|
1
|
Rodríguez-Gimeno A, Galdeano C. Drug Discovery Approaches to Target E3 Ligases. Chembiochem 2025; 26:e202400656. [PMID: 39686906 DOI: 10.1002/cbic.202400656] [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: 08/07/2024] [Revised: 10/31/2024] [Indexed: 12/18/2024]
Abstract
Targeting E3 ligases is a challenging area in drug discovery. Despite the human genome encoding for more than 600 E3 ubiquitin ligases, only a handful of E3 ligases have been pharmacologically modulated or exploited for targeted protein degradation (TPD) strategies. The main obstacle for hijacking these E3 ligases is the lack of small-molecule ligands. As research into this field advances, the identification of new small molecules capable of binding to E3 ligases has become an essential pursuit. These ligases not only expand the repertoire of druggable targets but also offer the potential for increased specificity and selectivity in protein degradation. The synergy between academia and industry is key, as it combines academic expertise in fundamental research with the industrial capabilities of translating these findings into novel therapeutics. In this review, we provide an overview of the different strategies employed in academia and industry to the discovery of new E3 ligases ligands, showing them with illustrative cases.
Collapse
Affiliation(s)
- Alejandra Rodríguez-Gimeno
- Department de Farmacia I Tecnología Farmacèutica, I Fisicoquímica, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
- Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
| | - Carles Galdeano
- Department de Farmacia I Tecnología Farmacèutica, I Fisicoquímica, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
- Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
| |
Collapse
|
|
2
|
Harris TJ, Trader DJ. Exploration of degrons and their ability to mediate targeted protein degradation. RSC Med Chem 2025:d4md00787e. [PMID: 39867589 PMCID: PMC11758578 DOI: 10.1039/d4md00787e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/12/2024] [Indexed: 01/28/2025] Open
Abstract
Degrons are short amino acid sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with the ubiquitin proteasome system (UPS). These amino acid sequences are often found in exposed regions of proteins serving as either a tethering point for an interaction with an E3 ligase or initiating signaling for the direct degradation of the protein. Recent advancements in the protein degradation field have shown the therapeutic potential of both classes of degrons through leveraging their degradative effects to engage specific protein targets. This review explores what targeted protein degradation applications degrons can be used in and how they have inspired new degrader technology to target a wide variety of protein substrates.
Collapse
Affiliation(s)
- Timothy J Harris
- Department of Pharmaceutical Sciences, University of California Irvine California 92617 USA
| | - Darci J Trader
- Department of Pharmaceutical Sciences, University of California Irvine California 92617 USA
- Department of Chemistry, University of California Irvine California 92617 USA
| |
Collapse
|
|
3
|
Yang J, Lim JT, Victor P, Corona MG, Chen C, Khawaja H, Pan Q, Paine-Murrieta GD, Schnellmann RG, Roe DJ, Gokhale PC, DeCaprio JA, Padi M. Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.01.565218. [PMID: 37961132 PMCID: PMC10635082 DOI: 10.1101/2023.11.01.565218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.
Collapse
Affiliation(s)
- Jiawen Yang
- University of Arizona Cancer Center, Tucson, Arizona, USA
| | - James T. Lim
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
| | - Paul Victor
- Department of Pharmacology and Toxicology, The University of Arizona R. Ken Coit College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona, USA
| | | | - Chen Chen
- University of Arizona Cancer Center, Tucson, Arizona, USA
- Department of Epidemiology and Biostatistics, University of Arizona Mel and Enid Zuckerman College of Public Health, Tucson, AZ, USA
| | - Hunain Khawaja
- University of Arizona Cancer Center, Tucson, Arizona, USA
| | - Qiong Pan
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
| | | | - Rick G. Schnellmann
- Department of Pharmacology and Toxicology, The University of Arizona R. Ken Coit College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona, USA
- The University of Arizona College of Medicine, Tucson, Arizona, USA
- The University of Arizona, BIO5 Institute, Tucson, Arizona, USA
- Southern Arizona VA Health Care System, USA
| | - Denise J. Roe
- Department of Epidemiology and Biostatistics, University of Arizona Mel and Enid Zuckerman College of Public Health, Tucson, AZ, USA
| | - Prafulla C. Gokhale
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - James A. DeCaprio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Megha Padi
- University of Arizona Cancer Center, Tucson, Arizona, USA
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
| |
Collapse
|
|
4
|
Hewer E, Fischer PD, Vassella E, Knabben L, Imboden S, Mueller MD, Rau TT, Dettmer MS. Lymphoid enhancer-binding factor 1 (LEF1) immunostaining as a surrogate for β-catenin ( CTNNB1) mutations. J Clin Pathol 2024:jcp-2024-209695. [PMID: 39653501 DOI: 10.1136/jcp-2024-209695] [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: 06/06/2024] [Accepted: 09/07/2024] [Indexed: 01/12/2025]
Abstract
AIMS Mutations affecting exon 3 of the β-catenin (CTNNB1) gene result in constitutive activation of WNT signalling and are a diagnostic hallmark of several tumour entities including desmoid-type fibromatosis. They also define clinically relevant tumour subtypes within certain entities, such as endometrioid carcinoma. In diagnostics, β-catenin immunohistochemistry is widely used as a surrogate for CTNNB1 mutations. Yet, it is often difficult to assess in practice, given that the characteristic nuclear translocation may be focal or hard to distinguish from the spillover of the normal membranous staining. METHODS We therefore examined lymphoid enhancer-binding factor 1 (LEF1) immunostaining, a nuclear marker of WNT activation that serves as a potential surrogate for CTNNB1 mutations. RESULTS In a cohort of endometrial carcinomas with known mutation status (n=130) LEF1 was 85% accurate in predicting CTNNB1 mutation status (64% sensitivity, 90% specificity) while β-catenin was 76% accurate (72% sensitivity; 77% specificity). Across a variety of entities characterised by CTNNB1 mutations as putative drivers, we found diffuse and strong expression of LEF1 in 77% of cases. LEF1 immunostaining proved easier to interpret than β-catenin immunostaining in 54% of cases, more difficult in 1% of cases and comparable in the remaining cases. CONCLUSION We conclude that LEF1 immunostaining is a useful surrogate marker for CTNNB1 mutations. It favourably complements β-catenin immunohistochemistry and outperforms the latter as a single marker.
Collapse
Affiliation(s)
- Ekkehard Hewer
- Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Pascal David Fischer
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Erik Vassella
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Laura Knabben
- Department of Gynaecology and Obstetrics, Bern University Hospital and University of Bern, Bern, Switzerland, Bern, Switzerland
| | - Sara Imboden
- Department of Gynaecology and Obstetrics, Bern University Hospital and University of Bern, Bern, Switzerland, Bern, Switzerland
| | - Michael D Mueller
- Department of Gynaecology and Obstetrics, Bern University Hospital and University of Bern, Bern, Switzerland, Bern, Switzerland
| | - Tilman T Rau
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany
| | - Matthias S Dettmer
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology, Klinikum Stuttgart, Stuttgart, Germany
| |
Collapse
|
|
5
|
Hirsch RM, Premsankar S, Kurnit KC, Chiou LF, Rabjohns EM, Lee HN, Broaddus RR, Vaziri C, Bowser JL. CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.624183. [PMID: 39605508 PMCID: PMC11601622 DOI: 10.1101/2024.11.18.624183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Missense mutations in exon 3 of CTNNB1, the gene encoding β-catenin, are associated with poor outcomes in endometrial carcinomas (EC). Clinically, CTNNB1 mutation status has been difficult to use as a predictive biomarker as β-catenin oncogenic activity is modified by other factors, and these determinants are unknown. Here we reveal that CD73 restrains the oncogenic activity of exon 3 β-catenin mutants, and its loss associates with recurrence. Using 7 patient-specific mutants, with genetic deletion or ectopic expression of CD73, we show that CD73 loss increases β-catenin-TCF/LEF transcriptional activity. In cells lacking CD73, membrane levels of mutant β-catenin decreased which corresponded with increased levels of nuclear and chromatin-bound mutant β-catenin. These results suggest CD73 sequesters mutant β-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied increased β-catenin-TCF/LEF activity seen with NT5E deletion, suggesting that the effect of CD73 loss on mutant β-catenin is mediated via attenuation of adenosine receptor signaling. RNA-seq analyses revealed that NT5E deletion alone drives pro-tumor Wnt/β-catenin gene expression and, with CD73 loss, β-catenin mutants dysregulate zinc-finger and non-coding RNA gene expression. We identify CD73 as a novel regulator of oncogenic β-catenin and help explain variability in patient outcomes in CTNNB1 mutant EC.
Collapse
Affiliation(s)
- Rebecca M. Hirsch
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Sunthoshini Premsankar
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Chancellor’s Science Scholars Program, University of North Carolina, Chapel Hill, NC, USA
| | - Katherine C. Kurnit
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA
| | - Lilly F. Chiou
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA
| | - Emily M. Rabjohns
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- Curriculum in Pathobiology and Translational Science, University of North Carolina, Chapel Hill, NC, USA
| | - Hannah N. Lee
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Russell R. Broaddus
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jessica L. Bowser
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| |
Collapse
|
|
6
|
Ferreira JM, Gonçalves CS, Costa BM. Emerging roles and biomarker potential of WNT6 in human cancers. Cell Commun Signal 2024; 22:538. [PMID: 39529066 PMCID: PMC11552340 DOI: 10.1186/s12964-024-01892-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024] Open
Abstract
The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies.
Collapse
Affiliation(s)
- Joana M Ferreira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Céline S Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bruno M Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, 4710-057, Portugal.
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| |
Collapse
|
|
7
|
Tümen D, Heumann P, Huber J, Hahn N, Macek C, Ernst M, Kandulski A, Kunst C, Gülow K. Unraveling Cancer's Wnt Signaling: Dynamic Control through Protein Kinase Regulation. Cancers (Basel) 2024; 16:2686. [PMID: 39123414 PMCID: PMC11312265 DOI: 10.3390/cancers16152686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/25/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Since the initial identification of oncogenic Wnt in mice and Drosophila, the Wnt signaling pathway has been subjected to thorough and extensive investigation. Persistent activation of Wnt signaling exerts diverse cancer characteristics, encompassing tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis. Here we review the principal signaling mechanisms and the regulatory influence of pathway-intrinsic and extrinsic kinases on cancer progression. Additionally, we underscore the divergences and intricate interplays of the canonical and non-canonical Wnt signaling pathways and their critical influence in cancer pathophysiology, exhibiting both growth-promoting and growth-suppressing roles across diverse cancer types.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (D.T.); (N.H.)
| |
Collapse
|
|
8
|
Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
Collapse
Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| |
Collapse
|
|
9
|
Huang Q, Xiao Y, Lan T, Lu Y, Huang L, Zheng D. WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling. Int J Oral Sci 2024; 16:7. [PMID: 38246919 PMCID: PMC10800352 DOI: 10.1038/s41368-024-00279-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/01/2024] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor progression. These findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.
Collapse
Affiliation(s)
- Qingling Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yi Xiao
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Ting Lan
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Youguang Lu
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Li Huang
- Department of Dentistry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
| | - Dali Zheng
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
| |
Collapse
|
|
10
|
Uppalapati SS, Guha L, Kumar H, Mandoli A. Nanotechnological Advancements for the Theranostic Intervention in Anaplastic Thyroid Cancer: Current Perspectives and Future Direction. Curr Cancer Drug Targets 2024; 24:245-270. [PMID: 37424349 DOI: 10.2174/1568009623666230707155145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/30/2023] [Accepted: 06/08/2023] [Indexed: 07/11/2023]
Abstract
Anaplastic thyroid cancer is the rarest, most aggressive, and undifferentiated class of thyroid cancer, accounting for nearly forty percent of all thyroid cancer-related deaths. It is caused by alterations in many cellular pathways like MAPK, PI3K/AKT/mTOR, ALK, Wnt activation, and TP53 inactivation. Although many treatment strategies, such as radiation therapy and chemotherapy, have been proposed to treat anaplastic thyroid carcinoma, they are usually accompanied by concerns such as resistance, which may lead to the lethality of the patient. The emerging nanotechnology-based approaches cater the purposes such as targeted drug delivery and modulation in drug release patterns based on internal or external stimuli, leading to an increase in drug concentration at the site of the action that gives the required therapeutic action as well as modulation in diagnostic intervention with the help of dye property materials. Nanotechnological platforms like liposomes, micelles, dendrimers, exosomes, and various nanoparticles are available and are of high research interest for therapeutic intervention in anaplastic thyroid cancer. The pro gression of the disease can also be traced by using magnetic probes or radio-labeled probes and quantum dots that serve as a diagnostic intervention in anaplastic thyroid cancer.
Collapse
Affiliation(s)
- Sai Swetha Uppalapati
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, India
| | - Lahanya Guha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, India
| | - Amit Mandoli
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, India
| |
Collapse
|
|
11
|
Lin X, Meng X, Lin J. The possible role of Wnt/β-catenin signalling in vitiligo treatment. J Eur Acad Dermatol Venereol 2023; 37:2208-2221. [PMID: 36912722 DOI: 10.1111/jdv.19022] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 02/08/2023] [Indexed: 03/14/2023]
Abstract
Vitiligo is a common chronic skin disease which has an adverse impact on patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote melanocytes to repigmentation. Wnt/β-catenin signalling pathway has been of recent interest in vitiligo. Wnt/β-catenin signalling pathway is downregulated in vitiligo. Upregulation of Wnt/β-catenin signalling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/β-catenin signalling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/β-catenin signalling can not only arrest the progress of active disease of vitiligo but also promote repigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/β-catenin signalling. Agents that can enhance the effect of Wnt/β-catenin signalling may become potential candidates for the development of new drugs for vitiligo treatment.
Collapse
Affiliation(s)
- Xiran Lin
- Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xianmin Meng
- Department of Pathology and Laboratory Medicine, Axia Women's Health, Oaks, Pennsylvania, USA
| | - Jingrong Lin
- Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| |
Collapse
|
|
12
|
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: 6] [Impact Index Per Article: 3.0] [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.
Collapse
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
| |
Collapse
|
|
13
|
Papatheodoridi A, Papatheodoridis G. Hepatocellular carcinoma: The virus or the liver? Liver Int 2023; 43 Suppl 1:22-30. [PMID: 35319167 DOI: 10.1111/liv.15253] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/28/2022] [Accepted: 03/19/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) represents a major public health problem being one of the most common causes of cancer-related deaths worldwide. Hepatitis B (HBV) and C viruses have been classified as oncoviruses and are responsible for the majority of HCC cases, while the role of hepatitis D virus (HDV) in liver carcinogenesis has not been elucidated. HDV/HBV coinfection is related to more severe liver damage than HBV mono-infection and recent studies suggest that HDV/HBV patients are at increased risk of developing HCC compared to HBV mono-infected patients. HBV is known to promote hepatocarcinogenesis via DNA integration into host DNA, disruption of molecular pathways by regulatory HBV x (HBx) protein and excessive oxidative stress. Recently, several molecular mechanisms have been proposed to clarify the pathogenesis of HDV-related HCC including activation of signalling pathways by specific HDV antigens, epigenetic dysregulation and altered gene expression. Alongside, ongoing chronic inflammation and impaired immune responses have also been suggested to facilitate carcinogenesis. Finally, cellular senescence seems to play an important role in chronic viral infection and inflammation leading to hepatocarcinogenesis. In this review, we summarize the current literature on the impact of HDV in HCC development and discuss the potential interplay between HBV, HDV and neighbouring liver tissue in liver carcinogenesis.
Collapse
Affiliation(s)
- Alkistis Papatheodoridi
- Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, "Alexandra" General Hospital of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
| |
Collapse
|
|
14
|
Cosgun KN, Jumaa H, Robinson ME, Kistner KM, Xu L, Xiao G, Chan LN, Lee J, Kume K, Leveille E, Fonseca-Arce D, Khanduja D, Ng HL, Feldhahn N, Song J, Chan WC, Chen J, Taketo MM, Kothari S, Davids MS, Schjerven H, Jellusova J, Müschen M. Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.13.532152. [PMID: 36993619 PMCID: PMC10054980 DOI: 10.1101/2023.03.13.532152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
UNLABELLED In most cell types, nuclear β-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of β-catenin but critically depended on GSK3β for effective β-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that β-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, β-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive β-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3β small molecule inhibitors to subvert β-catenin degradation. Clinically approved GSK3β-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of β-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3β-inhibitors for targeted engagement of lymphoid-specific β-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTS Unlike other cell lineages, B-cells express nuclear β-catenin protein at low baseline levels and depend on GSK3β for its degradation.In B-cells, β-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed β-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3β-dependent degradation of β-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3β-inhibitors for the treatment of refractory B-cell malignancies. GRAPHICAL ABSTRACT Abundant nuclear β-cateninβ-catenin pairs with TCF7 factors for transcriptional activation of MYCB-cells rely on efficient degradation of β-catenin by GSK3βB-cell-specific expression of Ikaros factors Unique vulnerability in B-cell tumors: GSK3β-inhibitors induce nuclear accumulation of β-catenin.β-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC.
Collapse
|
|
15
|
Muto S, Enta A, Maruya Y, Inomata S, Yamaguchi H, Mine H, Takagi H, Ozaki Y, Watanabe M, Inoue T, Yamaura T, Fukuhara M, Okabe N, Matsumura Y, Hasegawa T, Osugi J, Hoshino M, Higuchi M, Shio Y, Hamada K, Suzuki H. Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers. Biomedicines 2023; 11:biomedicines11010190. [PMID: 36672698 PMCID: PMC9855612 DOI: 10.3390/biomedicines11010190] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/β-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/β-catenin signaling. First, we will review the molecular biology of Wnt/β-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.
Collapse
Affiliation(s)
- Satoshi Muto
- Correspondence: ; Tel.: +81-24-547-1252; Fax: +81-24-548-2735
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Pagano E, Romano B, Cicia D, Iannotti FA, Venneri T, Lucariello G, Nanì MF, Cattaneo F, De Cicco P, D'Armiento M, De Luca M, Lionetti R, Lama S, Stiuso P, Zoppoli P, Falco G, Marchianò S, Fiorucci S, Capasso R, Di Marzo V, Borrelli F, Izzo AA. TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β-catenin signalling. Br J Pharmacol 2023; 180:235-251. [PMID: 36168728 PMCID: PMC10092658 DOI: 10.1111/bph.15960] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/22/2022] [Accepted: 09/09/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC). EXPERIMENTAL APPROACH TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8-/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC. KEY RESULTS TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1. CONCLUSION AND IMPLICATIONS Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.
Collapse
Affiliation(s)
- Ester Pagano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Barbara Romano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Donatella Cicia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabio A Iannotti
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy
| | - Tommaso Venneri
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppe Lucariello
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Francesca Nanì
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabio Cattaneo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Paola De Cicco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria D'Armiento
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Marcello De Luca
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Ruggiero Lionetti
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Stefania Lama
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Paola Stiuso
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pietro Zoppoli
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Geppino Falco
- Istituto di Ricerche Genetiche Gaetano Salvatore Biogem Scarl, Ariano Irpino, Italy.,Department of Biology, University of Naples Federico II, Naples, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - Vincenzo Di Marzo
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy.,Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, Canada.,Centre de Recherche de l'Institut de Pneumologie et Cardiologie de l'Université Laval, Faculté de Médecine, Université Laval, Québec, Canada.,Canada Research Excellence Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada
| | - Francesca Borrelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| |
Collapse
|
|
17
|
Yang G. Microsatellite instability/mismatch repair deficiency and activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland: A case report. Medicine (Baltimore) 2022; 101:e30311. [PMID: 36042639 PMCID: PMC9410697 DOI: 10.1097/md.0000000000030311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
RATIONALE Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated variant of gastric adenocarcinoma, which has been proposed as a novel disease entity. As a result of mismatch repair deficiency, microsatellite instability has been frequently observed in various human cancers and widely performed in the area of cancer pathogenesis. Herein, we report a case of gastric adenocarcinoma of fundic gland presented with microsatellite instability phenotype. PATIENT CONCERNS A 46-year-old man was referred to our hospital for abdominal distension and pain. DIAGNOSIS The patient contained 3 tumor lesions with different degrees of histologic differentiation and microsatellite instability. The lesions were located in the upper third of the stomach. The tumor size was 55 mm. Macroscopically, tumor showed an ulcerative type. In terms of depth of invasion, tumor lesion invaded into subserosa with lymphatic invasion. In addition, this patient did not present GNAS mutation but harbored AXIN2 mutation. By immunohistochemistry, the expression level of β-catenin protein in the nucleus of the carcinoma cells was obviously higher than that in normal nucleus. Compared with microsatellite instability-low lesion, PD-1, PD-L1, and CD8 were positive in the microsatellite instability-high lesions. INTERVENTIONS The patient underwent surgical resection and postoperative chemotherapy. OUTCOMES The patient experienced distant metastasis and died from severe complications after 6 months of treatment. LESSONS These results suggested that the mutation of Wnt component genes associated with Wnt/β-catenin signaling pathway activation may play a role in promoting the occurrence of gastric adenocarcinoma of fundic gland. This is the first report of a gastric adenocarcinoma of fundic gland with microsatellite instability. These findings modify our understanding of the pathophysiology of gastric adenocarcinoma of fundic gland.
Collapse
Affiliation(s)
- Guang Yang
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama university, Okayama, Japan
- Department of Pathology, Mudanjiang Medical University, Mudanjiang, China
- *Correspondence: Guang Yang, 2-5-1, Shikata-cho, Kita-ku, Okayama-city, Okayama 700-8558, Japan (e-mail: )
| |
Collapse
|
|
18
|
Kurnit KC, Fellman BM, Mills GB, Bowser JL, Xie S, Broaddus RR. Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic CTNNB1 mutation on recurrence-free survival. Int J Gynecol Cancer 2022; 32:869-874. [PMID: 35483739 PMCID: PMC10811601 DOI: 10.1136/ijgc-2021-003340] [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] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE The primary objective of this study was to determine whether women whose tumors harbor a somatic CTNNB1 mutation have longer recurrence-free survival if they receive traditional adjuvant therapy strategies compared with those who do not. METHODS A retrospective, stage I endometrial cancer cohort from MD Anderson Cancer Center was assessed. Clinical and pathological characteristics and type of adjuvant therapy (cuff brachytherapy, pelvic radiation, chemotherapy) were obtained by review of medical records. CTNNB1 exon 3 sequencing was performed. Summary statistics were calculated, and recurrence-free survival was measured using the Kaplan-Meier product-limit estimator. RESULTS The analysis included 253 patients, 245 with information regarding adjuvant therapy. Most patients had tumors of endometrioid histology (210/253, 83%) with superficial myometrial invasion (197/250, 79%) and no lymphatic/vascular space invasion (168/247, 68%). Tumor CTNNB1 mutations were present in 45 (18%) patients. Patients receiving adjuvant therapy were more likely to have higher-grade tumors, non-endometrioid histology, deep myometrial invasion, and lymphatic/vascular invasion. For patients with low-risk features not receiving adjuvant therapy, the presence of CTNNB1 mutation did not significantly impact recurrence-free survival (11.3 years wild-type vs 8.1 years mutant, p=0.65). The cohort was then limited to intermediate-risk tumors, defined as endometrioid histology of any grade with deep myometrial invasion and/or lymphatic/vascular space invasion. When recurrence-free survival was stratified by CTNNB1 mutation status and adjuvant therapy, patients with CTNNB1 mutations and no adjuvant therapy had the shortest recurrence-free survival at 1.6 years, followed by patients with CTNNB1 mutations who received adjuvant therapy (4.0 years), and wild-type CTNNB1 with and without adjuvant therapy (8.5 and 7.2 years, respectively) (comparison for all four groups, p=0.01). CONCLUSION In patients with intermediate-risk endometrioid endometrial cancers, the use of adjuvant therapy was associated with an improvement in recurrence-free survival for patients with tumor mutations in CTNNB1.
Collapse
Affiliation(s)
- Katherine C Kurnit
- Department of Obstetrics and Gynecology, University of Chicago Biological Sciences Division, Chicago, Illinois, USA
| | - Bryan M Fellman
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gordon B Mills
- Division of Oncologic Sciences Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Jessica L Bowser
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - SuSu Xie
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Russell R Broaddus
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
19
|
Abstract
Craniopharyngioma (CP) is an intracranial benign tumor that behaves aggressively due to its location, infiltration of the surrounding nervous tissue and high capacity for recurrence. Treatment of choice is surgery followed or not by radiotherapy. Recent advances in molecular biology techniques and the better understanding of the genetic alterations of the two histological types of CP have open new therapeutic perspectives with targeted drugs. Adamantinomatous CP (ACP) is associated with activating mutations of the CTNNB1 gene. Such mutations are accompanied by intracellular accumulation of β-catenin, an oncogenic protein that activates the intracellular Wnt/ β-catenin signaling pathway, which regulates the transcription of genes involved in cell proliferation. Therefore, the use of molecular therapies directed against the activation of the Wnt/ β-catenin pathway could be an attractive and promising therapeutic option in the management of ACPs. On the other hand, papillary CP (PCP) is associated with activating mutations in the BRAF gene. This gene encodes a BRAF protein that plays an important role in the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, which also regulates cell proliferation. The use of BRAF inhibitors either in monotherapy or in combination with mitogen-activated protein kinase (MEK) inhibitors has demonstrated therapeutic efficacy in isolated clinical cases of relapsed PCPs. A preliminary report of a recent phase II clinical trial has shown a therapeutic response in 93.7% of patients with BRAF V600E -mutated PCP, with an 85% reduction in tumor size. In the present review we comment on the efficacy and safety of the different drugs being used in patients with PCP.
Collapse
Affiliation(s)
- Pedro Iglesias
- Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro Segovia de Arana (IDIPHISA), Calle Manuel de Falla 1, 28222, Madrid, Spain.
| |
Collapse
|
|
20
|
Guendisch U, Loos B, Cheng PF, Dummer R, Levesque MP, Varum S, Sommer L. Loss of YY1, a Regulator of Metabolism in Melanoma, Drives Melanoma Cell Invasiveness and Metastasis Formation. Front Cell Dev Biol 2022; 10:916033. [PMID: 35693944 PMCID: PMC9178194 DOI: 10.3389/fcell.2022.916033] [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] [Received: 04/08/2022] [Accepted: 05/09/2022] [Indexed: 11/19/2022] Open
Abstract
Deregulation of cellular metabolism through metabolic rewiring and translational reprogramming are considered hallmark traits of tumor development and malignant progression. The transcription factor YY1 is a master regulator of metabolism that we have previously shown to orchestrate a metabolic program required for melanoma formation. In this study, we demonstrate that YY1, while being essential for primary melanoma formation, suppresses metastatic spreading. Its downregulation or loss resulted in the induction of an invasiveness gene program and sensitized melanoma cells for pro-invasive signaling molecules, such as TGF-β. In addition, NGFR, a key effector in melanoma invasion and phenotype switching, was among the most upregulated genes after YY1 knockdown. High levels of NGFR were also associated with other metabolic stress inducers, further indicating that YY1 knockdown mimics a metabolic stress program associated with an increased invasion potential in melanoma. Accordingly, while counteracting tumor growth, loss of YY1 strongly promoted melanoma cell invasiveness in vitro and metastasis formation in melanoma mouse models in vivo. Thus, our findings show that the metabolic regulator YY1 controls phenotype switching in melanoma.
Collapse
Affiliation(s)
- Ulf Guendisch
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Benjamin Loos
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Phil F. Cheng
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Sandra Varum
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Lukas Sommer
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
- *Correspondence: Lukas Sommer,
| |
Collapse
|
|
21
|
Cowan AD, Ciulli A. Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory. Annu Rev Biochem 2022; 91:295-319. [PMID: 35320687 DOI: 10.1146/annurev-biochem-032620-104421] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin-proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein-protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapse
Affiliation(s)
- Angus D Cowan
- Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, United Kingdom;
| | - Alessio Ciulli
- Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, United Kingdom;
| |
Collapse
|
|
22
|
Abstract
The Wnt pathway is central to a host of developmental and disease-related processes. The remarkable conservation of this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity to regulate the generation and spatial arrangement of distinct cell types. By regulating cell fate specification, mitotic activity, and cell polarity, Wnt signaling orchestrates development and tissue homeostasis, and its dysregulation is implicated in developmental defects, cancer, and degenerative disorders. We review advances in our understanding of this key pathway, from Wnt protein production and secretion to relay of the signal in the cytoplasm of the receiving cell. We discuss the evolutionary history of this pathway as well as endogenous and synthetic modulators of its activity. Finally, we highlight remaining gaps in our knowledge of Wnt signal transduction and avenues for future research. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapse
Affiliation(s)
- Ellen Youngsoo Rim
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
| | - Hans Clevers
- Hubrecht Institute and Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands
| | - Roel Nusse
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
| |
Collapse
|
|
23
|
Karagiannakos A, Adamaki M, Tsintarakis A, Vojtesek B, Fåhraeus R, Zoumpourlis V, Karakostis K. Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets. Cancers (Basel) 2022; 14:cancers14030664. [PMID: 35158934 PMCID: PMC8833388 DOI: 10.3390/cancers14030664] [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: 12/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.
Collapse
Affiliation(s)
- Alexandros Karagiannakos
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; (A.K.); (M.A.); (A.T.)
| | - Maria Adamaki
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; (A.K.); (M.A.); (A.T.)
| | - Antonis Tsintarakis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; (A.K.); (M.A.); (A.T.)
| | - Borek Vojtesek
- Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic; (B.V.); (R.F.)
| | - Robin Fåhraeus
- Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic; (B.V.); (R.F.)
- Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, F-75010 Paris, France
- Department of Medical Biosciences, Umeå University, 90185 Umeå, Sweden
- International Centre for Cancer Vaccine Science, University of Gdansk, 80-822 Gdansk, Poland
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; (A.K.); (M.A.); (A.T.)
- Correspondence: (V.Z.); (K.K.)
| | - Konstantinos Karakostis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; (A.K.); (M.A.); (A.T.)
- Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, F-75010 Paris, France
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Correspondence: (V.Z.); (K.K.)
| |
Collapse
|
|
24
|
Alaña L, Nunes-Xavier CE, Zaldumbide L, Martin-Guerrero I, Mosteiro L, Alba-Pavón P, Villate O, García-Obregón S, González-García H, Herraiz R, Astigarraga I, Pulido R, García-Ariza M. Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma. Cancers (Basel) 2022; 14:cancers14020421. [PMID: 35053583 PMCID: PMC8773623 DOI: 10.3390/cancers14020421] [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] [Received: 12/14/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary We have analyzed a panel of 88 pediatric medulloblastoma tumors for exon 3 mutations from the CTNNB1 gene and identified eight missense point-mutations and one in-frame deletion. We describe and functionally characterize a novel CTNNB1 in-frame deletion (c.109-111del, pSer37del, ΔS37) found in a pediatric patient with a classic medulloblastoma, WNT-activated grade IV (WHO 2016). To the best of our knowledge, this mutation has not been previously reported in medulloblastoma, and it is uncertain its role in the disease development and progression. Our analysis discloses gain-of-function properties for the new ΔS37 β-catenin variant. Abstract Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear β-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of β-catenin Ser37 residue (ΔS37). The ΔS37 β-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type β-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 β-catenin contributed to early medulloblastoma tumorigenesis.
Collapse
Affiliation(s)
- Lide Alaña
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
- Correspondence: ; Tel.: +34-946-006-000 (ext. 2401)
| | - Caroline E. Nunes-Xavier
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (C.E.N.-X.); (R.P.)
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310 Oslo, Norway
| | - Laura Zaldumbide
- Department of Pathology, Hospital Universitario de Cruces, Osakidetza, Plaza de Cruces 12, 48903 Barakaldo, Spain; (L.Z.); (L.M.)
| | - Idoia Martin-Guerrero
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
- Department of Genetics, Physical Anthropology and Animal Pathology, Faculty of Science and Technology, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain
| | - Lorena Mosteiro
- Department of Pathology, Hospital Universitario de Cruces, Osakidetza, Plaza de Cruces 12, 48903 Barakaldo, Spain; (L.Z.); (L.M.)
| | - Piedad Alba-Pavón
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
| | - Olatz Villate
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
| | - Susana García-Obregón
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
- Department of Physiology, Faculty of Medicine and Nursing, Campus de Leioa, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain
| | - Hermenegildo González-García
- Oncohematology Pediatric Unit, Department of Pediatrics, Hospital Universitario de Valladolid, C/Ramon y Cajal n°3, 47003 Valladolid, Spain; (H.G.-G.); (R.H.)
| | - Raquel Herraiz
- Oncohematology Pediatric Unit, Department of Pediatrics, Hospital Universitario de Valladolid, C/Ramon y Cajal n°3, 47003 Valladolid, Spain; (H.G.-G.); (R.H.)
| | - Itziar Astigarraga
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
- Pediatric Oncohematology Unit, Pediatrics Department, Hospital Universitario Cruces, Osakidetza, Plaza de Cruces 12, 48903 Barakaldo, Spain
- Pediatrics Department, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Plaza de Cruces 12, 48903 Barakaldo, Spain
| | - Rafael Pulido
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (C.E.N.-X.); (R.P.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Miguel García-Ariza
- Pediatric Oncology Group, Biocruces Bizkaia Health Research Institute, Plaza de Cruces 12, 48903 Barakaldo, Spain; (I.M.-G.); (P.A.-P.); (O.V.); (S.G.-O.); (I.A.); (M.G.-A.)
- Pediatric Oncohematology Unit, Pediatrics Department, Hospital Universitario Cruces, Osakidetza, Plaza de Cruces 12, 48903 Barakaldo, Spain
| |
Collapse
|
|
25
|
Recurrent CTNNB1 mutations in craniofacial osteomas. Mod Pathol 2022; 35:489-494. [PMID: 34725446 PMCID: PMC8964415 DOI: 10.1038/s41379-021-00956-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 11/08/2022]
Abstract
Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.1%), harbouring allelic frequencies ranging from 0.04 to 0.53, with the known S45P variant representing the most frequent alteration. Based on NanoString multiplex expression profiling performed in a subset of cases, CTNNB1-mutated osteomas segregated in a defined "WNT-cluster", substantiating functionality of CTNNB1 mutations which are associated with β-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/β-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/β-catenin in osteogenesis. Our study contributes to a better understanding of the molecular pathogenesis underlying osteoma development and establishes a helpful diagnostic molecular marker for morphologically challenging cases.
Collapse
|
|
26
|
UBQLN4 is activated by C/EBPβ and exerts oncogenic effects on colorectal cancer via the Wnt/β-catenin signaling pathway. Cell Death Dis 2021; 7:398. [PMID: 34930912 PMCID: PMC8688525 DOI: 10.1038/s41420-021-00795-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 11/24/2021] [Accepted: 12/10/2021] [Indexed: 01/17/2023]
Abstract
Ubiquilin 4 (UBQLN4) is an important member of the ubiquitin-like protein family. An increasing number of studies have shown that UBQLN4 is an important regulator of tumorigenesis. Nevertheless, the biological function and detailed mechanisms of UBQLN4 in colorectal cancer (CRC) development and progression remain unclear. Here, we identified UBQLN4 upregulation in CRC tissues and it is positively associated with CRC size, TNM stage, and lymphatic metastasis. Patients with high UBQLN4 expression had a poor prognosis. Functionally, overexpression of UBQLN4 significantly promoted CRC cell proliferation, migration, and invasion, while UBQLN4 silencing elicited the opposite effect. This result was consistent with the conclusion that UBQLN4 expression correlated positively with the CRC size and lymphatic metastasis. In vivo, UBQLN4 silencing also inhibited tumor growth. Mechanistically, using gene set enrichment analysis (GSEA) and western blot experiments, we identified that UBQLN4 activated the Wnt/β-catenin signaling pathway to upregulate β-catenin and c-Myc expression, thereby promoting CRC proliferation, migration and invasion. A rescue experiment further verified this conclusion. Dual luciferase reporter, real-time quantitative PCR (RT-qPCR), western blot and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) directly bound to the UBQLN4 core promoter region and activated its transcription, upregulating β-catenin and c-Myc expression to promote CRC progression. Thus, our findings suggest that UBQLN4 is a key oncogene in CRC and may be a promising target for the diagnosis and treatment of patients with CRC.
Collapse
|
|
27
|
Perret C. Axel Kahn et la carcinogenèse digestive : de l’oncogenèse ciblée à l’aventure de la β-caténine. Med Sci (Paris) 2021; 37 Hors série n° 2:35-37. [PMID: 34895461 DOI: 10.1051/medsci/2021227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
28
|
Naked cuticle inhibits wingless signaling in Drosophila wing development. Biochem Biophys Res Commun 2021; 576:1-6. [PMID: 34474244 DOI: 10.1016/j.bbrc.2021.08.077] [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: 08/04/2021] [Accepted: 08/26/2021] [Indexed: 11/21/2022]
Abstract
Wnt signaling is one of the major signaling pathways that regulate cell differentiation, tissue patterning and stem cell homeostasis and its dysfunction causes many human diseases, such as cancer. It is of tremendous interests to understand how Wnt signaling is regulated in a precise manner both temporally and spatially. Naked cuticle (Nkd) acts as a negative-feedback inhibitor for Wingless (Wg, a fly Wnt) signaling in Drosophila embryonic development. However, the role of Nkd remains controversial in later fly development, particularly on the canonical Wg pathway. In the present study, we show that nkd is essential for wing pattern formation, such that both gain and loss of nkd result in the disruption of Wg target expression in larvae stage and abnormal adult wing morphologies. Furthermore, we demonstrate that a thirty amino acid fragment in Nkd, identified previously in Wharton lab, is critical for the canonical Wg signaling, but is dispensable for Wg/planar cell polarity pathway. Putting aside the pleiotropic nature of nkd function, i.e. its role in the Decapentaplegic signaling, we conclude that Nkd universally inhibits the canonical Wg pathway across a life span of Drosophila development.
Collapse
|
|
29
|
Zhang Y, Liu Q, Wei W, Zhang G, Yan S, Dai R, Sun Y, Su D, Lv S, Xia Y, Li J, Li C. Bortezomib potentiates antitumor activity of mitoxantrone through dampening Wnt/β-catenin signal pathway in prostate cancer cells. BMC Cancer 2021; 21:1101. [PMID: 34645397 PMCID: PMC8515742 DOI: 10.1186/s12885-021-08841-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 10/05/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown. METHODS Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-Catenin and its target genes were characterized by western blot and Real-time PCR. RESULTS BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-Catenin signaling pathway compared to monotherapy. CONCLUSIONS This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-Catenin signaling pathway in prostate cancer cells.
Collapse
Affiliation(s)
- Ying Zhang
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Qiuzi Liu
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Wei Wei
- Center for Experimental Medicine, School of Public Health, Jining Medical University, Jining, 272067, China
| | - Guoan Zhang
- Institute of Cancer Pathology Research, Jining Medical University, Jining, 272067, China
| | - Siyuan Yan
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Rongrong Dai
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Ying Sun
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Dubo Su
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Shun Lv
- Laboratory animal center, Jining Medical University, Jining, 272067, China
| | - Yong Xia
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China
| | - Jing Li
- Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Changlin Li
- Institute of Precision Medicine, Jining Medical University, Jining, 272067, China.
| |
Collapse
|
|
30
|
Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells. Pharmaceuticals (Basel) 2021; 14:ph14090871. [PMID: 34577571 PMCID: PMC8465904 DOI: 10.3390/ph14090871] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context. This review summarizes the available information on the role of the Wnt/β-catenin pathway and its crosstalk with other signaling pathways in apoptosis induction in cancer cells and presents a modified dual-signal model for the function of β-catenin. Understanding the proapoptotic mechanisms induced by the Wnt/β-catenin pathway could open new therapeutic opportunities.
Collapse
Affiliation(s)
- Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
- Correspondence:
| | - Angel Escamilla-Ramirez
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | | | - Athenea Flores-Najera
- Centro Médico Nacional 20 de Noviembre, Departamento de Cirugía General, Ciudad de Mexico 03229, Mexico;
| | - Arturo Cruz-Salgado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
| |
Collapse
|
|
31
|
Hiremath IS, Goel A, Warrier S, Kumar AP, Sethi G, Garg M. The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies. J Cell Physiol 2021; 237:199-238. [PMID: 34431086 DOI: 10.1002/jcp.30561] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/28/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023]
Abstract
Several signaling pathways have been identified as important for developmental processes. One of such important cascades is the Wnt/β-catenin signaling pathway, which can regulate various physiological processes such as embryonic development, tissue homeostasis, and tissue regeneration; while its dysregulation is implicated in several pathological conditions especially cancers. Interestingly, deregulation of the Wnt/β-catenin pathway has been reported to be closely associated with initiation, progression, metastasis, maintenance of cancer stem cells, and drug resistance in human malignancies. Moreover, several genetic and experimental models support the inhibition of the Wnt/β-catenin pathway to answer the key issues related to cancer development. The present review focuses on different regulators of Wnt pathway and how distinct mutations, deletion, and amplification in these regulators could possibly play an essential role in the development of several cancers such as colorectal, melanoma, breast, lung, and leukemia. Additionally, we also provide insights on diverse classes of inhibitors of the Wnt/β-catenin pathway, which are currently in preclinical and clinical trial against different cancers.
Collapse
Affiliation(s)
- Ishita S Hiremath
- Department of Bioengineering, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Arul Goel
- La Canada High School, La Canada Flintridge, California, USA
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India.,Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Manoj Garg
- Amity Institute of Biotechnology, Amity University, Manesar, Haryana, India
| |
Collapse
|
|
32
|
Van Thillo Q, De Bie J, Seneviratne JA, Demeyer S, Omari S, Balachandran A, Zhai V, Tam WL, Sweron B, Geerdens E, Gielen O, Provost S, Segers H, Boeckx N, Marshall GM, Cheung BB, Isobe K, Kato I, Takita J, Amos TG, Deveson IW, McCalmont H, Lock RB, Oxley EP, Garwood MM, Dickins RA, Uyttebroeck A, Carter DR, Cools J, de Bock CE. Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia. Nat Commun 2021; 12:4164. [PMID: 34230493 PMCID: PMC8260768 DOI: 10.1038/s41467-021-24442-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.
Collapse
Affiliation(s)
- Quentin Van Thillo
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium
| | - Jolien De Bie
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
- Center for Human Genetics, UZ Leuven, Leuven, Belgium
| | - Janith A Seneviratne
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Sofie Demeyer
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium
| | - Sofia Omari
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Anushree Balachandran
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Vicki Zhai
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Wai L Tam
- Technology Innovation Lab, VIB, Gent, Belgium
| | - Bram Sweron
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
| | - Ellen Geerdens
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium
| | - Olga Gielen
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
| | - Sarah Provost
- Department of Human Genetics, KU Leuven, Leuven, Belgium
- Center for Cancer Biology, VIB, Leuven, Belgium
| | - Heidi Segers
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium
| | - Nancy Boeckx
- Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium
| | - Glenn M Marshall
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Belamy B Cheung
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Kiyotaka Isobe
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Itaru Kato
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junko Takita
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Timothy G Amos
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Ira W Deveson
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - Hannah McCalmont
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Richard B Lock
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
| | - Ethan P Oxley
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Maximilian M Garwood
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Ross A Dickins
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Anne Uyttebroeck
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium
| | - Daniel R Carter
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia
- School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia
| | - Jan Cools
- Department of Human Genetics, KU Leuven, Leuven, Belgium.
- Center for Cancer Biology, VIB, Leuven, Belgium.
- Leuvens Kanker Instituut (LKI), KU Leuven - UZ Leuven, Leuven, Belgium.
| | - Charles E de Bock
- Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia.
- School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
| |
Collapse
|
|
33
|
Visani M, Acquaviva G, De Leo A, Sanza V, Merlo L, Maloberti T, Brandes AA, Franceschi E, Di Battista M, Masetti M, Jovine E, Fiorino S, Pession A, Tallini G, de Biase D. Molecular alterations in pancreatic tumors. World J Gastroenterol 2021; 27:2710-2726. [PMID: 34135550 PMCID: PMC8173386 DOI: 10.3748/wjg.v27.i21.2710] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/25/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these “inconclusive” specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.
Collapse
Affiliation(s)
- Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Viviana Sanza
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Lidia Merlo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Alba A Brandes
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Enrico Franceschi
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Monica Di Battista
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Michele Masetti
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Elio Jovine
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna 40133, Italy
| | - Annalisa Pession
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| |
Collapse
|
|
34
|
Nuclear Beta-Catenin Expression in Endometrioid Intraepithelial Neoplasia (Atypical Hyperplasia) Does Not Predict Carcinoma on Subsequent Hysterectomy. Int J Gynecol Pathol 2021; 40:240-247. [PMID: 32897964 DOI: 10.1097/pgp.0000000000000695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Beta-catenin (BC) mutations are associated with a high risk of recurrence in otherwise low-grade, early-stage uterine endometrioid adenocarcinomas. Recent literature suggests nuclear BC expression by immunohistochemistry is highly sensitive and specific for BC mutations. The significance of BC expression in endometrioid intraepithelial neoplasia (EIN/atypical hyperplasia) and its relationship to altered differentiation patterns in EIN has yet to be fully explored. Cases meeting current diagnostic criteria for EIN based on H&E examination were obtained from 2 institutions (years 1999-2014). Patterns of altered differentiation (eg, tubal, squamous morular metaplasia, mucinous, secretory) were noted. Representative blocks were stained for BC, and expression patterns recorded. Follow-up and demographic data was obtained from the electronic medical record. Ninety-six cases were included (84 biopsies, 12 hysterectomies). BC nuclear expression was identified in 41 cases (42.7%), with 33 of 41 demonstrating foci of nonmorular BC staining. BC staining in any component of EIN was not significantly associated with the presence of carcinoma on subsequent hysterectomy (P=0.79). When restricting to nonmorular BC, the results were the same (P=0.56). Cases with tubal differentiation were significantly less likely to demonstrate nonmorular BC than cases with no specific pattern of differentiation (P<0.01). EIN frequently demonstrates BC nuclear positivity, especially in cases without tubal differentiation. BC nuclear expression in EIN does not appear to be associated with an increased likelihood of carcinoma on subsequent hysterectomy. Our results do not support routine use of BC immunohistochemistry as a prognostic biomarker in cases of EIN.
Collapse
|
|
35
|
Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res 2021; 167:105532. [DOI: 10.1016/j.phrs.2021.105532] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/14/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
|
|
36
|
Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/β-Catenin Signaling. Pharm Res 2021; 38:479-490. [PMID: 33646504 DOI: 10.1007/s11095-021-03009-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/19/2021] [Indexed: 10/22/2022]
Abstract
PURPOSE Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/β-catenin signaling that enhances proliferation in melanoma cells. METHODS Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/β-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/β-catenin signaling were examined. RESULTS FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/β-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells. CONCLUSION These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.
Collapse
|
|
37
|
Wang Z, Li Z, Ji H. Direct targeting of β-catenin in the Wnt signaling pathway: Current progress and perspectives. Med Res Rev 2021; 41:2109-2129. [PMID: 33475177 DOI: 10.1002/med.21787] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/30/2020] [Accepted: 01/05/2021] [Indexed: 12/28/2022]
Abstract
Aberrant activation of the Wnt/β-catenin signaling circuit is associated with cancer recurrence and relapse, cancer invasion and metastasis, and cancer immune evasion. Direct targeting of β-catenin, the central hub in this signaling pathway, is a promising strategy to suppress the hyperactive β-catenin signaling but has proven to be highly challenging. Substantial efforts have been made to discover compounds that bind with β-catenin, block β-catenin-mediated protein-protein interactions, and suppress β-catenin signaling. Herein, we characterize potential small-molecule binding sites in β-catenin, summarize bioactive small molecules that directly target β-catenin, and review structure-based inhibitor optimization, structure-activity relationship, and biological activities of reported inhibitors. This knowledge will benefit future inhibitor development and β-catenin-related drug discovery.
Collapse
Affiliation(s)
- Zhen Wang
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Zilu Li
- Department of Chemistry, University of South Florida, Tampa, Florida, USA
| | - Haitao Ji
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.,Department of Chemistry, University of South Florida, Tampa, Florida, USA
| |
Collapse
|
|
38
|
Xie J, Huang L, Lu YG, Zheng DL. Roles of the Wnt Signaling Pathway in Head and Neck Squamous Cell Carcinoma. Front Mol Biosci 2021; 7:590912. [PMID: 33469547 PMCID: PMC7814318 DOI: 10.3389/fmolb.2020.590912] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/21/2020] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck tumor. It is a high incidence malignant tumor associated with a low survival rate and limited treatment options. Accumulating conclusions indicate that the Wnt signaling pathway plays a vital role in the pathobiological process of HNSCC. The canonical Wnt/β-catenin signaling pathway affects a variety of cellular progression, enabling tumor cells to maintain and further promote the immature stem-like phenotype, proliferate, prolong survival, and gain invasiveness. Genomic studies of head and neck tumors have shown that although β-catenin is not frequently mutated in HNSCC, its activity is not inhibited by mutations in upstream gene encoding β-catenin, NOTCH1, FAT1, and AJUBA. Genetic defects affect the components of the Wnt pathway in oral squamous cell carcinoma (OSCC) and the epigenetic mechanisms that regulate inhibitors of the Wnt pathway. This paper aims to summarize the groundbreaking discoveries and recent advances involving the Wnt signaling pathway and highlight the relevance of this pathway in head and neck squamous cell cancer, which will help provide new insights into improving the treatment of human HNSCC by interfering with the transcriptional signaling of Wnt.
Collapse
Affiliation(s)
- Jing Xie
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.,Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Li Huang
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.,Department of Dentistry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - You-Guang Lu
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.,Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Da-Li Zheng
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
39
|
Ali SR, Dobbs TD, Slade R, Whitaker IS. Multidimensional indicators of scholarly impact in the skin oncology literature: is there a correlation between bibliometric and altmetric profiles? J Plast Surg Hand Surg 2020; 55:232-241. [PMID: 33356756 DOI: 10.1080/2000656x.2020.1858842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Bibliometric and altmetric analyses are used to identify landmark publications in their respective research field. We hypothesised that highly cited skin oncology articles correlate positively with the Oxford Evidence Based Medicine scoring level, altmetric score (AS) and rank within the top 100 manuscripts.Methods: Thomson Reuter's Web of Science citation indexing database was searched to identify all English-language skin oncology full-text articles in the last 75 years. The top 100 articles with the highest citation count were analysed by subject matter, publishing journal, author, year, institution, individual and five-year impact factor, AS and Oxford EBM level. Results: 180,132 articles were identified. The most cited article (Hodi et al.) demonstrated improved survival with ipilimumab in patients with metastatic melanoma (7894 citations). The article with the highest AS was Esteva et al. (AS = 576.7, 'dermatologist-level classification of skin cancer with deep neural networks'). No difference was found between evidence level and citation count (r = -0.1239, p = 0.2291), but a significant difference was seen for AS (r = -0.3024, p = 0.0028). AS scores increased over time, whereas bibliometrics did not. Conclusion: This work highlights the most influential work in the skin oncology field in the last 75 years. We have identified a differential relationship between commonly used metrics and evidence level in the field of skin oncology. As the digitalisation of research output and consumption increases, both bibliometric and altmetric analyses need to be considered when an article's impact is being assessed.
Collapse
Affiliation(s)
- Stephen R Ali
- Reconstructive Surgery and Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea, UK.,Welsh Centre for Burns and Plastic Surgery Morriston Hospital, Swansea, UK
| | - Thomas D Dobbs
- Reconstructive Surgery and Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea, UK.,Welsh Centre for Burns and Plastic Surgery Morriston Hospital, Swansea, UK
| | - Robert Slade
- Welsh Centre for Burns and Plastic Surgery Morriston Hospital, Swansea, UK
| | - Iain S Whitaker
- Reconstructive Surgery and Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea, UK.,Welsh Centre for Burns and Plastic Surgery Morriston Hospital, Swansea, UK
| |
Collapse
|
|
40
|
Schwarzmueller L, Bril O, Vermeulen L, Léveillé N. Emerging Role and Therapeutic Potential of lncRNAs in Colorectal Cancer. Cancers (Basel) 2020; 12:E3843. [PMID: 33352769 PMCID: PMC7767007 DOI: 10.3390/cancers12123843] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Maintenance of the intestinal epithelium is dependent on the control of stem cell (SC) proliferation and differentiation. The fine regulation of these cellular processes requires a complex dynamic interplay between several signaling pathways, including Wnt, Notch, Hippo, EGF, Ephrin, and BMP/TGF-β. During the initiation and progression of colorectal cancer (CRC), key events, such as oncogenic mutations, influence these signaling pathways, and tilt the homeostatic balance towards proliferation and dedifferentiation. Therapeutic strategies to specifically target these deregulated signaling pathways are of particular interest. However, systemic blocking or activation of these pathways poses major risks for normal stem cell function and tissue homeostasis. Interestingly, long non-coding RNAs (lncRNAs) have recently emerged as potent regulators of key cellular processes often deregulated in cancer. Because of their exceptional tissue and tumor specificity, these regulatory RNAs represent attractive targets for cancer therapy. Here, we discuss how lncRNAs participate in the maintenance of intestinal homeostasis and how they can contribute to the deregulation of each signaling pathway in CRC. Finally, we describe currently available molecular tools to develop lncRNA-targeted cancer therapies.
Collapse
Affiliation(s)
- Laura Schwarzmueller
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Oscar Bril
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nicolas Léveillé
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| |
Collapse
|
|
41
|
Agrawal A, Datta C, Panda CK, Pal DK. Association of beta-catenin and CD44 in the development of renal cell carcinoma. Urologia 2020; 88:125-129. [PMID: 33300451 DOI: 10.1177/0391560320980672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION AND OBJECTIVE Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers. Approximately 25%-30% of patients present with metastatic disease at the time of diagnosis, and metastatic RCC is a treatment-resistant malignancy. Altered expression of cell adhesion molecules such as CD44 on tumor cells suggests a pathogenetic mechanism for tumor metastasis and may provide prognostic information for particular tumors. These cell matrix interactions of CD44 play a role in tumor cell invasion and metastasis. The Wnt/beta-catenin pathway turned out to be a promising target as it is involved in the regulation of cell proliferation, differentiation and apoptosis induction. METHOD In this study, the expression of beta-catenin and CD44 was analyzed in primary renal cell carcinoma (RCC) samples to understand their association with development of the disease. For this purpose, immunohistochemical expression analysis of beta-catenin and CD44 was performed in 30 primary RCC histological samples and normal kidney tissues in different subtypes at different clinical stages of Indian patients (year: 2017-2019). RESULT Most of the patients who presented were diagnosed as clear cell carcinoma and it was observed that expression of CD44 was high in patients with high stage tumors. Also beta-catenin was increased in advanced grade tumors, but there was insignificant correlation between high expression of molecules and survival or recurrence of disease. CONCLUSION Both cd44 and beta-catenin activation was noted in patients with clear cell carcinoma, more in advanced tumors. Both can be promising targets for treatment in clear cell RCCs.
Collapse
Affiliation(s)
- Akash Agrawal
- Department of Urology, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal, India
| | - Chhanda Datta
- Department of Pathology, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| | - Dilip Kumar Pal
- Department of Urology, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal, India
| |
Collapse
|
|
42
|
Xu X, Zhang M, Xu F, Jiang S. Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities. Mol Cancer 2020; 19:165. [PMID: 33234169 PMCID: PMC7686704 DOI: 10.1186/s12943-020-01276-5] [Citation(s) in RCA: 314] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Wnt signaling is a highly conserved signaling pathway that plays a critical role in controlling embryonic and organ development, as well as cancer progression. Genome-wide sequencing and gene expression profile analyses have demonstrated that Wnt signaling is involved mainly in the processes of breast cancer proliferation and metastasis. The most recent studies have indicated that Wnt signaling is also crucial in breast cancer immune microenvironment regulation, stemness maintenance, therapeutic resistance, phenotype shaping, etc. Wnt/β-Catenin, Wnt-planar cell polarity (PCP), and Wnt-Ca2+ signaling are three well-established Wnt signaling pathways that share overlapping components and play different roles in breast cancer progression. In this review, we summarize the main findings concerning the relationship between Wnt signaling and breast cancer and provide an overview of existing mechanisms, challenges, and potential opportunities for advancing the therapy and diagnosis of breast cancer.
Collapse
Affiliation(s)
- Xiufang Xu
- School of Medical Imaging, Hangzhou Medical College, Hangzhou, 310053 Zhejiang China
| | - Miaofeng Zhang
- Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 Zhejiang China
| | - Faying Xu
- School of Medical Imaging, Hangzhou Medical College, Hangzhou, 310053 Zhejiang China
| | - Shaojie Jiang
- School of Medical Imaging, Hangzhou Medical College, Hangzhou, 310053 Zhejiang China
| |
Collapse
|
|
43
|
Bellei B, Migliano E, Picardo M. A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue. Cancers (Basel) 2020; 12:cancers12113400. [PMID: 33212834 PMCID: PMC7697272 DOI: 10.3390/cancers12113400] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Melanoma cells reside in a complex stromal microenvironment, which is a critical component of disease onset and progression. Mesenchymal or fibroblastic cell type are the most abundant cellular element of tumor stroma. Factors secreted by melanoma cells can activate non-malignant associated fibroblasts to become melanoma associate fibroblasts (MAFs). MAFs promote tumorigenic features by remodeling the extracellular matrix, supporting tumor cells proliferation, neo-angiogenesis and drug resistance. Additionally, environmental factors may contribute to the acquisition of pro-tumorigenic phenotype of fibroblasts. Overall, in melanoma, perturbed tissue homeostasis contributes to modulation of major oncogenic intracellular signaling pathways not only in tumor cells but also in neighboring cells. Thus, targeted molecular therapies need to be considered from the reciprocal point of view of melanoma and stromal cells. Abstract The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor–stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment.
Collapse
Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
- Correspondence: ; Tel.: +39-0652666246
| | - Emilia Migliano
- Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| |
Collapse
|
|
44
|
Clinicopathologic and Immunohistochemical Correlates of CTNNB1 Mutated Endometrial Endometrioid Carcinoma. Int J Gynecol Pathol 2020; 39:119-127. [PMID: 30702464 DOI: 10.1097/pgp.0000000000000583] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Endometrial endometrioid carcinomas (EECs) with exon 3 CTNNB1 mutations characterize a more aggressive subset of tumors in patients with low-grade low-stage disease. Thus, prospectively identifying these cases may be clinically relevant. The aim of this study was to examine the feasibility of β-catenin and Cyclin D1 immunohistochemistry to identify EECs harboring CTNNB1 mutations and to evaluate the clinicopathologic features of EECs with exon 3 CTNNB1 mutations. Thirty-nine CTNNB1 mutated EECs and 40 CTNNB1 wild-type EECs were identified from a cohort of previously sequenced endometrial carcinomas using a targeted next-generation sequencing panel. Immunohistochemistry for β-catenin and Cyclin D1 was performed on all cases. Immunohistochemistry results were correlated with CTNNB1 mutation status and clinicopathologic parameters. Patients with CTNNB1 mutated EECs were younger than those with CTNNB1 wild-type (56.2 vs. 61.5 y; P=0.033). Nuclear β-catenin expression correlated with exon 3 CTNNB1 mutation (P<0.0001) with a sensitivity of 91% and a specificity of 89%. Cyclin D1 expression correlated with CTNNB1 exon 3 mutation with relatively high specificity (90%) but low sensitivity (29%). Recurrence rate in patients with stage IA disease at diagnosis was significantly higher in patients whose tumors were CTNNB1 mutated compared with CTNNB1 wild-type (30% vs. 0%; P=0.025) and included distant metastases; all recurrent tumors in this group harbored exon 3 mutations and were histologically low grade (5 grade 1, 2 grade 2). Nuclear β-catenin expression appears to be an acceptable proxy for CTNNB1 mutation.
Collapse
|
|
45
|
Asaoka Y, Tanaka A. Clinical implications of WNT/β-catenin signaling for hepatocellular carcinoma. Glob Health Med 2020; 2:269-272. [PMID: 33330820 DOI: 10.35772/ghm.2020.01099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors have entered clinical practice for the treatment of hepatocellular carcinoma (HCC). Several previous studies for other cancers have revealed that tumor mutation burden, tumor PD-L1 expression and cytotoxic T-cell infiltration are predictive of treatment response. The genetic analysis of HCC has shown that β-catenin mutation might be a biomarker predicting the poor response against immune checkpoint inhibitors. β-catenin is a transcription factor downstream of WNT signaling and somatic mutations of this gene are the third most common in HCC. WNT signaling is an important signal for organogenesis and is also involved in the maintenance of stem cells in several organs. Recently, clinical and basic studies have shown the specific roles of WNT/β-catenin signaling in many aspects of hepatic function and carcinogenesis including metabolic zonation and inflammation, and sub-classification and radiologic features of HCC. Base on the review on the recent advances of research investigating WNT/β-catenin signaling associated with hepatocytes, we speculate the clinical role of this signal on the immunotherapy for HCC, which suggests that an era of genetic mutation profiles may be coming to add to the HCC treatment algorithm.
Collapse
Affiliation(s)
- Yoshinari Asaoka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
46
|
Yadav BK, Yadav R, Kang HG, Kim KW, Lee CH, Shin BS. Association of Genetic Variation in a Wnt Signaling Pathway Gene ( β-Catenin) with Susceptibility to Leukoaraiosis. Genet Test Mol Biomarkers 2020; 24:708-716. [PMID: 33026847 DOI: 10.1089/gtmb.2020.0111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Aim: Blood-brain barrier (BBB) disruption is the primary initiating cause of cerebral small-vessel diseases including leukoaraiosis (LA). β-Catenin is a key regulator of the BBB and plays an important role in cell-cell adhesion at adherens junctions by interacting with cadherin molecules. Thus, β-Catenin may be a good candidate gene for LA. We performed a genetic analyses to investigate the association between β-catenin alleles and LA. Materials and Methods: A total of 339 LA cases and 203 controls were enrolled from individuals who underwent brain magnetic resonance imaging with obtainable vascular risk factors. Genotyping of β-catenin single nucleotide polymorphisms (SNPs), including rs1880481 C > A, rs13072632 C > T, and rs4135385 A > G, was performed by real-time polymerase chain reaction using a LightCycler 2.0. Results: Two SNPs, rs1880481 and rs4135385, showed significant differences in their allelic frequencies between the control and LA groups and the combinatorial effects of the risk alleles for these two SNPs also significantly increased the risk of LA. The G-T-A, A-T-A, and A-T-G haplotypes for the three SNPs showed significant differences in both types of LA: LA-periventricular white matter and LA-deep white matter. However, the C-T-G haplotype was only significantly different for LA-PVWM, while the A-C-A was only significantly different for LA-DWM. The combination of diabetes mellitis, hypertension, and these risk alleles increased the likelihood of both types of LA. Conclusion: This study provides evidence that β-catenin polymorphisms and their associated haplotypes are associated with susceptibility to LA.
Collapse
Affiliation(s)
- Binod Kumar Yadav
- Department of Biochemistry, Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
| | - Renu Yadav
- Department of Dietary, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
| | - Hyun Goo Kang
- Department of Neurology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.,Department of Neurology, Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Ko Woon Kim
- Department of Neurology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.,Department of Neurology, Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Chan-Hyuk Lee
- Department of Neurology, Jeonbuk National University Hospital, Jeonju, Republic of Korea
| | - Byoung-Soo Shin
- Department of Neurology, Jeonbuk National University Medical School, Jeonju, Republic of Korea.,Department of Neurology, Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea
| |
Collapse
|
|
47
|
Rapetti-Mauss R, Berenguier C, Allegrini B, Soriani O. Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers. Front Pharmacol 2020; 11:525020. [PMID: 33117152 PMCID: PMC7552962 DOI: 10.3389/fphar.2020.525020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence point out the important roles of ion channels in the physiopathology of cancers, so that these proteins are now considered as potential new therapeutic targets and biomarkers in this disease. Indeed, ion channels have been largely described to participate in many hallmarks of cancers such as migration, invasion, proliferation, angiogenesis, and resistance to apoptosis. At the molecular level, the development of cancers is characterised by alterations in transduction pathways that control cell behaviors. However, the interactions between ion channels and cancer-related signaling pathways are poorly understood so far. Nevertheless, a limited number of reports have recently addressed this important issue, especially regarding the interaction between ion channels and one of the main driving forces for cancer development: the Wnt/β-catenin signaling pathway. In this review, we propose to explore and discuss the current knowledge regarding the interplay between ion channels and the Wnt/β-catenin signaling pathway in cancers.
Collapse
|
|
48
|
IMU1003, an atrarate derivative, inhibits Wnt/β-catenin signaling. Biochem Biophys Res Commun 2020; 532:440-445. [PMID: 32891433 DOI: 10.1016/j.bbrc.2020.08.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 12/22/2022]
Abstract
Aberrant activation of the canonical Wnt/β-catenin signaling pathway triggers tumorigenesis in various tissues. This study identified an atrarate compound, IMU14, derived from filamentous fungi as an inhibitor of Wnt/β-catenin signaling in phenotypic chemical inhibitor screening of the zebrafish eyeless phenotype. Its derivatization resulted in synthesis of IMU1003 with enhanced Wnt inhibitory activity. IMU1003 inhibited β-catenin/TCF-dependent transcriptional activation and decreased nuclear β-catenin level. In addition, IMU1003 selectively decreased viability and target gene products of the Wnt/β-catenin signaling pathway in human non-colorectal cancer cell lines harboring intact APC and β-catenin. Therefore, atrarate derivatives inhibit Wnt/β-catenin signaling and show anticancer potential, and we developed a new class of chemical backbones for Wnt/β-catenin signaling inhibitors.
Collapse
|
|
49
|
Inferring clonal composition from multiple tumor biopsies. NPJ Syst Biol Appl 2020; 6:27. [PMID: 32843649 PMCID: PMC7447821 DOI: 10.1038/s41540-020-00147-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 07/15/2020] [Indexed: 01/09/2023] Open
Abstract
Knowledge about the clonal evolution of a tumor can help to interpret the function of its genetic alterations by identifying initiating events and events that contribute to the selective advantage of proliferative, metastatic, and drug-resistant subclones. Clonal evolution can be reconstructed from estimates of the relative abundance (frequency) of subclone-specific alterations in tumor biopsies, which, in turn, inform on its composition. However, estimating these frequencies is complicated by the high genetic instability that characterizes many cancers. Models for genetic instability suggest that copy number alterations (CNAs) can influence mutation-frequency estimates and thus impede efforts to reconstruct tumor phylogenies. Our analysis suggested that accurate mutation frequency estimates require accounting for CNAs—a challenging endeavour using the genetic profile of a single tumor biopsy. Instead, we propose an optimization algorithm, Chimæra, to account for the effects of CNAs using profiles of multiple biopsies per tumor. Analyses of simulated data and tumor profiles suggested that Chimæra estimates are consistently more accurate than those of previously proposed methods and resulted in improved phylogeny reconstructions and subclone characterizations. Our analyses inferred recurrent initiating mutations in hepatocellular carcinomas, resolved the clonal composition of Wilms’ tumors, and characterized the acquisition of mutations in drug-resistant prostate cancers.
Collapse
|
|
50
|
Hou S, Chen X, Li M, Huang X, Liao H, Tian B. Higher expression of cell division cycle-associated protein 5 predicts poorer survival outcomes in hepatocellular carcinoma. Aging (Albany NY) 2020; 12:14542-14555. [PMID: 32694239 PMCID: PMC7425481 DOI: 10.18632/aging.103501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/04/2020] [Indexed: 02/05/2023]
Abstract
The upregulation of cell division cycle associated protein 5 (CDCA5) has been observed in various cancer types. However, the prognostic value of CDCA5 and its underlying mechanism contributing to tumorigenesis in hepatocellular carcinoma (HCC) remain poorly understood. We used tissue microarray (TMA) to evaluate the prognosis of 304 HCC samples based on their CDCA5 expression, and analyzed the genomic features correlated with CDCA5 by using dataset from The Cancer Genome Atlas (TCGA). Compared with adjacent normal tissues, increased expression of CDCA5 was found in HCC tissues. Moreover, higher expression of CDCA5 was associated with inferior OS and DFS outcomes in HCC patients. The enrichment plots showed that the gene signatures in cell cycle, DNA replication and p53 pathways were enriched in patients with higher CDCA5 expression. Meanwhile, statistically higher mutations burdens in TP53 could also be observed in CDCA5-high patients. Integrative analysis based on miRNAseq and methylation data demonstrated a potential association between CDCA5 expression and epigenetic changes. In conclusion, our study provided the evidence of CDCA5 as an oncogenic promoter in HCC and the potential function of CDCA5 in affecting tumor microenvironment.
Collapse
Affiliation(s)
- Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xing Chen
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Mao Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xing Huang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haotian Liao
- Department of Liver Surgery and Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|