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Oliveira-Silva JM, Oliveira LS, Chiminazo CB, Fonseca R, de Souza CVE, Aissa AF, de Almeida Lima GD, Ionta M, Castro-Gamero AM. WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells. Cancer Chemother Pharmacol 2025; 95:22. [PMID: 39821335 DOI: 10.1007/s00280-024-04731-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: 09/01/2024] [Accepted: 11/25/2024] [Indexed: 01/19/2025]
Abstract
PURPOSE Histone deacetylase 6 (HDAC6) plays a critical role in tumorigenesis and tumor progression, contributing to proliferation, chemoresistance, and cell motility by regulating microtubule architecture. Despite its upregulation in melanoma tissues and cell lines, the specific biological roles of HDAC6 in melanoma are not well understood. This study aims to explore the functional effects and underlying mechanisms of WT161, a selective HDAC6 inhibitor, in melanoma cell lines. METHODS Cell proliferation was assessed using both 2D and 3D cell culture systems, including MTT assays, spheroid growth analyses, and colony formation assays. The interaction between WT161 and the chemotherapeutic agents temozolomide (TMZ) or dacarbazine (DTIC) was evaluated using the Chou-Talalay method. Apoptotic cell death was analyzed through flow cytometry, while migration, adhesion, and invasion assays were conducted to evaluate the motility capacities of melanoma cells. Western blot assays quantified α-tubulin acetylation (Lys40), PARP cleavage, and protein levels of β-catenin and E-cadherin. RESULTS WT161 significantly reduced cell growth in both 2D and 3D cultures, decreased clonogenic capacity, and showed synergistic interactions with TMZ and DTIC. The inhibitor also induced apoptotic cell death and enhanced TMZ-induced apoptosis. Additionally, WT161 reduced cell migration and invasion while increasing cell adhesion. These effects were linked to changes in β-catenin and E-cadherin levels, depending on the specific cell type evaluated. CONCLUSION Our study underscores the pivotal role of HDAC6 in melanoma progression, establishing it as a promising therapeutic target. We provide the first comprehensive evidence of WT161's anti-melanoma effects, setting the stage for further research into HDAC6 inhibitors as a potential strategy for melanoma treatment.
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Affiliation(s)
- João Marcos Oliveira-Silva
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Leilane Sales Oliveira
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Carolina Berraut Chiminazo
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | | | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Graziela Domingues de Almeida Lima
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil
| | - Angel Mauricio Castro-Gamero
- Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
- Postgraduate Program in Biosciences Applied to Health (PPGB), Federal University of Alfenas (UNIFAL-MG), Alfenas, MG, 37130-001, Brazil.
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2
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Vera O, Martinez M, Soto-Vargas Z, Wang K, Xu X, Ruiz-Buceta S, Mecozzi N, Chadourne M, Posorske B, Angarita A, Bok I, Liu Q, Murikipudi H, Kim Y, Messina JL, Tsai KY, Major MB, Lau EK, Yu X, Ibanez-de-Caceres I, Karreth FA. The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.03.611024. [PMID: 39282450 PMCID: PMC11398417 DOI: 10.1101/2024.09.03.611024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG~MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation.
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Affiliation(s)
- Olga Vera
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
- Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, 28046 Madrid, Spain
- Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, 28046 Madrid, Spain
| | - Michael Martinez
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Zulaida Soto-Vargas
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Kaizhen Wang
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
- Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA
| | - Xiaonan Xu
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Sara Ruiz-Buceta
- Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, 28046 Madrid, Spain
- Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, 28046 Madrid, Spain
| | - Nicol Mecozzi
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
- Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA
| | - Manon Chadourne
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Benjamin Posorske
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Ariana Angarita
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Ilah Bok
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA
| | - Qian Liu
- Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Harini Murikipudi
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Yumi Kim
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Jane L. Messina
- Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Kenneth Y. Tsai
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Michael B. Major
- Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA
| | - Eric K. Lau
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Xiaoqing Yu
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Inmaculada Ibanez-de-Caceres
- Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, 28046 Madrid, Spain
- Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, 28046 Madrid, Spain
| | - Florian A. Karreth
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
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3
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Hirsch M, Pal S, Mehrabadi FR, Malikic S, Gruen C, Sassano A, Pérez-Guijarro E, Merlino G, Sahinalp C, Molloy EK, Day CP, Przytycka TM. Stochastic modelling of single-cell gene expression adaptation reveals non-genomic contribution to evolution of tumor subclones. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.17.588869. [PMID: 38712152 PMCID: PMC11071284 DOI: 10.1101/2024.04.17.588869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Cancer progression is an evolutionary process driven by the selection of cells adapted to gain growth advantage. We present the first formal study on the adaptation of gene expression in subclonal evolution. We model evolutionary changes in gene expression as stochastic Ornstein-Uhlenbeck processes, jointly leveraging the evolutionary history of subclones and single-cell expression data. Applying our model to sublines derived from single cells of a mouse melanoma revealed that sublines with distinct phenotypes are underlined by different patterns of gene expression adaptation, indicating non-genetic mechanisms of cancer evolution. Interestingly, sublines previously observed to be resistant to anti-CTLA-4 treatment showed adaptive expression of genes related to invasion and non-canonical Wnt signaling, whereas sublines that responded to treatment showed adaptive expression of genes related to proliferation and canonical Wnt signaling. Our results suggest that clonal phenotypes emerge as the result of specific adaptivity patterns of gene expression.
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Affiliation(s)
- M.G. Hirsch
- National Library of Medicine, NIH, Bethesda, Maryland, USA
- Department of Computer Science, University of Maryland, College Park, Maryland USA
| | - Soumitra Pal
- Neurobiology Neurodegeneration and Repair Lab, National Eye Institute, NIH, Bethesda, Maryland, USA
| | - Farid Rashidi Mehrabadi
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer institute, NIH, Bethesda, Maryland, USA
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Salem Malikic
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer institute, NIH, Bethesda, Maryland, USA
| | - Charli Gruen
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Antonella Sassano
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Eva Pérez-Guijarro
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM, CSIC-UAM), Madrid, Spain
| | - Glenn Merlino
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Cenk Sahinalp
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer institute, NIH, Bethesda, Maryland, USA
| | - Erin K. Molloy
- Department of Computer Science, University of Maryland, College Park, Maryland USA
- University of Maryland Institute for Advanced Computer Studies, College Park, Maryland USA
| | - Chi-Ping Day
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
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4
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Mendelson K, Martin TC, Nguyen CB, Hsu M, Xu J, Lang C, Dummer R, Saenger Y, Messina JL, Sondak VK, Desman G, Hasson D, Bernstein E, Parsons RE, Celebi JT. Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation. JCI Insight 2024; 9:e166611. [PMID: 38319712 PMCID: PMC11063936 DOI: 10.1172/jci.insight.166611] [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: 10/31/2022] [Accepted: 02/02/2024] [Indexed: 02/07/2024] Open
Abstract
Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state, whereas invasiveness genes were linked with Epgn3 high-risk status. We identified the ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems, suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/Epgn3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
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Affiliation(s)
- Karen Mendelson
- Department of Dermatology, NYU Grossman School of Medicine, New York, New York, USA
| | - Tiphaine C. Martin
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christie B. Nguyen
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Graduate School of Biological Sciences, Icahn School of Medicine, New York, New York, USA
| | - Min Hsu
- Department of Dermatology, NYU Grossman School of Medicine, New York, New York, USA
| | - Jia Xu
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Claudia Lang
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Yvonne Saenger
- Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Jane L. Messina
- Department of Pathology and Cell Biology, USF Morsani College of Medicine, Tampa, Florida, USA
- Moffitt Cancer Center, Tampa, Florida, USA
| | - Vernon K. Sondak
- Department of Pathology and Cell Biology, USF Morsani College of Medicine, Tampa, Florida, USA
- Moffitt Cancer Center, Tampa, Florida, USA
| | - Garrett Desman
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dan Hasson
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Graduate School of Biological Sciences, Icahn School of Medicine, New York, New York, USA
| | - Emily Bernstein
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Graduate School of Biological Sciences, Icahn School of Medicine, New York, New York, USA
| | - Ramon E. Parsons
- Department of Oncological Sciences and
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Julide Tok Celebi
- Department of Dermatology, NYU Grossman School of Medicine, New York, New York, USA
- Department of Pathology, NYU Grossman School of Medicine, New York, New York, USA
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5
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Hargadon KM. Genetic dysregulation of immunologic and oncogenic signaling pathways associated with tumor-intrinsic immune resistance: a molecular basis for combination targeted therapy-immunotherapy for cancer. Cell Mol Life Sci 2023; 80:40. [PMID: 36629955 PMCID: PMC11072992 DOI: 10.1007/s00018-023-04689-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 01/02/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023]
Abstract
Since the turn of the century, advances in targeted therapy and immunotherapy have revolutionized the treatment of cancer. Although these approaches have far outperformed traditional therapies in various clinical settings, both remain plagued by mechanisms of innate and acquired resistance that limit therapeutic efficacy in many patients. With a focus on tumor-intrinsic resistance to immunotherapy, this review highlights our current understanding of the immunologic and oncogenic pathways whose genetic dysregulation in cancer cells enables immune escape. Emphasis is placed on genomic, epigenomic, transcriptomic, and proteomic aberrations that influence the activity of these pathways in the context of immune resistance. Specifically, the role of pathways that govern interferon signaling, antigen processing and presentation, and immunologic cell death as determinants of tumor immune susceptibility are discussed. Likewise, mechanisms of tumor immune resistance mediated by dysregulated RAS-MAPK, WNT, PI3K-AKT-mTOR, and cell cycle pathways are described. Finally, this review highlights the ways in which recent insight into genetic dysregulation of these immunologic and oncogenic signaling pathways is informing the design of combination targeted therapy-immunotherapy regimens that aim to restore immune susceptibility of cancer cells by overcoming resistance mechanisms that often limit the success of monotherapies.
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Affiliation(s)
- Kristian M Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA.
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6
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Wang H, Zhang H, Chen Y, Wang H, Tian Y, Yi X, Shi Q, Zhao T, Zhang B, Gao T, Guo S, Li C, Guo W. Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF. Cells 2022; 11:cells11223580. [PMID: 36429010 PMCID: PMC9688625 DOI: 10.3390/cells11223580] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/β-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/β-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting β-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/β-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/β-catenin-MITF pathway. Ultimately, pharmacological inhibition of β-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/β-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/β-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy.
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Affiliation(s)
- Hao Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Hengxiang Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yuhan Chen
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Huina Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yangzi Tian
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xiuli Yi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Qiong Shi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Tao Zhao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Baolu Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Tianwen Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Sen Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting. Stem Cells Int 2022; 2022:9653244. [PMID: 35800881 PMCID: PMC9256444 DOI: 10.1155/2022/9653244] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/07/2022] [Indexed: 12/22/2022] Open
Abstract
Cancer is characterized by an abnormal growth of the cells in an uncontrolled manner. These cells have the potential to invade and can eventually turn into malignancy, leading to highly fatal forms of tumor. Small subpopulations of cancer cells that are long-lived with the potential of excessive self-renewal and tumor formation are called cancer stem cells (CSCs) or cancer-initiating cells or tumor stem cells. CSCs can be found in tissues, such as breast, brain, lung, liver, ovary, and testis; however, their origin is still a matter of debate. These cells can differentiate and possess self-renewal capacity maintained by numerous intracellular signal transduction pathways, such as the Wnt/β-catenin signaling, Notch signaling, transforming growth factor-β signaling, and Hedgehog signaling. They can also contribute to numerous malignancies and are an important reason for tumor recurrence and metastasis because they are resistant to the known therapeutic strategies that mainly target the bulk of the tumor cells. This review contains collected and compiled information after analyzing published works of the last three decades. The goal was to gather information of recent breakthroughs related to CSCs, strategies to target CSCs' niche (e.g., nanotechnology with tumor biology), and their signaling pathways for cancer therapy. Moreover, the role of metformin, an antidiabetic drug, acting as a chemotherapeutic agent on CSCs by inhibiting cellular transformation and its selective killing is also addressed.
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8
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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: 60] [Impact Index Per Article: 15.0] [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.
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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
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9
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Wolf LM, Lambert AM, Haenlin J, Boutros M. EVI/WLS function is regulated by ubiquitination and linked to ER-associated degradation by ERLIN2. J Cell Sci 2021; 134:271857. [PMID: 34406391 PMCID: PMC8435288 DOI: 10.1242/jcs.257790] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 07/12/2021] [Indexed: 12/16/2022] Open
Abstract
WNT signalling is important for development in all metazoans and is associated with various human diseases. The ubiquitin–proteasome system (UPS) and regulatory endoplasmic reticulum-associated degradation (ERAD) have been implicated in the production of WNT proteins. Here, we investigated how the WNT secretory factor EVI (also known as WLS) is ubiquitylated, recognised by ERAD components and subsequently removed from the secretory pathway. We performed a focused immunoblot-based RNAi screen for factors that influence EVI/WLS protein stability. We identified the VCP-binding proteins FAF2 and UBXN4 as novel interaction partners of EVI/WLS and showed that ERLIN2 links EVI/WLS to the ubiquitylation machinery. Interestingly, we also found that EVI/WLS is ubiquitylated and degraded in cells irrespective of their level of WNT production. This K11, K48 and K63-linked ubiquitylation is mediated by the E2 ubiquitin-conjugating enzymes UBE2J2, UBE2K and UBE2N, but is independent of the E3 ubiquitin ligases HRD1 (also known as SYVN1) and GP78 (also known as AMFR). Taken together, our study identifies factors that link the UPS to the WNT secretory pathway and provides mechanistic details of the fate of an endogenous substrate of regulatory ERAD in mammalian cells. This article has an associated First Person interview with the first author of the paper. Summary: The WNT secretory factor EVI/WLS is ubiquitylated and linked to ER-associated degradation by multiple proteins, providing insight into the link between WNT signalling and the ubiquitin–proteasome system.
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Affiliation(s)
- Lucie M Wolf
- German Cancer Research Center (DKFZ), Division of Signalling and Functional Genomics and Heidelberg University, BioQuant & Department for Cell and Molecular Biology, Medical Faculty Mannheim, D-69120 Heidelberg, Germany
| | - Annika M Lambert
- German Cancer Research Center (DKFZ), Division of Signalling and Functional Genomics and Heidelberg University, BioQuant & Department for Cell and Molecular Biology, Medical Faculty Mannheim, D-69120 Heidelberg, Germany
| | - Julie Haenlin
- German Cancer Research Center (DKFZ), Division of Signalling and Functional Genomics and Heidelberg University, BioQuant & Department for Cell and Molecular Biology, Medical Faculty Mannheim, D-69120 Heidelberg, Germany
| | - Michael Boutros
- German Cancer Research Center (DKFZ), Division of Signalling and Functional Genomics and Heidelberg University, BioQuant & Department for Cell and Molecular Biology, Medical Faculty Mannheim, D-69120 Heidelberg, Germany
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10
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Jobe NP, Åsberg L, Andersson T. Reduced WNT5A signaling in melanoma cells favors an amoeboid mode of invasion. Mol Oncol 2021; 15:1835-1848. [PMID: 33969605 PMCID: PMC8253101 DOI: 10.1002/1878-0261.12974] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 02/25/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Tumor cells invade and spread via either a mesenchymal or an amoeboid mode of migration. Amoeboid tumor cells have a rounded morphology and pronounced RhoA activity. Here, we investigate how WNT5A signaling, a tumor promotor in melanoma, relates to Rho GTPase activity and amoeboid migration. We compared melanoma cells with low (HTB63 cells) and high (WM852 cells) WNT5A expression. HTB63 cells exhibited an amoeboid morphology and had higher RhoA activity but lower invasiveness than WM852 cells in a three‐dimensional (3D) collagen matrix. We next explored the relationships between WNT5A, morphology, and invasive behavior. WNT5A knockdown impaired Rho GTPase Cdc42 activity, resulting in reduced invasion of amoeboid and mesenchymal melanoma cells. Interestingly, knockdown of WNT5A or inhibition of its secretion in WM852 cells expressing wild‐type BRAF also led to increased RhoA activity via decreased RND3 expression, resulting in predominantly amoeboid morphology. In contrast, such treatments had the opposite effects on RND3 expression and RhoA activity in HTB63 cells expressing the active BRAFV600 mutation. However, treatment of HTB63 cells with a BRAF inhibitor made them respond to WNT5A knockdown in a similar manner as WM852 cells expressing wild‐type BRAF. We next found that dual targeting of WNT5A and RhoA more effectively reduced melanoma cell invasion than targeting either protein individually. Taken together, our results suggest that low WNT5A signaling in melanoma cells promotes a rounded amoeboid type of invasion, which quite likely serves as a compensatory response to decreased WNT5A/Cdc42‐driven invasion. This phenomenon partially explains the enduring melanoma cell invasion observed after impaired WNT5A signaling and has therapeutic implications. Our results suggest that dual targeting of WNT5A and RhoA signaling is a more effective strategy for controlling the invasion of BRAF wild‐type and BRAFV600 mutated melanomas treated with a BRAF inhibitor than targeting either of the proteins individually.
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Affiliation(s)
- Njainday Pulo Jobe
- Experimental Pathology, Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Lisa Åsberg
- Experimental Pathology, Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Tommy Andersson
- Experimental Pathology, Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
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11
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Shami Shah A, Cao X, White AC, Baskin JM. PLEKHA4 Promotes Wnt/β-Catenin Signaling-Mediated G 1-S Transition and Proliferation in Melanoma. Cancer Res 2021; 81:2029-2043. [PMID: 33574086 PMCID: PMC8137570 DOI: 10.1158/0008-5472.can-20-2584] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/29/2020] [Accepted: 02/05/2021] [Indexed: 11/16/2022]
Abstract
Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1-S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation. SIGNIFICANCE: This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.
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Affiliation(s)
- Adnan Shami Shah
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York
| | - Xiaofu Cao
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York
| | - Andrew C White
- Department of Biomedical Sciences, Cornell University, Ithaca, New York
| | - Jeremy M Baskin
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York.
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York
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12
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Douglass SM, Fane ME, Sanseviero E, Ecker BL, Kugel CH, Behera R, Kumar V, Tcyganov EN, Yin X, Liu Q, Chhabra Y, Alicea GM, Kuruvilla R, Gabrilovich DI, Weeraratna AT. Myeloid-Derived Suppressor Cells Are a Major Source of Wnt5A in the Melanoma Microenvironment and Depend on Wnt5A for Full Suppressive Activity. Cancer Res 2021; 81:658-670. [PMID: 33262126 PMCID: PMC8330365 DOI: 10.1158/0008-5472.can-20-1238] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
Metastatic dissemination remains a significant barrier to successful therapy for melanoma. Wnt5A is a potent driver of invasion in melanoma and is believed to be secreted from the tumor microenvironment (TME). Our data suggest that myeloid-derived suppressor cells (MDSC) in the TME are a major source of Wnt5A and are reliant upon Wnt5A for multiple actions. Knockdown of Wnt5A specifically in the myeloid cells demonstrated a clear decrease in Wnt5A expression within the TME in vivo as well as a decrease in intratumoral MDSC and regulatory T cell (Treg). Wnt5A knockdown also decreased the immunosuppressive nature of MDSC and decreased expression of TGFβ1 and arginase 1. In the presence of Wnt5A-depleted MDSC, tumor-infiltrating lymphocytes expressed decreased PD-1 and LAG3, suggesting a less exhausted phenotype. Myeloid-specific Wnt5A knockdown also led to decreased lung metastasis. Tumor-infiltrating MDSC from control animals showed a strong positive correlation with Treg, which was completely ablated in animals with Wnt5A-negative MDSC. Overall, our data suggest that while MDSC contribute to an immunosuppressive and less immunogenic environment, they exhibit an additional function as the major source of Wnt5A in the TME. SIGNIFICANCE: These findings demonstrate that myeloid cells provide a major source of Wnt5A to facilitate metastatic potential in melanoma cells and rely on Wnt5A for their immunosuppressive function.
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Affiliation(s)
- Stephen M Douglass
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Mitchell E Fane
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Brett L Ecker
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Reeti Behera
- The Wistar Institute, Philadelphia, Pennsylvania
| | - Vinit Kumar
- The Wistar Institute, Philadelphia, Pennsylvania
| | | | - Xiangfan Yin
- The Wistar Institute, Philadelphia, Pennsylvania
| | - Qin Liu
- The Wistar Institute, Philadelphia, Pennsylvania
| | - Yash Chhabra
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Gretchen M Alicea
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Rejji Kuruvilla
- Department of Biology, Johns Hopkins University, Baltimore, Maryland
| | | | - Ashani T Weeraratna
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
- Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
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13
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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.
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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;
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14
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van Loon K, Huijbers EJM, Griffioen AW. Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis. Cancer Metastasis Rev 2020; 40:191-203. [PMID: 33140138 PMCID: PMC7897195 DOI: 10.1007/s10555-020-09941-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022]
Abstract
Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.
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Affiliation(s)
- Karlijn van Loon
- Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands
| | - Elisabeth J M Huijbers
- Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.
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15
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Rodriguez-Hernandez I, Maiques O, Kohlhammer L, Cantelli G, Perdrix-Rosell A, Monger J, Fanshawe B, Bridgeman VL, Karagiannis SN, Penin RM, Marcolval J, Marti RM, Matias-Guiu X, Fruhwirth GO, Orgaz JL, Malanchi I, Sanz-Moreno V. WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion. Nat Commun 2020; 11:5315. [PMID: 33082334 PMCID: PMC7575593 DOI: 10.1038/s41467-020-18951-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/14/2020] [Indexed: 12/19/2022] Open
Abstract
Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
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Affiliation(s)
- Irene Rodriguez-Hernandez
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Oscar Maiques
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Leonie Kohlhammer
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
| | - Gaia Cantelli
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
- Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA
| | - Anna Perdrix-Rosell
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Joanne Monger
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
| | - Bruce Fanshawe
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, Kings' College London, London, SE1 7EH, UK
| | - Victoria L Bridgeman
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Sophia N Karagiannis
- St John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London and NIHR Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London, SE1 9RT, UK
| | - Rosa M Penin
- Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, l'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Joaquim Marcolval
- Department of Dermatology, Hospital Universitari de Bellvitge, IDIBELL, l'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Rosa M Marti
- Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRB LleidaI, CIBERONC, 25198, Lleida, Spain
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRB Lleida, CIBERONC, 25198, Lleida, Spain
| | - Gilbert O Fruhwirth
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, Kings' College London, London, SE1 7EH, UK
| | - Jose L Orgaz
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK
- Instituto de Investigaciones Biomedicas 'Alberto Sols', CSIC-UAM, 28029, Madrid, Spain
| | - Ilaria Malanchi
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Victoria Sanz-Moreno
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK.
- Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, SE1 1UL, UK.
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16
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Gajos-Michniewicz A, Czyz M. WNT Signaling in Melanoma. Int J Mol Sci 2020; 21:E4852. [PMID: 32659938 PMCID: PMC7402324 DOI: 10.3390/ijms21144852] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided.
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Affiliation(s)
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92–215 Lodz, Poland;
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17
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The Role of Carcinogenesis-Related Biomarkers in the Wnt Pathway and Their Effects on Epithelial-Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12030555. [PMID: 32121061 PMCID: PMC7139589 DOI: 10.3390/cancers12030555] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/27/2022] Open
Abstract
As oral squamous cell carcinoma (OSCC) can develop from potentially malignant disorders (PMDs), it is critical to develop methods for early detection to improve the prognosis of patients. Epithelial-mesenchymal transition (EMT) plays an important role during tumor progression and metastasis. The Wnt signaling pathway is an intercellular pathway in animals that also plays a fundamental role in cell proliferation and regeneration, and in the function of many cell or tissue types. Specific components of master regulators such as epithelial cadherin (E-cadherin), Vimentin, adenomatous polyposis coli (APC), Snail, and neural cadherin (N-cadherin), which are known to control the EMT process, have also been implicated in the Wnt cascade. Here, we review recent findings on the Wnt signaling pathway and the expression mechanism. These regulators are known to play roles in EMT and tumor progression, especially in OSCC. Characterizing the mechanisms through which both EMT and the Wnt pathway play a role in these cellular pathways could increase our understanding of the tumor genesis process and may allow for the development of improved therapeutics for OSCC.
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18
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Webster MR, Fane ME, Alicea GM, Basu S, Kossenkov AV, Marino GE, Douglass SM, Kaur A, Ecker BL, Gnanapradeepan K, Ndoye A, Kugel C, Valiga A, Palmer J, Liu Q, Xu X, Morris J, Yin X, Wu H, Xu W, Zheng C, Karakousis GC, Amaravadi RK, Mitchell TC, Almeida FV, Xiao M, Rebecca VW, Wang YJ, Schuchter LM, Herlyn M, Murphy ME, Weeraratna AT. Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma. Mol Cell 2019; 77:633-644.e5. [PMID: 31836388 DOI: 10.1016/j.molcel.2019.11.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 07/17/2019] [Accepted: 11/06/2019] [Indexed: 12/29/2022]
Abstract
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
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Affiliation(s)
- Marie R Webster
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
| | - Mitchell E Fane
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Gretchen M Alicea
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA
| | - Subhasree Basu
- Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA
| | | | - Gloria E Marino
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Stephen M Douglass
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Amanpreet Kaur
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA
| | - Brett L Ecker
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Department of Surgery, University of Pennsylvania Hospital, Philadelphia, PA 19104, USA
| | - Keerthana Gnanapradeepan
- Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Abibatou Ndoye
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; University of the Sciences, Philadelphia, PA 19104, USA
| | - Curtis Kugel
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Alexander Valiga
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Jessica Palmer
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Qin Liu
- Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Xiaowei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jessicamarie Morris
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Xiangfan Yin
- Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Hong Wu
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Wei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Cathy Zheng
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Giorgos C Karakousis
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ravi K Amaravadi
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tara C Mitchell
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Filipe V Almeida
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Min Xiao
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Vito W Rebecca
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Ying-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310003, China
| | - Lynn M Schuchter
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Tara Miller Melanoma Center at Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Meenhard Herlyn
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A
| | - Maureen E Murphy
- Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Ashani T Weeraratna
- Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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19
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Molecular background of skin melanoma development and progression: therapeutic implications. Postepy Dermatol Alergol 2019; 36:129-138. [PMID: 31320844 PMCID: PMC6627250 DOI: 10.5114/ada.2019.84590] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/18/2018] [Indexed: 12/19/2022] Open
Abstract
Melanoma is the most aggressive skin cancer with an increasing number of cases worldwide and curable mostly in its early stage. The improvement in patients' survival in advanced melanoma has been achieved only recently, due to development of new biological drugs for targeted therapies and immunotherapy. Further progress in the treatment of melanoma is clearly dependent on the better understanding of its complex biology. This review describes the most important molecular mechanisms and genetic events underlying skin melanoma development and progression, depicts the way of action of newly developed drugs and indicates new potential therapeutic targets.
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20
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Ghosh N, Hossain U, Mandal A, Sil PC. The Wnt signaling pathway: a potential therapeutic target against cancer. Ann N Y Acad Sci 2019; 1443:54-74. [PMID: 31017675 DOI: 10.1111/nyas.14027] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/05/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
The role of the evolutionarily conserved Wnt signaling pathway is well documented in several cellular processes, such as cell proliferation, differentiation, cell motility, and maintenance of the stem cell niche. The very first indication that aberrant Wnt signaling can cause carcinogenesis came from a finding that the mutation of the adenomatous polyposis coli gene (APC) predisposes a person to colorectal carcinoma. Later, with progressing research it became clear that abnormal activation or mutation of the genes related to this pathway could drive tumorigenesis. Here, we review recent advances in research regarding Wnt signaling regulation and its role in several cancer subtypes. Additionally, the utility of Wnt pathway-targeted cancer therapy intervention is also highlighted, with an overview of current approaches to target the Wnt pathway in oncogenesis and the future scopes and challenges associated with them.
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Affiliation(s)
- Noyel Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Uday Hossain
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Ankita Mandal
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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21
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Deng W, Fernandez A, McLaughlin SL, Klinke DJ. WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition. J Biol Chem 2019; 294:5261-5280. [PMID: 30723155 DOI: 10.1074/jbc.ra118.006122] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 01/26/2019] [Indexed: 01/03/2023] Open
Abstract
Besides intrinsic changes, malignant cells also release soluble signals that reshape their microenvironment. Among these signals is WNT1-inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein whose expression is elevated in several cancers, including melanoma, and is associated with reduced survival of patients diagnosed with primary melanoma. Here, we found that WISP1 knockout increases cell proliferation and represses wound healing, migration, and invasion of mouse and human melanoma cells in multiple in vitro assays. Metastasis assays revealed that WISP1 knockout represses tumor metastasis of B16F10 and YUMM1.7 melanoma cells in both C57BL/6Ncrl and NOD-scid IL2Rγnull (NSG) mice. WT B16F10 cells having an invasion phenotype in a transwell assay possessed a gene expression signature similar to that observed in the epithelial-mesenchymal transition (EMT), including E-cadherin repression and fibronectin and N-cadherin induction. Upon WISP1 knockout, expression of these EMT signature genes went in the opposite direction in both mouse and human cell lines, and EMT-associated gene expression was restored upon exposure to media containing WISP1 or to recombinant WISP1 protein. In vivo, Wisp1 knockout-associated metastasis repression was reversed by the reintroduction of either WISP1 or snail family transcriptional repressor 1 (SNAI1). Experiments testing EMT gene activation and inhibition with recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates AKT Ser/Thr kinase and that MEK/ERK signaling pathways shift melanoma cells from proliferation to invasion. Our results indicate that WISP1 present within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.
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Affiliation(s)
- Wentao Deng
- From the Department of Microbiology, Immunology, and Cell Biology.,the West Virginia University Cancer Institute
| | - Audry Fernandez
- From the Department of Microbiology, Immunology, and Cell Biology.,the West Virginia University Cancer Institute
| | - Sarah L McLaughlin
- the West Virginia University Cancer Institute.,the Animal Models and Imaging Facility, and
| | - David J Klinke
- From the Department of Microbiology, Immunology, and Cell Biology, .,the West Virginia University Cancer Institute.,the Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown, West Virginia 26505
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22
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Ogawa M, Yaginuma T, Nakatomi C, Nakajima T, Tada-Shigeyama Y, Addison WN, Urata M, Matsubara T, Watanabe K, Matsuo K, Sato T, Honda H, Hikiji H, Watanabe S, Kokabu S. Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity. Oncotarget 2019; 10:404-414. [PMID: 30719233 PMCID: PMC6349449 DOI: 10.18632/oncotarget.26552] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 12/20/2018] [Indexed: 11/25/2022] Open
Abstract
Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 μM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.
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Affiliation(s)
- Masahiro Ogawa
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.,Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tatsuki Yaginuma
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Chihiro Nakatomi
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tsuyoshi Nakajima
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Yukiyo Tada-Shigeyama
- Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - William N Addison
- Research Unit, Shriners Hospitals for Children-Canada, Department of Human Genetics, McGill University, Montreal, Quebec, Canada
| | - Mariko Urata
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Takuma Matsubara
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Koji Watanabe
- Division of Developmental Stomatognathic Function Science, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Kou Matsuo
- Division of Oral Pathology, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tsuyoshi Sato
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan
| | - Hiromi Honda
- School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Hisako Hikiji
- School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Seiji Watanabe
- Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Shoichiro Kokabu
- Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
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23
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Chen Y, Zou D, Wang N, Tan T, Liu Y, Zhao Q, Pu Y, Thapa RJ, Chen J. SFRP5 inhibits the migration and invasion of melanoma cells through Wnt signaling pathway. Onco Targets Ther 2018; 11:8761-8772. [PMID: 30584334 PMCID: PMC6287589 DOI: 10.2147/ott.s181146] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Secreted frizzled-related protein 5 (SFRP5) plays a key role in the development and progression of multiple tumors. However, the role and underlying mechanisms of SFRP5 in melanoma cells remain unknown. Materials and methods We used immunohistochemistry and Western blot analysis to detect the expression of SFRP5 in melanoma tissues and melanoma cells, respectively. Furthermore, both in vitro and in vivo assays were used to determine the effect of SFRP5 on malignant behavior in melanoma cells. Results We found that SFRP5 was markedly downregulated in melanoma tissues and cell lines. The SFRP5 overexpression exhibited no effect on the proliferation and apoptosis of melanoma cells but markedly suppressed the migration and invasion of melanoma cells in vitro. Regarding mechanisms, the SFRP5 overexpression inhibited the migration and invasion of melanoma cells by suppressing the epithelial–mesenchymal transition process and decreasing the matrix metalloproteinase-2/9 expression through the Wnt signaling pathway. Finally, in a xenograft animal model, we illustrated that the SFRP5 overexpression suppressed the tumor growth by decreasing angiogenesis and declined lung metastasis. Conclusion This study suggests that SFRP5 expression could be potentially useful in the invasion and metastasis of melanoma and serve as a putative promising target for human melanoma therapy.
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Affiliation(s)
- Yangmei Chen
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Daopei Zou
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Nan Wang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Tao Tan
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yu Liu
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Qing Zhao
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Yihuan Pu
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Rabin Jung Thapa
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Jin Chen
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
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24
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Liou GY. CD133 as a regulator of cancer metastasis through the cancer stem cells. Int J Biochem Cell Biol 2018; 106:1-7. [PMID: 30399449 DOI: 10.1016/j.biocel.2018.10.013] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/28/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
Cancer stem cells are the cancer cells that have abilities to self-renew, differentiate into defined progenies, and initiate and maintain tumor growth. They also contribute to cancer metastasis and therapeutic resistance, both of which are the major causes of cancer mortality. Among the reported makers of the cancer stem cells, CD133 is the most well-known marker for isolating and studying cancer stem cells in different types of cancer. The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy. Despite very limited information on physiological functions of CD133, many ongoing studies are aimed to reveal the mechanisms that CD133 utilizes to modulate cancer dissemination and drug resistance with a long-term goal for bringing down the number of cancer deaths. In this review, in addition to the regulation of CD133, and its involvement in cancer initiation, and development, the recent updates on how CD133 modulates cancer dissemination, and therapeutic resistance are provided. The key signaling pathways that are upstream or downstream of CD133 during these processes are summarized. A comprehensive understanding of CD133-mediated cancer initiation, development, and dissemination through its pivotal role in cancer stem cells will offer new strategies in cancer therapy.
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Affiliation(s)
- Geou-Yarh Liou
- Clark Atlanta University, Center for Cancer Research & Therapeutic Development, and Department of Biological Sciences, 223 James P. Brawley Drive SW, Atlanta, GA 30314, USA.
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25
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Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy. Biosci Rep 2018; 38:BSR20180511. [PMID: 30166456 PMCID: PMC6167501 DOI: 10.1042/bsr20180511] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/14/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.
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26
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Bagati A, Bianchi-Smiraglia A, Moparthy S, Kolesnikova K, Fink EE, Lipchick BC, Kolesnikova M, Jowdy P, Polechetti A, Mahpour A, Ross J, Wawrzyniak JA, Yun DH, Paragh G, Kozlova NI, Berman AE, Wang J, Liu S, Nemeth MJ, Nikiforov MA. Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1. Cell Rep 2018; 20:2820-2832. [PMID: 28930679 DOI: 10.1016/j.celrep.2017.08.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 08/11/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022] Open
Abstract
Lineage-specific regulation of tumor progression by the same transcription factor is understudied. We find that levels of the FOXQ1 transcription factor, an oncogene in carcinomas, are decreased during melanoma progression. Moreover, in contrast to carcinomas, FOXQ1 suppresses epithelial-to-mesenchymal transition, invasion, and metastasis in melanoma cells. We find that these lineage-specific functions of FOXQ1 largely depend on its ability to activate (in carcinomas) or repress (in melanoma) transcription of the N-cadherin gene (CDH2). We demonstrate that FOXQ1 interacts with nuclear β-catenin and TLE proteins, and the β-catenin/TLE ratio, which is higher in carcinoma than melanoma cells, determines the effect of FOXQ1 on CDH2 transcription. Accordingly, other FOXQ1-dependent phenotypes can be manipulated by altering nuclear β-catenin or TLE proteins levels. Our data identify FOXQ1 as a melanoma suppressor and establish a mechanism underlying its inverse lineage-specific transcriptional regulation of transformed phenotypes.
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Affiliation(s)
- Archis Bagati
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | | - Sudha Moparthy
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Kateryna Kolesnikova
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Emily E Fink
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Brittany C Lipchick
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Masha Kolesnikova
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Peter Jowdy
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Anthony Polechetti
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Amin Mahpour
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jason Ross
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Joseph A Wawrzyniak
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Dong Hyun Yun
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Gyorgy Paragh
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA; Department of Dermatology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | | - Albert E Berman
- Orekhovich Institute of Biomedical Chemistry, Moscow 119121, Russia
| | - Jianmin Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Michael J Nemeth
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Mikhail A Nikiforov
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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27
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Abstract
Cancer cell migration is essential for metastasis, during which cancer cells move through the tumor and reach the blood vessels. In vivo, cancer cells are exposed to contact guidance and chemotactic cues. Depending on the strength of such cues, cells will migrate in a random or directed manner. While similar cues may also stimulate cell proliferation, it is not clear whether cell cycle progression affects migration of cancer cells and whether this effect is different in random versus directed migration. In this study, we tested the effect of cell cycle progression on contact guided migration in 2D and 3D environments, in the breast carcinoma cell line, FUCCI-MDA-MB-231. The results were quantified from live cell microscopy images using the open source lineage editing and validation image analysis tools (LEVER). In 2D, cells were placed inside 10 μm-wide microchannels to stimulate contact guidance, with or without an additional chemotactic gradient of the soluble epidermal growth factor. In 3D, contact guidance was modeled by aligned collagen fibers. In both 2D and 3D, contact guidance was cell cycle-dependent, while the addition of the chemo-attractant gradient in 2D increased cell velocity and persistence in directionally migrating cells, regardless of their cell cycle phases. In both 2D and 3D contact guidance, cells in the G1 phase of the cell cycle outperformed cells in the S/G2 phase in terms of migration persistence and instantaneous velocity. These data suggest that in the presence of contact guidance cues in vivo, breast carcinoma cells in the G1 phase of the cell cycle may be more efficient in reaching the neighboring vasculature.
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Affiliation(s)
| | - Edgar Cardenas De La Hoz
- Department of Electrical and Computer Engineering, College of Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA
| | - Andrew R Cohen
- Department of Electrical and Computer Engineering, College of Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA
| | - Bojana Gligorijevic
- Bioengineering department, College of Engineering, Temple University, Philadelphia, Pennsylvania 19122, USA.,Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
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28
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Katoh M. Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review). Int J Mol Med 2018; 42:713-725. [PMID: 29786110 PMCID: PMC6034925 DOI: 10.3892/ijmm.2018.3689] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/16/2018] [Indexed: 12/13/2022] Open
Abstract
β-catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E-cadherin/CDH1, N-cadherin/CDH2, VE-cadherin/CDH5 and α-catenins), transmembrane-type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain-of-function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss-of-function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β-catenin target genes. β-catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β-catenin and NF-κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β-catenin-targeted therapeutics are functionally classified into β-catenin inhibitors targeting upstream regulators (AZ1366, ETC-159, G007-LK, GNF6231, ipafricept, NVP-TNKS656, rosmantuzumab, vantictumab, WNT-C59, WNT974 and XAV939), β-catenin inhibitors targeting protein-protein interactions (CGP049090, CWP232228, E7386, ICG-001, LF3 and PRI-724), β-catenin inhibitors targeting epigenetic regulators (PKF118-310), β-catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β-catenin inhibitors targeting transmembrane-type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first-line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β-catenin inhibitors may be applicable for the prevention of organ fibrosis, second-line HCC prevention and treating β-catenin-driven cancer. The multi-layered prevention and treatment strategy of β-catenin-related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.
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Affiliation(s)
- Masaru Katoh
- Department of Omics Network, National Cancer Center, Chuo Ward, Tokyo 104‑0045, Japan
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29
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Segura MF, Jubierre L, Li S, Soriano A, Koetz L, Gaziel-Sovran A, Masanas M, Kleffman K, Dankert JF, Walsh MJ, Hernando E. Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions. Oncotarget 2018; 8:26298-26311. [PMID: 28412746 PMCID: PMC5432258 DOI: 10.18632/oncotarget.15459] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 02/06/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases.The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Krüppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.
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Affiliation(s)
- Miguel F Segura
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA.,Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Luz Jubierre
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - SiDe Li
- Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aroa Soriano
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Lisa Koetz
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Avital Gaziel-Sovran
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Marc Masanas
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Kevin Kleffman
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - John F Dankert
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Martin J Walsh
- Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eva Hernando
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
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30
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Lobos-González L, Silva V, Araya M, Restovic F, Echenique J, Oliveira-Cruz L, Fitzpatrick C, Briones M, Villegas J, Villota C, Vidaurre S, Borgna V, Socias M, Valenzuela S, Lopez C, Socias T, Varas M, Díaz J, Burzio LO, Burzio VA. Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors. Oncotarget 2018; 7:58331-58350. [PMID: 27507060 PMCID: PMC5295434 DOI: 10.18632/oncotarget.11110] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 07/19/2016] [Indexed: 01/23/2023] Open
Abstract
We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.
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Affiliation(s)
- Lorena Lobos-González
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile
| | - Verónica Silva
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Mariela Araya
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Franko Restovic
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Present address: Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Javiera Echenique
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Luciana Oliveira-Cruz
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Christopher Fitzpatrick
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile
| | - Macarena Briones
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Jaime Villegas
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile
| | - Claudio Villota
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile
| | - Soledad Vidaurre
- Andes Biotechnologies SpA, Santiago, Chile.,Facultad de Salud, Deporte y Recreación, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Vincenzo Borgna
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Servicio de Urología, Hospital Barros-Lucco-Trudeau, Santiago, Chile
| | | | | | - Constanza Lopez
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Teresa Socias
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | | | - Jorge Díaz
- Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile
| | - Luis O Burzio
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile
| | - Verónica A Burzio
- Andes Biotechnologies SpA, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile.,Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile
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31
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Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B. The role of Wnt/β-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines. Oncotarget 2017; 7:43295-43314. [PMID: 27175588 PMCID: PMC5190024 DOI: 10.18632/oncotarget.9232] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/10/2016] [Indexed: 12/13/2022] Open
Abstract
Deregulations or mutations of WNT/β-catenin signaling have been associated to both tumour formation and progression. However, contradictory results concerning the role of β-catenin in human melanoma address an open question on its oncogenic nature and prognostic value in this tumour. Changes in WNT signaling pathways have been linked to phenotype switching of melanoma cells between a highly proliferative/non-invasive and a slow proliferative/metastatic condition. We used a novel panel of cell lines isolated from melanoma specimens, at initial passages, to investigate phenotype differences related to the levels and activity of WNT/β-catenin signaling pathway. This in vitro cell system revealed a marked heterogeneity that comprises, in some cases, two distinct tumour-derived subpopulations of cells presenting a different activation level and cellular distribution of β-catenin. In cells derived from the same tumor, we demonstrated that the prevalence of LEF1 (high β-catenin expressing cells) or TCF4 (low β-catenin expressing cells) as β-catenin partner for DNA binding, is associated to the expression of two distinct profiles of WNT-responsive genes. Interestingly, melanoma cells expressing relative low level of β-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy.
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Affiliation(s)
- Daniela Kovacs
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Emilia Migliano
- Department of Plastic and Reconstructive Surgery, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Luca Muscardin
- Dermatopathological Laboratory, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Vitaliano Silipo
- Department of Oncologic Dermatology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Caterina Catricalà
- Department of Oncologic Dermatology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
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32
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low neurotrophin receptor CD271 regulates phenotype switching in melanoma. Nat Commun 2017; 8:1988. [PMID: 29215016 PMCID: PMC5719420 DOI: 10.1038/s41467-017-01573-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 09/29/2017] [Indexed: 01/22/2023] Open
Abstract
Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. According to the “phenotype switching” model, the aggressive nature of melanoma cells results from their intrinsic potential to dynamically switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state. Here we identify the low affinity neurotrophin receptor CD271 as a key effector of phenotype switching in melanoma. CD271 plays a dual role in this process by decreasing proliferation, while simultaneously promoting invasiveness. Dynamic modification of CD271 expression allows tumor cells to grow at low levels of CD271, to reduce growth and invade when CD271 expression is high, and to re-expand at a distant site upon decrease of CD271 expression. Mechanistically, the cleaved intracellular domain of CD271 controls proliferation, while the interaction of CD271 with the neurotrophin receptor Trk-A modulates cell adhesiveness through dynamic regulation of a set of cholesterol synthesis genes relevant for patient survival. The aggressive nature of melanoma cells relies on their ability to switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state; however, the mechanisms governing this switch are unclear. Here, using in vivo models of human melanoma, the authors show that CD271 is a key regulator of phenotype switching and metastasis formation.
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33
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Grzywa TM, Paskal W, Włodarski PK. Intratumor and Intertumor Heterogeneity in Melanoma. Transl Oncol 2017; 10:956-975. [PMID: 29078205 PMCID: PMC5671412 DOI: 10.1016/j.tranon.2017.09.007] [Citation(s) in RCA: 197] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/14/2017] [Accepted: 09/17/2017] [Indexed: 12/25/2022] Open
Abstract
Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.
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Affiliation(s)
- Tomasz M Grzywa
- The Department of Histology and Embryology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1b, 02-091 Warsaw, Poland
| | - Wiktor Paskal
- The Department of Histology and Embryology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1b, 02-091 Warsaw, Poland
| | - Paweł K Włodarski
- The Department of Histology and Embryology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1b, 02-091 Warsaw, Poland.
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34
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Katoh M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). Int J Oncol 2017; 51:1357-1369. [PMID: 29048660 PMCID: PMC5642388 DOI: 10.3892/ijo.2017.4129] [Citation(s) in RCA: 320] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 09/15/2017] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.
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Affiliation(s)
- Masaru Katoh
- Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan
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35
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Ndoye A, Budina-Kolomets A, Kugel CH, Webster MR, Kaur A, Behera R, Rebecca VW, Li L, Brafford PA, Liu Q, Gopal YNV, Davies MA, Mills GB, Xu X, Wu H, Herlyn M, Nicastri MC, Winkler JD, Soengas MS, Amaravadi RK, Murphy ME, Weeraratna AT. ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma. Cancer Res 2017; 77:5873-5885. [PMID: 28887323 DOI: 10.1158/0008-5472.can-17-0907] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/21/2017] [Accepted: 08/30/2017] [Indexed: 12/13/2022]
Abstract
Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. ©2017 AACR.
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Affiliation(s)
- Abibatou Ndoye
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania.,The University of the Sciences, Philadelphia, Pennsylvania
| | - Anna Budina-Kolomets
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania.,The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Curtis H Kugel
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | - Marie R Webster
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | - Amanpreet Kaur
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania.,The University of the Sciences, Philadelphia, Pennsylvania
| | - Reeti Behera
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | - Vito W Rebecca
- The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ling Li
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | | | - Qin Liu
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | | | - Michael A Davies
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gordon B Mills
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaowei Xu
- The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hong Wu
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Meenhard Herlyn
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
| | | | | | - Maria S Soengas
- Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | | | - Maureen E Murphy
- The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania
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36
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Katoh M, Katoh M. Molecular genetics and targeted therapy of WNT-related human diseases (Review). Int J Mol Med 2017; 40:587-606. [PMID: 28731148 PMCID: PMC5547940 DOI: 10.3892/ijmm.2017.3071] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 07/12/2017] [Indexed: 12/15/2022] Open
Abstract
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.
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Affiliation(s)
| | - Masaru Katoh
- Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan
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37
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Arozarena I, Wellbrock C. Targeting invasive properties of melanoma cells. FEBS J 2017; 284:2148-2162. [PMID: 28196297 DOI: 10.1111/febs.14040] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 01/26/2017] [Accepted: 02/10/2017] [Indexed: 02/11/2024]
Abstract
Melanoma is a skin cancer notorious for its metastatic potential. As an initial step of the metastatic cascade, melanoma cells part from the primary tumour and invade the surrounding tissue, which is crucial for their dissemination and the formation of distant secondary tumours. Over the last two decades, our understanding of both, general and melanoma specific mechanisms of invasion has significantly improved, but to date no efficient therapeutic strategy tackling the invasive properties of melanoma cells has reached the clinic. In this review, we assess the major contributions towards the understanding of the molecular biology of melanoma cell invasion with a focus on melanoma specific traits. These traits are based on the neural crest origin of melanoma cells and explain their intrinsic invasive nature. A particular emphasis is given not only to lineage specific signalling mediated by TGFβ, and noncanonical and canonical WNT signalling, but also to the role of PDE5A and RHO-GTPases in modulating modes of melanoma cell invasion. We discuss existing caveats in the current understanding of the metastatic properties of melanoma cells, as well as the relevance of the 'phenotype switch' model and 'co-operativity' between different phenotypes in heterogeneous tumours. At the centre of these phenotypes is the lineage commitment factor microphthalmia-associated transcription factor, one of the most crucial regulators of the balance between de-differentiation (neural crest specific gene expression) and differentiation (melanocyte specific gene expression) that defines invasive and noninvasive melanoma cell phenotypes. Finally, we provide insight into the current evidence linking resistance to targeted therapies to invasive properties of melanoma cells.
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Affiliation(s)
- Imanol Arozarena
- Cancer Signalling Group, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Claudia Wellbrock
- Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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38
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Cheng Q, Wu J, Zhang Y, Liu X, Xu N, Zuo F, Xu J. SOX4 promotes melanoma cell migration and invasion though the activation of the NF-κB signaling pathway. Int J Mol Med 2017. [PMID: 28627651 PMCID: PMC5504990 DOI: 10.3892/ijmm.2017.3030] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
SOX4 has been reported to be abnormally expressed in many types of cancer, including melanoma. However, its role in cell proliferation and metastasis remains controversial. In this study, SOX4 was downregulated or overexpressed in A375, A2058 and A875 melanoma cells by siRNA or lentivirus transfection, respectively. Cell metastasis was observed by Transwell assay. In an aim to elucidate the underlying mechanisms, we determined the expression of nuclear factor-κB (NF-κB) by real-time PCR assay and western blot analysis. Our data indicated that SOX4 knockdown inhibited melanoma cell migration and invasion. In the melanoma cells in which SOX4 was downregulated, the expression levels of NF-κB/p65, matrix metalloproteinase (MMP)2 and MMP9 were suppressed at both the mRNA and protein levels. Conversely, the overexpression of SOX4 promoted melanoma cell migration and invasion. In the melanoma cells in which SOX4 was overexpressed, the expression levels of NF-κB/p65, MMP2 and MMP9 were increased at both the mRNA and protein level. On the whole, our findings indicate that SOX4 promotes melanoma cell migration and invasion through the activation of the NF-κB/p65 signaling pathway. Thus, SOX4 may prove to be a potential therapeutic target for the treatment of melanoma.
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Affiliation(s)
- Qiong Cheng
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jinfeng Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Yaohua Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xiao Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Nan Xu
- Department of Dermatology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Fuguo Zuo
- Department of Dermatology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Jinhua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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39
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Zwezdaryk KJ, Combs JA, Morris CA, Sullivan DE. Regulation of Wnt/β-catenin signaling by herpesviruses. World J Virol 2016; 5:144-154. [PMID: 27878101 PMCID: PMC5105047 DOI: 10.5501/wjv.v5.i4.144] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 07/19/2016] [Accepted: 08/06/2016] [Indexed: 02/05/2023] Open
Abstract
The Wnt/β-catenin signaling pathway is instrumental in successful differentiation and proliferation of mammalian cells. It is therefore not surprising that the herpesvirus family has developed mechanisms to interact with and manipulate this pathway. Successful coexistence with the host requires that herpesviruses establish a lifelong infection that includes periods of latency and reactivation or persistence. Many herpesviruses establish latency in progenitor cells and viral reactivation is linked to host-cell proliferation and differentiation status. Importantly, Wnt/β-catenin is tightly connected to stem/progenitor cell maintenance and differentiation. Numerous studies have linked Wnt/β-catenin signaling to a variety of cancers, emphasizing the importance of Wnt/β-catenin pathways in development, tissue homeostasis and disease. This review details how the alpha-, beta-, and gammaherpesviruses interact and manipulate the Wnt/β-catenin pathway to promote a virus-centric agenda.
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40
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Chen H, Cheng CY. Planar cell polarity (PCP) proteins and spermatogenesis. Semin Cell Dev Biol 2016; 59:99-109. [PMID: 27108805 PMCID: PMC5071175 DOI: 10.1016/j.semcdb.2016.04.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/18/2016] [Indexed: 11/24/2022]
Abstract
In adult mammalian testes, spermatogenesis is comprised of several discrete cellular events that work in tandem to support the transformation and differentiation of diploid spermatogonia to haploid spermatids in the seminiferous epithelium during the seminiferous epithelial cycle. These include: self-renewal of spermatogonial stem cells via mitosis and their transformation into differentiated spermatogonia, meiosis I/II, spermiogenesis and the release of sperms at spermiation. Studies have shown that these cellular events are under precise and coordinated controls of multiple proteins and signaling pathways. These events are also regulated by polarity proteins that are known to confer classical apico-basal (A/B) polarity in other epithelia. Furthermore, spermatid development is likely supported by planar cell polarity (PCP) proteins since polarized spermatids are aligned across the plane of seminiferous epithelium in an orderly fashion, analogous to hair cells in the cochlea of the inner ear. Thus, the maximal number of spermatids can be packed and supported by a fixed population of differentiated Sertoli cells in the limited space of the seminiferous epithelium in adult testes. In this review, we briefly summarize recent findings regarding the role of PCP proteins in the testis. This information should be helpful in future studies to better understand the role of PCP proteins in spermatogenesis.
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Affiliation(s)
- Haiqi Chen
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, United States
| | - C Yan Cheng
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, United States.
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Liu Y, Huang D, Wang Z, Wu C, Zhang Z, Wang D, Li Z, Zhu T, Yang S, Sun W. LMO2 attenuates tumor growth by targeting the Wnt signaling pathway in breast and colorectal cancer. Sci Rep 2016; 6:36050. [PMID: 27779255 PMCID: PMC5078767 DOI: 10.1038/srep36050] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 10/06/2016] [Indexed: 12/23/2022] Open
Abstract
The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. Recently, the cytosolic localization of LMO2 was revealed in multiple epithelial tissues and a variety of solid tumors. However, the function of LMO2 in these epithelia and solid tumors remains largely unclear. The Wnt signaling pathway is a crucial determinant of development, and abnormalities in several key segments of this pathway contribute to oncogenesis. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins. These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor β-catenin in the canonical Wnt signaling pathway. Meanwhile, significantly decreased expression of LMO2 was detected in breast and colorectal cancers, and the downregulation of LMO2 in these cells increased cell proliferation and reduced apoptosis. Taken together, the data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system.
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Affiliation(s)
- Ye Liu
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Di Huang
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Zhaoyang Wang
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Chao Wu
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Zhao Zhang
- Department of Anorectal, Tianjin Union Medical Center, Tianjin, China
| | - Dan Wang
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Zongjin Li
- Laboratory of Stem cells in School of Medicine, Nankai University, Tianjin, China
| | - Tianhui Zhu
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Shuang Yang
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
| | - Wei Sun
- Laboratory of Molecular Genetics in School of Medicine, Nankai University, Tianjin, China
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Kaur A, Webster MR, Weeraratna AT. In the Wnt-er of life: Wnt signalling in melanoma and ageing. Br J Cancer 2016; 115:1273-1279. [PMID: 27764844 PMCID: PMC5129830 DOI: 10.1038/bjc.2016.332] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/10/2016] [Accepted: 09/15/2016] [Indexed: 12/21/2022] Open
Abstract
Although the clinical landscape of melanoma is improving rapidly, metastatic melanoma remains a deadly disease. Age remains one of the greatest risk factors for melanoma, and patients older than 55 have a much poorer prognosis than younger individuals, even when the data are controlled for grade and stage. The reasons for this disparity have not been fully uncovered, but there is some recent evidence that Wnt signalling may have a role. Wnt signalling is known to have roles both in cancer progression as well as in organismal ageing. In melanoma, the interplay of Wnt signalling pathways is complex, with different members of the Wnt family guiding different aspects of invasion and proliferation. Here, we will briefly review the current literature addressing the roles of different Wnt pathways in melanoma pathogenesis, provide an overview of Wnt signalling during ageing, and discuss the intersection between melanoma and ageing in terms of Wnt signalling.
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Affiliation(s)
- Amanpreet Kaur
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.,University of the Sciences, Philadelphia, PA, USA
| | - Marie R Webster
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA
| | - Ashani T Weeraratna
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA
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The role of dendritic cells in cancer. Semin Immunopathol 2016; 39:307-316. [PMID: 27638181 DOI: 10.1007/s00281-016-0592-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 09/02/2016] [Indexed: 12/15/2022]
Abstract
Though present in low numbers, dendritic cells (DCs) are recognized as major players in the control of cancer by adaptive immunity. The roles of cytotoxic CD8+ T-cells and Th1 helper CD4+ T-cells are well-documented in murine models of cancer and associated with a profound prognostic impact when infiltrating human tumors, but less information is known about how these T-cells gain access to the tumor or how they are primed to become tumor-specific. Here, we highlight recent findings that demonstrate a vital role of CD103+ DCs, which have been shown to be experts in cross-priming and the induction of anti-tumor immunity. We also focus on two different mediators that impair the function of tumor-associated DCs: prostaglandin E2 and β-catenin. Both of these mediators seem to be important for the exclusion of T-cells in the tumor microenvironment and may represent key pathways to target in optimized treatment regimens against cancer.
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sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 2016; 532:250-4. [PMID: 27042933 PMCID: PMC4833579 DOI: 10.1038/nature17392] [Citation(s) in RCA: 295] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/02/2016] [Indexed: 12/14/2022]
Abstract
Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.
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Nucleotide Excision Repair and Vitamin D--Relevance for Skin Cancer Therapy. Int J Mol Sci 2016; 17:372. [PMID: 27058533 PMCID: PMC4848881 DOI: 10.3390/ijms17040372] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/02/2016] [Accepted: 03/04/2016] [Indexed: 02/06/2023] Open
Abstract
Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.
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Morsalin S, Yang C, Fang J, Reddy S, Kayarthodi S, Childs E, Matthews R, Rao VN, Reddy ESP. Molecular Mechanism of β-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers. JOURNAL OF PHARMACEUTICAL SCIENCES AND PHARMACOLOGY 2015; 2:208-216. [PMID: 28497076 PMCID: PMC5423671 DOI: 10.1166/jpsp.2015.1069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In the United States of America, prostate cancer is the second most common age-related cancer among men. African-American men have the highest incidence of, and mortality rate from this disease in the United States. According to the American Cancer Society, 29% of all cancer cases and 9% of all cancer deaths are a result of prostate cancer. Individuals who are at highest risk include African-American men, men over 60 years of age, and those with a family history of the disease. African-Americans also have twice the risk of developing prostate cancer as compared to Caucasians. Erythroblastosis virus E26 transformation-specific (ETS) factors play an important role in human cancers. ETS Variant 1 (ETV1), an ETS factor, is notable for its association in prostate cancers, where truncated ETV1 (dETV1) or its full length counterpart is overexpressed in approximately 10% of the prostate cancer patients. Prostate cancer tumorigenesis may be initiated by deregulation of the Wnt/β-catenin pathway. Mutations that stabilize β-catenin were shown to contribute to the loss of cell-growth control in tumorigenesis. We hypothesized that ETV1's interaction with components of the Wnt/β-catenin pathway may alter β-catenin's interaction with downstream tumor-suppressor genes, which are critical in regulating apoptosis and cell-growth properties of prostate cells. Our results demonstrate for the first time that ETV1 alters β-catenin activity by activating kinases that regulate Wnt/β-catenin activity through post-translational modification in prostate cancer cells. We further demonstrate that therapeutic agents such as PD98059, that reverse effect of ETV1 on Wnt/β-catenin signaling pathway, can be used to target ETV1-positive prostate cancer cells. These therapeutic agents could have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority patients. Understanding the role of ETV1 in Wnt/β-catenin pathway will also allow us to develop better diagnostic tools, which can be used as a biomarker for ETV1-positive prostate cancers.
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Affiliation(s)
- Sharif Morsalin
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Chunshu Yang
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Jinbo Fang
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Sampreet Reddy
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Shubhalaxmi Kayarthodi
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Ed Childs
- Department of Surgery, Morehouse School of Medicine, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Roland Matthews
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - Veena N. Rao
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
| | - E. Shyam P. Reddy
- Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, RM 10C009, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA
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