani
- Department of Medical Laboratory Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran,
Iran
| | - Negin Davoudi
- Department of Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Afrisham
- Department of Medical Laboratory Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran,
Iran
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26
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Wang Z, Qu YJ, Cui M. Modulation of stem cell fate in intestinal homeostasis, injury and repair. World J Stem Cells 2023; 15:354-368. [PMID: 37342221 PMCID: PMC10277971 DOI: 10.4252/wjsc.v15.i5.354] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/31/2023] [Accepted: 04/24/2023] [Indexed: 05/26/2023] Open
Abstract
The mammalian intestinal epithelium constitutes the largest barrier against the external environment and makes flexible responses to various types of stimuli. Epithelial cells are fast-renewed to counteract constant damage and disrupted barrier function to maintain their integrity. The homeostatic repair and regeneration of the intestinal epithelium are governed by the Lgr5+ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to the different epithelial cell types. Protracted biological and physicochemical stress may challenge epithelial integrity and the function of ISCs. The field of ISCs is thus of interest for complete mucosal healing, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel diseases. Here, we review the current understanding of the signals and mechanisms that control homeostasis and regeneration of the intestinal epithelium. We focus on recent insights into the intrinsic and extrinsic elements involved in the process of intestinal homeostasis, injury, and repair, which fine-tune the balance between self-renewal and cell fate specification in ISCs. Deciphering the regulatory machinery that modulates stem cell fate would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.
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Affiliation(s)
- Zhe Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan-Ji Qu
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Min Cui
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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27
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Sinha S, Aizawa S, Nakano Y, Rialdi A, Choi HY, Shrestha R, Pan SQ, Chen Y, Li M, Kapelanski-Lamoureux A, Yochum G, Sher L, Monga SP, Lazaris A, Machida K, Karin M, Guccione E, Tsukamoto H. Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis. Nat Commun 2023; 14:2651. [PMID: 37156770 PMCID: PMC10167314 DOI: 10.1038/s41467-023-38406-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 05/02/2023] [Indexed: 05/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.
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Affiliation(s)
- Sonal Sinha
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Satoka Aizawa
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Yasuhiro Nakano
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0022, Japan
| | - Alexander Rialdi
- Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, New York, NY, 10029, USA
| | - Hye Yeon Choi
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Rajan Shrestha
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Stephanie Q Pan
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Yibu Chen
- USC Libraries Bioinformatics Services of the University of Southern California, Los Angeles, CA, 90089, USA
| | - Meng Li
- USC Libraries Bioinformatics Services of the University of Southern California, Los Angeles, CA, 90089, USA
| | | | - Gregory Yochum
- Department of Surgery, Pennsylvania State University, Hershey, PA, 17033, USA
| | - Linda Sher
- Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Satdarshan Paul Monga
- Department of Pathology, University of Pittsburg School of Medicine, Pittsburg, PA, 15213, USA
| | - Anthoula Lazaris
- Research Institute of the McGill University Health Centre, Montreal, QC, H3A 0G4, Canada
| | - Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Michael Karin
- Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA
| | - Ernesto Guccione
- Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, New York, NY, 10029, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA.
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28
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King CM, Marx OM, Ding W, Koltun WA, Yochum GS. TCF7L1 Regulates LGR5 Expression in Colorectal Cancer Cells. Genes (Basel) 2023; 14:481. [PMID: 36833408 PMCID: PMC9956233 DOI: 10.3390/genes14020481] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/06/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity. However, the WREs at the LGR5 gene locus and how TCF factors directly regulate LGR5 gene expression in CRC have not been fully defined. Here, we report that TCF family member, TCF7L1, plays a significant role in regulating LGR5 expression in CRC cells. We demonstrate that TCF7L1 binds to a novel promoter-proximal WRE through association with a consensus TBE at the LGR5 locus to repress LGR5 expression. Using CRISPR activation and interference (CRISPRa/i) technologies to direct epigenetic modulation, we demonstrate that this WRE is a critical regulator of LGR5 expression and spheroid formation capacity of CRC cells. Furthermore, we found that restoring LGR5 expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing LGR5 gene expression to govern the spheroid formation potential of CRC cells.
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Affiliation(s)
- Carli M. King
- Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17036, USA
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA
| | - Olivia M. Marx
- Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17036, USA
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA
| | - Wei Ding
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA
| | - Walter A. Koltun
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA
| | - Gregory S. Yochum
- Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17036, USA
- Department of Surgery, Division of Colon & Rectal Surgery, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17036, USA
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Zhu J, Teng X, Wang L, Zheng M, Meng Y, Liu T, Liu Y, Huan H, Gong D, Xie P. Prolactin promotes crop epithelial proliferation of domestic pigeons (Columba livia) through the Hippo signaling pathway. J Anim Sci 2023; 101:skad312. [PMID: 37721785 PMCID: PMC10576522 DOI: 10.1093/jas/skad312] [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: 07/26/2023] [Accepted: 09/15/2023] [Indexed: 09/19/2023] Open
Abstract
The purpose of this study was to investigate whether prolactin (PRL) regulates the proliferation of pigeon crop epithelium through the Hippo signaling pathway during the breeding cycle. Twenty-four pairs of adult pigeons were allotted to four groups by different breeding stages, and their crops and serum were sampled. Eighteen pairs of young pigeons were selected and divided into three groups for the injection experiments. The results showed that the serum PRL content and crop epithelial thickness of pigeons increased significantly at day 17 of incubation (I17) and day 1 of chick-rearing (R1). In males, the mRNA levels of yes-associated transcriptional regulator (YAP) and snail family transcriptional repressor 2 (SNAI2) were peaked at I17, and the gene levels of large tumor suppressor kinase 1 (LATS1), serine/threonine kinase 3 (STK3), TEA domain transcription factor 3 (TEAD3), connective tissue growth factor (CTGF), MYC proto-oncogene (c-Myc) and SRY-box transcription factor 2 (SOX2) reached the maximum value at R1. In females, the gene expression of YAP, STK3, TEAD3, and SOX2 reached the greatest level at I17, the expression profile of SAV1, CTGF, and c-Myc were maximized at R1. In males, the protein levels of LATS1 and YAP were maximized at R1 and the CTGF expression was upregulated at I17. In females, LATS1, YAP, and CTGF reached a maximum value at I17, and the expression level of phosphorylated YAP was minimized at I17 in males and females. Subcutaneous injection of prolactin (injected for 6 d, 10 μg per kg body weight every day) on the left crop of pigeons can promote the proliferation of crop epithelium by increasing the CTGF level and reducing the phosphorylation level of YAP. YAP-TEAD inhibitor verteporfin (injection for 6 d, 2.5 mg per kg body weight every day) can inhibit the proliferation of crop epithelium induced by prolactin by inhibiting YAP and CTGF expression. In conclusion, PRL can participate in crop cell proliferation of pigeons by promoting the expression of YAP and CTGF in Hippo pathway.
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Affiliation(s)
- Jianguo Zhu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, P.R.China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P.R.China
| | - Xingyi Teng
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266000, P.R.China
| | - Liuxiong Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P.R.China
| | - Mingde Zheng
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P.R.China
| | - Yu Meng
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P.R.China
| | - Tingwu Liu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, P.R.China
| | - Ying Liu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, P.R.China
| | - Haixia Huan
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, P.R.China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P.R.China
| | - Peng Xie
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian 223300, P.R.China
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Piccolo S, Panciera T, Contessotto P, Cordenonsi M. YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches. NATURE CANCER 2023; 4:9-26. [PMID: 36564601 PMCID: PMC7614914 DOI: 10.1038/s43018-022-00473-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 10/31/2022] [Indexed: 12/24/2022]
Abstract
Our understanding of the function of the transcriptional regulators YAP and TAZ (YAP/TAZ) in cancer is advancing. In this Review, we provide an update on recent progress in YAP/TAZ biology, their regulation by Hippo signaling and mechanotransduction and highlight open questions. YAP/TAZ signaling is an addiction shared by multiple tumor types and their microenvironments, providing many malignant attributes. As such, it represents an important vulnerability that may offer a broad window of therapeutic efficacy, and here we give an overview of the current treatment strategies and pioneering clinical trials.
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Affiliation(s)
- Stefano Piccolo
- Department of Molecular Medicine, University of Padua, Padua, Italy.
- IFOM-ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.
| | - Tito Panciera
- Department of Molecular Medicine, University of Padua, Padua, Italy
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Wang LL, Zheng W, Liu XL, Yin F. Somatic mutations in FAT cadherin family members constitute an underrecognized subtype of colorectal adenocarcinoma with unique clinicopathologic features. World J Clin Oncol 2022; 13:779-788. [PMID: 36337316 PMCID: PMC9630991 DOI: 10.5306/wjco.v13.i10.779] [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: 07/26/2022] [Revised: 08/25/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The FAT cadherin family members (FAT1, FAT2, FAT3 and FAT4) are conserved tumor suppressors that are recurrently mutated in several types of human cancers, including colorectal carcinoma (CRC). AIM To characterize the clinicopathologic features of CRC patients with somatic mutations in FAT cadherin family members. METHODS We analyzed 526 CRC cases from The Cancer Genome Atlas PanCancer Atlas dataset. CRC samples were subclassified into 2 groups based on the presence or absence of somatic mutations in FAT1, FAT2, FAT3 and FAT4. Individual clinicopathological data were collected after digital slide review. Statistical analysis was performed using t tests and chi-square tests. RESULTS This CRC study cohort had frequent mutations in the FAT1 (10.5%), FAT2 (11.2%), FAT3 (15.4%) and FAT4 (23.4%) genes. Two hundred CRC patients (38.0%) harbored somatic mutations in one or more of the FAT family genes and were grouped into the FAT mutated CRC subtype. The FAT-mutated CRC subtype was more commonly located on the right side of the colon (51.0%) than in the rest of the cohort (30.1%, P < 0.001). It showed favorable clinicopathologic features, including a lower rate of positive lymph nodes (pN1-2: 33.5% vs 46.4%, P = 0.005), a lower rate of metastasis to another site or organ (pM1: 7.5% vs 16.3%, P = 0.006), and a trend toward an early tumor stage (pT1-2: 25.0% vs 18.7%, P = 0.093). FAT somatic mutations were significantly enriched in microsatellite instability CRC (28.0% vs 2.1%, P < 0.001). However, FAT somatic mutations in microsatellite stable CRC demonstrated similar clinicopathologic behaviors, as well as a trend of a better disease-free survival rate (hazard ratio = 0.539; 95% confidence interval: 0.301-0.967; log-rank P = 0.073). CONCLUSION FAT cadherin family genes are frequently mutated in CRC, and their mutation profile defines a subtype of CRC with favorable clinicopathologic characteristics.
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Affiliation(s)
- Liang-Li Wang
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Xiu-Li Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022; 10:biomedicines10102512. [PMID: 36289774 PMCID: PMC9599207 DOI: 10.3390/biomedicines10102512] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.
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Alkailani MI, Aittaleb M, Tissir F. WNT signaling at the intersection between neurogenesis and brain tumorigenesis. Front Mol Neurosci 2022; 15:1017568. [PMID: 36267699 PMCID: PMC9577257 DOI: 10.3389/fnmol.2022.1017568] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
Neurogenesis and tumorigenesis share signaling molecules/pathways involved in cell proliferation, differentiation, migration, and death. Self-renewal of neural stem cells is a tightly regulated process that secures the accuracy of cell division and eliminates cells that undergo mitotic errors. Abnormalities in the molecular mechanisms controlling this process can trigger aneuploidy and genome instability, leading to neoplastic transformation. Mutations that affect cell adhesion, polarity, or migration enhance the invasive potential and favor the progression of tumors. Here, we review recent evidence of the WNT pathway’s involvement in both neurogenesis and tumorigenesis and discuss the experimental progress on therapeutic opportunities targeting components of this pathway.
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Affiliation(s)
- Maisa I. Alkailani
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Mohamed Aittaleb
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Fadel Tissir
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
- *Correspondence: Fadel Tissir,
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Lu S, Jiang M, Chen Q, Luo X, Cao Z, Huang H, Zheng M, Du J. Upregulated YAP promotes oncogenic CTNNB1 expression contributing to molecular pathology of hepatoblastoma. Pediatr Blood Cancer 2022; 69:e29705. [PMID: 35404538 DOI: 10.1002/pbc.29705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Hepatoblastoma (HB) is one of the most common cancers in children. Recent studies have shown that the occurrence of nuclear accumulation of β-catenin reaches 90%-100% because of the anomalous activation of the Wnt pathway in HB patients. Furthermore, emerging studies have shown that concomitant activated forms of YAP and β-catenin trigger the formation and progression of HB. YAP might play a vital role in β-catenin-mediated HB development. However, the molecular mechanisms by which YAP/TEAD4 transcription factor regulates CTNNB1 underlying HB pathogenesis are still unclear. PROCEDURE YAP and CTNNB1 expression and correlation were analyzed by a combination of network enrichment analysis and gene set enrichment analysis of the public microarray datasets (GSE131329 and GSE81928). The protein levels of YAP and β-catenin were further validated by Western blotting in paired patients' samples. The direct interplay between YAP/TEAD4 and the promoter region of CTNNB1 was proven by the combination of dual-luciferase report assay and chromatin immunoprecipitation assay. RESULTS YAP-conserved signature and WNT signaling pathway were significantly enriched in HB patients, with upregulated expression of YAP and β-catenin compared to non-HB patients. Further functional assays demonstrated that YAP/TEAD4 transcription factor complex could bind to the CTNNB1 promoter region directly to promote β-catenin expression and cell proliferation. Targeting the YAP/TEAD4 complex with a specific small-molecule compound markedly suppressed HepaG2 cell proliferation. CONCLUSIONS As the upstream transcription factor of CTNNB1, YAP/TEAD4 is a promising target for the treatment of HB patients with high levels of YAP and β-catenin.
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Affiliation(s)
- Songxian Lu
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Min Jiang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qi Chen
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xufeng Luo
- Institute for Lymphoma Research, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Zhenjie Cao
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Huang
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mingjun Zheng
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junpeng Du
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Wang Y, Chen H, Yu J, Kang W, To KF. Recent insight into the role and therapeutic potential of YAP/TAZ in gastrointestinal cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188787. [PMID: 36041574 DOI: 10.1016/j.bbcan.2022.188787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/25/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
With the rapid development of cancer treatment, gastrointestinal (GI) cancers are still the most prevalent malignancies with high morbidity and mortality worldwide. Dysregulation of the Hippo signaling pathway has been recognized to play a critical role during cancer development and adopted for monitoring disease progression and therapy response. Despite the well-documented tumor proliferation and metastasis, recent efforts in two core Hippo components, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), have identified as the driving forces behind cancer metabolism, stemness, tumor immunity, and therapy resistance. Understanding the molecular mechanisms by which YAP/TAZ facilitates the tumorigenesis and progression of GI cancer, and identifying novel therapeutic strategies for targeting YAP/TAZ are crucial to GI cancer treatment and prevention. In this study, we summarize the latest findings on the function and regulatory mechanisms of YAP/TAZ in GI cancers, and highlight the translational significance of targeting YAP/TAZ for cancer therapies.
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Affiliation(s)
- Yifei Wang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Huarong Chen
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
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Švec J, Šťastná M, Janečková L, Hrčkulák D, Vojtěchová M, Onhajzer J, Kříž V, Galušková K, Šloncová E, Kubovčiak J, Pfeiferová L, Hrudka J, Matěj R, Waldauf P, Havlůj L, Kolář M, Kořínek V. TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial-Mesenchymal Transition and Invasiveness. Cancers (Basel) 2022; 14:4137. [PMID: 36077674 PMCID: PMC9454662 DOI: 10.3390/cancers14174137] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/09/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.
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Affiliation(s)
- Jiří Švec
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
- Department of Oncology, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic
| | - Monika Šťastná
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Lucie Janečková
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Dušan Hrčkulák
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Martina Vojtěchová
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Jakub Onhajzer
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Vítězslav Kříž
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Kateřina Galušková
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Eva Šloncová
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Jan Kubovčiak
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Lucie Pfeiferová
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
- Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic
| | - Jan Hrudka
- Department of Pathology, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic
| | - Radoslav Matěj
- Department of Pathology, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic
- Department of Pathology and Molecular Medicine, Third Medical Faculty, Charles University, Thomayer University Hospital, Ruská 87, 100 00 Praha, Czech Republic
| | - Petr Waldauf
- Department of Anaesthesia and Intensive Care Medicine, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic
| | - Lukáš Havlůj
- Department of General Surgery, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic
| | - Michal Kolář
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
| | - Vladimír Kořínek
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
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Mizutani T, Orisaka M, Miyazaki Y, Morichika R, Uesaka M, Miyamoto K, Yoshida Y. Inhibition of YAP/TAZ-TEAD activity induces cytotrophoblast differentiation into syncytiotrophoblast in human trophoblast. Mol Hum Reprod 2022; 28:6673154. [PMID: 35993908 DOI: 10.1093/molehr/gaac032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
During placentation, placental cytotrophoblast (CT) cells differentiate into syncytiotrophoblast (ST) cells and extravillous trophoblast (EVT) cells. In the placenta, the expression of various genes is regulated by the Hippo pathway through a transcription complex, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)-TEA domain transcription factor (TEAD) (YAP/TAZ-TEAD) activity. YAP/TAZ-TEAD activity is controlled by multiple factors and signaling, such as cyclic AMP (cAMP) signaling. cAMP signaling is believed to be involved in the regulation of trophoblast function but is not yet fully understood. Here we showed that YAP/TAZ-TEAD expressions and their activities were altered by cAMP stimulation in BeWo cells, a human choriocarcinoma cell line. The repression of YAP/TAZ-TEAD activity induced the expression of ST-specific genes without cAMP stimulation, and transduction of constitutively active YAP, i.e., YAP-5SA, resulted in the repression of 8Br-cAMP-induced expressions of ST-specific genes in a TEAD-dependent manner. We also investigated the role of YAP/TAZ-TEAD in maintaining CT cells and their differentiation into ST and EVT cells using human trophoblast stem (TS) cells. YAP/TAZ-TEAD activity was involved in maintaining the stemness of TS cells. Induction or repression of YAP/TAZ-TEAD activity resulted in marked changes in the expression of ST-specific genes. Using primary CT cells, which spontaneously differentiate into ST-like cells, the effects of YAP-5SA transduction were investigated, and the expression of ST-specific genes was found to be repressed. These results indicate that the inhibition of YAP/TAZ-TEAD activity, with or without cAMP stimulation, is essential for the differentiation of CT cells into ST cells.
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Affiliation(s)
- Tetsuya Mizutani
- Department of Nursing, Faculty of Nursing and Welfare Sciences, Fukui Prefectural University, Japan
| | - Makoto Orisaka
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Japan
| | - Yumiko Miyazaki
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Japan
| | - Ririko Morichika
- Department of Nursing, Faculty of Nursing and Welfare Sciences, Fukui Prefectural University, Japan
| | - Miki Uesaka
- Department of Nursing, Faculty of Nursing and Welfare Sciences, Fukui Prefectural University, Japan.,Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Japan
| | | | - Yoshio Yoshida
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Japan
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O-GlcNAcylation: An Emerging Protein Modification Regulating the Hippo Pathway. Cancers (Basel) 2022; 14:cancers14123013. [PMID: 35740678 PMCID: PMC9221189 DOI: 10.3390/cancers14123013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The contact point between the Hippo pathway, which serves as a central hub for various external environments, and O-GlcNAcylation, which is a non-canonical glycosylation process acting as a dynamic regulator in various signal transduction pathways, has recently been identified. This review aims to summarize the function of O-GlcNAcylation as an intrinsic and extrinsic regulator of the Hippo pathway. Abstract The balance between cellular proliferation and apoptosis and the regulation of cell differentiation must be established to maintain tissue homeostasis. These cellular responses involve the kinase cascade-mediated Hippo pathway as a crucial regulator. Hence, Hippo pathway dysregulation is implicated in diverse diseases, including cancer. O-GlcNAcylation is a non-canonical glycosylation that affects multiple signaling pathways through its interplay with phosphorylation in the nucleus and cytoplasm. An abnormal increase in the O-GlcNAcylation levels in various cancer cells is a potent factor in Hippo pathway dysregulation. Intriguingly, Hippo pathway dysregulation also disrupts O-GlcNAc homeostasis, leading to a persistent elevation of O-GlcNAcylation levels, which is potentially pathogenic in several diseases. Therefore, O-GlcNAcylation is gaining attention as a protein modification that regulates the Hippo pathway. This review presents a framework on how O-GlcNAcylation regulates the Hippo pathway and forms a self-perpetuating cycle with it. The pathological significance of this self-perpetuating cycle and clinical strategies for targeting O-GlcNAcylation that causes Hippo pathway dysregulation are also discussed.
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Wu H, Liu Y, Liao Z, Mo J, Zhang Q, Zhang B, Zhang L. The role of YAP1 in liver cancer stem cells: proven and potential mechanisms. Biomark Res 2022; 10:42. [PMID: 35672802 PMCID: PMC9171972 DOI: 10.1186/s40364-022-00387-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023] Open
Abstract
YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.
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Affiliation(s)
- Haofeng Wu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Zhibin Liao
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Jie Mo
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Qiaofeng Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Bixiang Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Lei Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, 030032, China.
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Fabris L, Milani C, Fiorotto R, Mariotti V, Kaffe E, Seller B, Sonzogni A, Strazzabosco M, Cadamuro M. Dysregulation of the Scribble/YAP/β-catenin axis sustains the fibroinflammatory response in a PKHD1 -/- mouse model of congenital hepatic fibrosis. FASEB J 2022; 36:e22364. [PMID: 35593740 PMCID: PMC9150862 DOI: 10.1096/fj.202101924r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/25/2022] [Accepted: 05/10/2022] [Indexed: 11/11/2022]
Abstract
Congenital hepatic fibrosis (CHF), a genetic cholangiopathy characterized by fibropolycystic changes in the biliary tree, is caused by mutations in the PKHD1 gene, leading to defective fibrocystin (FPC), changes in planar cell polarity (PCP) and increased β-catenin-dependent chemokine secretion. In this study, we aimed at understanding the role of Scribble (a protein involved in PCP), Yes-associated protein (YAP), and β-catenin in the regulation of the fibroinflammatory phenotype of FPC-defective cholangiocytes. Immunohistochemistry showed that compared with wild type (WT) mice, in FPC-defective (Pkhd1del4/del4 ) mice nuclear expression of YAP/TAZ in cystic cholangiocytes, significantly increased and correlated with connective tissue growth factor (CTGF) expression and pericystic fibrosis, while Scribble expression on biliary cyst cells was markedly decreased. Cholangiocytes isolated from WT mice showed intense Scribble immunoreactivity at the membrane, but minimal nuclear expression of YAP, which conversely increased, together with CTGF, after small interfering RNA (siRNA) silencing of Scribble. In FPC-defective cholangiocytes, inhibition of YAP nuclear import reduced β-catenin nuclear expression, and CTGF, integrin β6, CXCL1, and CXCL10 mRNA levels, whereas inhibition of β-catenin signaling did not affect nuclear translocation of YAP. Notably, siRNA silencing of Scribble and YAP in WT cholangiocytes mimics the fibroinflammatory changes of FPC-defective cholangiocytes. Conditional deletion of β-catenin in Pkhd1del4/del4 mice reduced cyst growth, inflammation and fibrosis, without affecting YAP nuclear expression. In conclusion, the defective anchor of Scribble to the membrane facilitates the nuclear translocation of YAP and β-catenin with gain of a fibroinflammatory phenotype. The Scribble/YAP/β-catenin axis is a critical factor in the sequence of events linking the genetic defect to fibrocystic trait of cholangiocytes in CHF.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine (DMM), University of Padova, Padova, Italy
- International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy
- Liver Center, Department of Internal Medicine, Yale University, New Haven (CT), US
| | - Chiara Milani
- School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Romina Fiorotto
- Liver Center, Department of Internal Medicine, Yale University, New Haven (CT), US
| | - Valeria Mariotti
- Department of Molecular Medicine (DMM), University of Padova, Padova, Italy
- Liver Center, Department of Internal Medicine, Yale University, New Haven (CT), US
| | - Eleanna Kaffe
- Liver Center, Department of Internal Medicine, Yale University, New Haven (CT), US
| | - Barbara Seller
- School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Aurelio Sonzogni
- Department of Pathology, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven (CT), US
- Corresponding authors: Mario Strazzabosco, MD, PhD, Department of Internal Medicine, Yale University School of Medicine, Cedar Street 333 Room LMP1080, New Haven, CT 06517, USA. Phone: +1‐203‐785‐5110, , Massimiliano Cadamuro, PhD, Department of Molecular Medicine, University of Padova, Gabelli Street 63, Padova, 35121, Italy. Phone: +39-049-827-6113,
| | - Massimiliano Cadamuro
- Department of Molecular Medicine (DMM), University of Padova, Padova, Italy
- International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy
- Corresponding authors: Mario Strazzabosco, MD, PhD, Department of Internal Medicine, Yale University School of Medicine, Cedar Street 333 Room LMP1080, New Haven, CT 06517, USA. Phone: +1‐203‐785‐5110, , Massimiliano Cadamuro, PhD, Department of Molecular Medicine, University of Padova, Gabelli Street 63, Padova, 35121, Italy. Phone: +39-049-827-6113,
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Khoramjoo SM, Kazemifard N, Baradaran Ghavami S, Farmani M, Shahrokh S, Asadzadeh Aghdaei H, Sherkat G, Zali MR. Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs). Front Med (Lausanne) 2022; 9:865131. [PMID: 35677821 PMCID: PMC9170180 DOI: 10.3389/fmed.2022.865131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.
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Affiliation(s)
- Seyed Mobin Khoramjoo
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Kazemifard
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Shaghayegh Baradaran Ghavami
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zhang Y, Wang X, Zhou X. Functions of Yes-association protein (YAP) in cancer progression and anticancer therapy resistance. BRAIN SCIENCE ADVANCES 2022. [DOI: 10.26599/bsa.2022.9050008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The Hippo pathway, a highly conserved kinase cascade, regulates cell proliferation, apoptosis, organ size, and tissue homeostasis. Dysregulation of this pathway reportedly plays an important role in the progression of various human cancers. Yes-association protein (YAP), the Hippo pathway’s core effector, is considered a marker for cancer therapy and patient prognosis. In addition, studies have indicated that YAP is involved in promoting anticancer drug resistance. This review summarizes current knowledge on YAP’s role in cancer progression, anticancer drug resistance, and advances in the development of YAP-targeting drugs. A thorough understanding of the complex interactions among molecular, cellular, and environmental factors concerning YAP function in cancer progression may provide new insight into the underlying mechanism of anticancer drug resistance. It might lead to improved prognosis through novel combined therapies.
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Affiliation(s)
- Yu Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiang Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiuping Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
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Simula L, Alifano M, Icard P. How Phosphofructokinase-1 Promotes PI3K and YAP/TAZ in Cancer: Therapeutic Perspectives. Cancers (Basel) 2022; 14:cancers14102478. [PMID: 35626081 PMCID: PMC9139230 DOI: 10.3390/cancers14102478] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary We propose that PFK1 promotes a positive feedback loop with PI3K/AKT and YAP/TAZ signaling pathways in cancer cells. Therefore, targeting PFK1 (or its product F-1,6-BP) could improve the efficacy of PI3K and YAP/TAZ inhibitors currently tested in clinical trials. To this aim, we suggest the use of citrate, which is a physiologic and potent inhibitor of PFK1. Abstract PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this “citrate strategy” efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER+ and lung RAS-driven tumors in mice without apparent toxicities.
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Affiliation(s)
- Luca Simula
- Department of Infection, Immunity and Inflammation, Cochin Institute, INSERM U1016, CNRS UMR8104, University of Paris, 75014 Paris, France;
| | - Marco Alifano
- INSERM U1138, Integrative Cancer Immunology, University of Paris, 75006 Paris, France;
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France
| | - Philippe Icard
- Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France
- UNICAEN, INSERM U1086 Interdisciplinary Research Unit for Cancer Prevention and Treatment, Normandie Université, 14000 Caen, France
- Correspondence:
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [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: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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Daks A, Vasileva E, Fedorova O, Shuvalov O, Barlev NA. The Role of Lysine Methyltransferase SET7/9 in Proliferation and Cell Stress Response. Life (Basel) 2022; 12:life12030362. [PMID: 35330113 PMCID: PMC8949485 DOI: 10.3390/life12030362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 12/14/2022] Open
Abstract
Lysine-specific methyltransferase 7 (KMT7) SET7/9, aka Set7, Set9, or SetD7, or KMT5 was discovered 20 years ago, yet its biological role remains rather enigmatic. In this review, we analyze the particularities of SET7/9 enzymatic activity and substrate specificity with respect to its biological importance, mostly focusing on its two well-characterized biological functions: cellular proliferation and stress response.
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Affiliation(s)
- Alexandra Daks
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Elena Vasileva
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
- Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA
| | - Olga Fedorova
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Oleg Shuvalov
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Nickolai A. Barlev
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
- Correspondence:
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Hasebe T, Fujimoto K, Ishizuya-Oka A. Essential roles of YAP-TEAD complex in adult stem cell development during thyroid hormone-induced intestinal remodeling of Xenopus laevis. Cell Tissue Res 2022; 388:313-329. [PMID: 35211820 DOI: 10.1007/s00441-022-03600-5] [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: 08/17/2021] [Accepted: 02/16/2022] [Indexed: 11/24/2022]
Abstract
During amphibian metamorphosis which is triggered by thyroid hormone (TH), the small intestine is extensively remodeled from the larval to adult form. In the Xenopus laevis intestine, some of the larval epithelial cells dedifferentiate into adult stem cells, which newly form the adult epithelium similar to the mammalian one. We have previously shown that TH-activated Shh, Wnt and Notch signaling pathways play important roles in adult epithelial development. Here we focus on the Hippo signaling pathway, which is known to interact with these pathways in the mammalian intestine. Our quantitative RT-PCR analysis indicates that the expression of genes involved in this pathway including YAP1, TAZ, TEAD1 and core kinases is differently regulated by TH in the metamorphosing intestine. Additionally, we show by in situ hybridization and immunohistochemistry that the transcriptional co-activator YAP1, a major effector of the Hippo signaling, is expressed in the adult stem cells and connective tissue cells surrounding them and that YAP1 protein is localized in either nucleus or cytoplasm of the stem cells. We further show that YAP1 binds its binding partner TEAD1 (transcription factor) in vivo and that their interaction is inhibited by verteporfin (VP). More importantly, by using VP in organ culture of the tadpole intestine, we experimentally demonstrate that the inhibition of YAP1-TEAD1 interaction decreases both TH-induced stem cells expressing LGR5 and nearby connective tissue cells in number and proliferation, leading to the failure of adult epithelial development. Our results indicate that YAP-TEAD complex is required for stem cell development during intestinal remodeling.
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Affiliation(s)
- Takashi Hasebe
- Department of Biology, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo, 180-0023, Japan.
| | - Kenta Fujimoto
- Department of Biology, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo, 180-0023, Japan
| | - Atsuko Ishizuya-Oka
- Department of Biology, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo, 180-0023, Japan
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Qiu T, Zhang D, Xu J, Li X, Wang D, Zhao F, Qian Y, Xu J, Xu T, Zhang H, Chen X. Yes-associated protein gene overexpression regulated by β-catenin promotes gastric cancer cell tumorigenesi. Technol Health Care 2022; 30:425-440. [PMID: 35124617 PMCID: PMC9028613 DOI: 10.3233/thc-thc228039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Yes-associated protein (YAP) has been reported to act as a candidate human oncogene and played a critical role in the development of multiple cancer types. OBJECTIVE: We aimed to investigate the expression, function, and underlying mechanisms of YAP in gastric cancer (GC). METHODS: Expression levels of YAP in gastric tissues were tested. CCK8 assay, clonogenic assay, apoptosis assay, transwell assay, cell scratch assay and animal study were conducted to explore the function of YAP. Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay were performed to explore the underlying mechanism. Survival analysis was carried out to reveal the relationship between YAP and clinical outcome. RESULTS: YAP was upregulated in gastric cancer tissues and correlates with poor prognosis. YAP could promote GC cells proliferation, metastatic capacity, inhibit GC cells apoptosis in vitro and in vivo. Bothβ-catenin and YAP were mainly localized withi the tumor cell nuclei. β-catenincould upregulate YAP expression by binding to the promotor region of YAP. Patients with both YAP and β-catenin negetive expression had a better prognosis than others. CONCLUSIONS: YAP overexpression is driven by aberrant Wnt β-catenin signalingand then contributed to the GC tumorigenesis and progression. Thus, YAP might be a potential target for GC treatment.
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Affiliation(s)
- Tianzhu Qiu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Diancai Zhang
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Xu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Li
- Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Deqiang Wang
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fengjiao Zhao
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yingying Qian
- Department of Respiratory, Nanjing First Hospital, Nanjing Medical University Nanjing, Jiangsu, China
| | - Jin Xu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Tongpeng Xu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hao Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaofeng Chen
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Oncology, PuKou Branch Hospital of Jiangsu Province Hospital (NanJing PuKou Central Hospital), Nanjing, Jiangsu, China
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48
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Wang X, Guan Y, Xiang S, Clark KL, Alexander PG, Simonian LE, Deng Y, Lin H. Role of Canonical Wnt/β-Catenin Pathway in Regulating Chondrocytic Hypertrophy in Mesenchymal Stem Cell-Based Cartilage Tissue Engineering. Front Cell Dev Biol 2022; 10:812081. [PMID: 35141220 PMCID: PMC8820467 DOI: 10.3389/fcell.2022.812081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/06/2022] [Indexed: 01/14/2023] Open
Abstract
In the past 3 decades, the cartilage repair potential of mesenchymal stromal cells, or mesenchymal stem cells (MSCs), has been widely examined in animal studies. Unfortunately, the phenotype and physical properties of MSC-derived cartilage tissue are not comparable to native hyaline cartilage. In particular, chondrocytic hypertrophy, a phenotype that is not observed in healthy hyaline cartilage, is concomitant with MSC chondrogenesis. Given that hypertrophic chondrocytes potentially undergo apoptosis or convert into osteoblasts, this undesired phenotype needs to be prevented or minimized before MSCs can be used to repair cartilage injuries in the clinic. In this review, we first provide an overview of chondrocytic hypertrophy and briefly summarize current methods for suppressing hypertrophy in MSC-derived cartilage. We then highlight recent progress on modulating the canonical Wnt/β-catenin pathway for inhibiting hypertrophy. Specially, we discuss the potential crosstalk between Wnt/β-catenin with other pathways in regulating hypertrophy. Lastly, we explore future perspectives to further understand the role of Wnt/β-catenin in chondrocytic hypertrophy.
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Affiliation(s)
- Xueqi Wang
- Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yiming Guan
- Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shiyu Xiang
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Karen L. Clark
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Peter G. Alexander
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lauren E. Simonian
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Yuhao Deng
- Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Hang Lin, ; Yuhao Deng,
| | - Hang Lin
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- *Correspondence: Hang Lin, ; Yuhao Deng,
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49
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Zarka M, Haÿ E, Cohen-Solal M. YAP/TAZ in Bone and Cartilage Biology. Front Cell Dev Biol 2022; 9:788773. [PMID: 35059398 PMCID: PMC8764375 DOI: 10.3389/fcell.2021.788773] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/23/2021] [Indexed: 12/25/2022] Open
Abstract
YAP and TAZ were initially described as the main regulators of organ growth during development and more recently implicated in bone biology. YAP and TAZ are regulated by mechanical and cytoskeletal cues that lead to the control of cell fate in response to the cellular microenvironment. The mechanical component represents a major signal for bone tissue adaptation and remodelling, so YAP/TAZ contributes significantly in bone and cartilage homeostasis. Recently, mice and cellular models have been developed to investigate the precise roles of YAP/TAZ in bone and cartilage cells, and which appear to be crucial. This review provides an overview of YAP/TAZ regulation and function, notably providing new insights into the role of YAP/TAZ in bone biology.
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Affiliation(s)
- Mylène Zarka
- INSERM UMR 1132 BIOSCAR, Hôpital Lariboisière, Paris, France.,Faculté de Santé, Université de Paris, Paris, France
| | - Eric Haÿ
- INSERM UMR 1132 BIOSCAR, Hôpital Lariboisière, Paris, France.,Faculté de Santé, Université de Paris, Paris, France
| | - Martine Cohen-Solal
- INSERM UMR 1132 BIOSCAR, Hôpital Lariboisière, Paris, France.,Faculté de Santé, Université de Paris, Paris, France
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50
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Antitumor Effect of Sclerostin against Osteosarcoma. Cancers (Basel) 2021; 13:cancers13236015. [PMID: 34885123 PMCID: PMC8656567 DOI: 10.3390/cancers13236015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Osteosarcoma is highly variable and heterogeneous, which is one of the reasons for its resistance to treatment. Because osteosarcoma is defined by abnormal bone formation, we hypothesize its suppression could lead to effective treatment for all types of osteosarcomas. Sclerostin is secreted by osteocytes and inhibits the canonical pathway by binding to LRP5/6, thereby suppressing bone formation. The resulting suppression of bone formation leads to bone loss and osteoporosis. Here, we investigated the antitumor effect of sclerostin against osteosarcoma and found that sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Abstract Various risk factors and causative genes of osteosarcoma have been reported in the literature; however, its etiology remains largely unknown. Bone formation is a shared phenomenon in all types of osteosarcomas, and sclerostin is an extracellular soluble factor secreted by osteocytes that prevents bone formation by inhibiting the Wnt signaling pathway. We aimed to investigate the antitumor effect of sclerostin against osteosarcoma. Osteosarcoma model mice were prepared by transplantation into the dorsal region of C3H/He and BALB/c-nu/nu mice using osteosarcoma cell lines LM8 (murine) and 143B (human), respectively. Cell proliferations were evaluated by using alamarBlue and scratch assays. The migratory ability of the cells was evaluated using a migration assay. Sclerostin was injected intraperitoneally for 7 days to examine the suppression of tumor size and extension of survival. The administration of sclerostin to osteosarcoma cells significantly inhibited the growth and migratory ability of osteosarcoma cells. Kaplan–Meier curves and survival data demonstrated that sclerostin significantly inhibited tumor growth and improved survival. Sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Osteosarcoma model mice inhibited tumor growth and prolonged survival periods by the administration of sclerostin. The effect of existing anticancer drugs such as doxorubicin should be investigated for future clinical applications.
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