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1
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Brandner S. Rodent models of tumours of the central nervous system. Mol Oncol 2024; 18:2842-2870. [PMID: 39324445 PMCID: PMC11619804 DOI: 10.1002/1878-0261.13729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 07/03/2024] [Accepted: 08/23/2024] [Indexed: 09/27/2024] Open
Abstract
Modelling of human diseases is an essential component of biomedical research, to understand their pathogenesis and ultimately, develop therapeutic approaches. Here, we will describe models of tumours of the central nervous system, with focus on intrinsic CNS tumours. Model systems for brain tumours were established as early as the 1920s, using chemical carcinogenesis, and a systematic analysis of different carcinogens, with a more refined histological analysis followed in the 1950s and 1960s. Alternative approaches at the time used retroviral carcinogenesis, allowing a more topical, organ-centred delivery. Most of the neoplasms arising from this approach were high-grade gliomas. Whilst these experimental approaches did not directly demonstrate a cell of origin, the localisation and growth pattern of the tumours already pointed to an origin in the neurogenic zones of the brain. In the 1980s, expression of oncogenes in transgenic models allowed a more targeted approach by expressing the transgene under tissue-specific promoters, whilst the constitutive inactivation of tumour suppressor genes ('knock out')-often resulted in embryonic lethality. This limitation was elegantly solved by engineering the Cre-lox system, allowing for a promoter-specific, and often also time-controlled gene inactivation. More recently, the use of the CRISPR Cas9 technology has significantly increased experimental flexibility of gene expression or gene inactivation and thus added increased value of rodent models for the study of pathogenesis and establishing preclinical models.
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Affiliation(s)
- Sebastian Brandner
- Department of Neurodegenerative DiseaseUCL Queen Square Institute of Neurology and Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Foundation TrustLondonUK
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2
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Ghosh A, Riester M, Pal J, Lainde KA, Tangermann C, Wanninger A, Dueren UK, Dhamija S, Diederichs S. Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily conserved amino acid patterns. Nat Commun 2024; 15:9209. [PMID: 39448564 PMCID: PMC11502859 DOI: 10.1038/s41467-024-52779-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 09/20/2024] [Indexed: 10/26/2024] Open
Abstract
Nonstop extension mutations, a.k.a. stop-lost or stop-loss mutations, convert a stop codon into a sense codon resulting in translation into the 3' untranslated region until the next in-frame stop codon, thereby extending the C-terminus of a protein. In cancer, only nonstop mutations in SMAD4 have been functionally characterized, while the impact of other nonstop mutations remain unknown. Here, we exploit our pan-cancer NonStopDB dataset and test all 2335 C-terminal extensions arising from somatic nonstop mutations in cancer for their impact on protein expression. In a high-throughput screen, 56.1% of the extensions effectively reduce protein abundance. Extensions of multiple tumor suppressor genes like PTEN, APC, B2M, CASP8, CDKN1B and MLH1 are effective and validated for their suppressive impact. Importantly, the effective extensions possess a higher hydrophobicity than the neutral extensions linking C-terminal hydrophobicity with protein destabilization. Analyzing the proteomes of eleven different species reveals conserved patterns of amino acid distribution in the C-terminal regions of all proteins compared to the proteomes like an enrichment of lysine and arginine and a depletion of glycine, leucine, valine and isoleucine across species and kingdoms. These evolutionary selection patterns are disrupted in the cancer-derived effective nonstop extensions.
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Affiliation(s)
- Avantika Ghosh
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany
| | - Marisa Riester
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Jagriti Pal
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Kadri-Ann Lainde
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Carla Tangermann
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany
| | - Angela Wanninger
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany
| | - Ursula K Dueren
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Sonam Dhamija
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Sven Diederichs
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany.
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3
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Menges CW, Hassan D, Cheung M, Bellacosa A, Testa JR. Alterations of the AKT Pathway in Sporadic Human Tumors, Inherited Susceptibility to Cancer, and Overgrowth Syndromes. Curr Top Microbiol Immunol 2024. [PMID: 39192048 DOI: 10.1007/82_2024_278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The AKT kinases are critical signaling molecules that regulate cellular physiology upon the activation of tyrosine kinase receptors and phosphatidylinositol 3-kinases (PI3K). AKT kinases govern many cellular processes considered hallmarks of cancer, including cell proliferation and survival, cell size, tumor invasion, metastasis, and angiogenesis. AKT signaling is regulated by multiple tumor suppressors and oncogenic proteins whose loss or activation, respectively, leads to dysregulation of this pathway, thereby contributing to oncogenesis. Herein, we review the enormous body of literature documenting how the AKT pathway becomes hyperactivated in sporadic human tumors and various hereditary cancer syndromes. We also discuss the role of activating mutations of AKT pathway genes in various chimeric overgrowth disorders, including Proteus syndrome, hypoglycemia with hypertrophy, CLOVES and SOLAMEN syndromes, and hemimegalencephaly.
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Affiliation(s)
- Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Eurofins Lancaster Laboratories Professional Scientific Services, Lancaster, PA, 17601, USA
| | - Dalal Hassan
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Mitchell Cheung
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
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4
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Kaushal JB, Takkar S, Batra SK, Siddiqui JA. Diverse landscape of genetically engineered mouse models: Genomic and molecular insights into prostate cancer. Cancer Lett 2024; 593:216954. [PMID: 38735382 PMCID: PMC11799897 DOI: 10.1016/j.canlet.2024.216954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/26/2024] [Accepted: 05/08/2024] [Indexed: 05/14/2024]
Abstract
Prostate cancer (PCa) is a significant health concern for men worldwide and is particularly prevalent in the United States. It is a complex disease presenting different molecular subtypes and varying degrees of aggressiveness. Transgenic/genetically engineered mouse models (GEMMs) greatly enhanced our understanding of the intricate molecular processes that underlie PCa progression and have offered valuable insights into potential therapeutic targets for this disease. The integration of whole-exome and whole-genome sequencing, along with expression profiling, has played a pivotal role in advancing GEMMs by facilitating the identification of genetic alterations driving PCa development. This review focuses on genetically modified mice classified into the first and second generations of PCa models. We summarize whether models created by manipulating the function of specific genes replicate the consequences of genomic alterations observed in human PCa, including early and later disease stages. We discuss cases where GEMMs did not fully exhibit the expected human PCa phenotypes and possible causes of the failure. Here, we summarize the comprehensive understanding, recent advances, strengths and limitations of the GEMMs in advancing our insights into PCa, offering genetic and molecular perspectives for developing novel GEMM models.
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Affiliation(s)
- Jyoti B Kaushal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Simran Takkar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE-68198, USA.
| | - Jawed A Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA.
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5
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Francis JC, Capper A, Rust AG, Ferro K, Ning J, Yuan W, de Bono J, Pettitt SJ, Swain A. Identification of genes that promote PI3K pathway activation and prostate tumour formation. Oncogene 2024; 43:1824-1835. [PMID: 38654106 PMCID: PMC11164682 DOI: 10.1038/s41388-024-03028-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 04/02/2024] [Accepted: 04/05/2024] [Indexed: 04/25/2024]
Abstract
We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.
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Affiliation(s)
- Jeffrey C Francis
- Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK
| | - Amy Capper
- Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK
| | - Alistair G Rust
- Genomics Facility, Institute of Cancer Research, London, UK
- Genomic Data Sciences, GlaxoSmithKline, Stevenage, UK
| | - Klea Ferro
- Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK
| | - Jian Ning
- Tumour Modelling Facility, Institute of Cancer Research, London, SW3 6JB, UK
| | - Wei Yuan
- Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Johann de Bono
- Institute of Cancer Research and Royal Marsden Hospital, London, UK
| | - Stephen J Pettitt
- The CRUK Gene Function Laboratory, Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Amanda Swain
- Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK.
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6
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Boti MA, Adamopoulos PG, Vassilacopoulou D, Scorilas A. Unraveling the Concealed Transcriptomic Landscape of PTEN in Human Malignancies. Curr Genomics 2023; 24:250-262. [PMID: 38169628 PMCID: PMC10758127 DOI: 10.2174/0113892029265367231013113304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/29/2023] [Accepted: 09/19/2023] [Indexed: 01/05/2024] Open
Abstract
Background Phosphatase and tensin homolog, widely known as PTEN, is a major negative regulator of the PI3K/AKT/mTOR signaling pathway, involved in the regulation of a variety of important cellular processes, including cell proliferation, growth, survival, and metabolism. Since most of the molecules involved in this biological pathway have been described as key regulators in cancer, the study of the corresponding genes at several levels is crucial. Objective Although previous studies have elucidated the physiological role of PTEN under normal conditions and its involvement in carcinogenesis and cancer progression, the transcriptional profile of PTEN has been poorly investigated. Methods In this study, instead of conducting the "gold-standard" direct RNA sequencing that fails to detect less abundant novel mRNAs due to the decreased sequencing depth, we designed and implemented a multiplexed PTEN-targeted sequencing approach that combined both short- and long-read sequencing. Results Our study has highlighted a broad spectrum of previously unknown PTEN mRNA transcripts and assessed their expression patterns in a wide range of human cancer and non-cancer cell lines, shedding light on the involvement of PTEN in cell cycle dysregulation and thus tumor development. Conclusion The identification of the described novel PTEN splice variants could have significant implications for understanding PTEN regulation and function, and provide new insights into PTEN biology, opening new avenues for monitoring PTEN-related diseases, including cancer.
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Affiliation(s)
- Michaela A. Boti
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis G. Adamopoulos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Dido Vassilacopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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7
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Capuozzo M, Celotto V, Landi L, Ferrara F, Sabbatino F, Perri F, Cascella M, Granata V, Santorsola M, Ottaiano A. Beyond Body Size: Adiponectin as a Key Player in Obesity-Driven Cancers. Nutr Cancer 2023; 75:1848-1862. [PMID: 37873648 DOI: 10.1080/01635581.2023.2272343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 10/25/2023]
Abstract
Obesity, a complex and multifactorial disease influenced by genetic, environmental, and psychological factors, has reached epidemic proportions globally, posing a significant health challenge. In addition to its established association with cardiovascular disease and type II diabetes, obesity has been implicated as a risk factor for various cancers. However, the precise biological mechanisms linking obesity and cancer remain largely understood. Adipose tissue, an active endocrine organ, produces numerous hormones and bioactive molecules known as adipokines, which play a crucial role in metabolism, immune responses, and systemic inflammation. Notably, adiponectin (APN), the principal adipocyte secretory protein, exhibits reduced expression levels in obesity. In this scoping review, we explore and discuss the role of APN in influencing cancer in common malignancies, including lung, breast, colorectal, prostate, gastric, and endometrial cancers. Our review aims to emphasize the critical significance of investigating this field, as it holds great potential for the development of innovative treatment strategies that specifically target obesity-related malignancies. Furthermore, the implementation of more rigorous and comprehensive prevention and treatment policies for obesity is imperative in order to effectively mitigate the risk of associated diseases, such as cancer.
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Affiliation(s)
| | | | | | | | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Salerno, Italy
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
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8
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Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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9
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Navaridas R, Vidal‐Sabanés M, Ruiz‐Mitjana A, Altés G, Perramon‐Güell A, Yeramian A, Egea J, Encinas M, Gatius S, Matias‐Guiu X, Dolcet X. In Vivo Intra-Uterine Delivery of TAT-Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53-Deficient Endometrial Cancers. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303134. [PMID: 37749866 PMCID: PMC10646277 DOI: 10.1002/advs.202303134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/25/2023] [Indexed: 09/27/2023]
Abstract
Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans-activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT-Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high-grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.
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Affiliation(s)
- Raúl Navaridas
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Maria Vidal‐Sabanés
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Anna Ruiz‐Mitjana
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Gisela Altés
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Aida Perramon‐Güell
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Andree Yeramian
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Joaquim Egea
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Mario Encinas
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Sonia Gatius
- Oncologic Pathology Group, Department of Basic Medical SciencesBiomedical Research Institute of Lleida (IRBLleida), CIBERONC.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Xavier Matias‐Guiu
- Oncologic Pathology Group, Department of Basic Medical SciencesBiomedical Research Institute of Lleida (IRBLleida), CIBERONC.Av. Rovira Roure 80LleidaCatalonia25198Spain
| | - Xavier Dolcet
- Developmental and Oncogenic Signalling Group, Department of Basic Medical Sciences and Department of Experimental MedicineInstitut de Recerca Biomèdica de Lleida, IRBLleida. University of Lleida, UdL.Av. Rovira Roure 80LleidaCatalonia25198Spain
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10
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Leroux AE, Biondi RM. The choreography of protein kinase PDK1 and its diverse substrate dance partners. Biochem J 2023; 480:1503-1532. [PMID: 37792325 DOI: 10.1042/bcj20220396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/24/2023] [Accepted: 08/31/2023] [Indexed: 10/05/2023]
Abstract
The protein kinase PDK1 phosphorylates at least 24 distinct substrates, all of which belong to the AGC protein kinase group. Some substrates, such as conventional PKCs, undergo phosphorylation by PDK1 during their synthesis and subsequently get activated by DAG and Calcium. On the other hand, other substrates, including members of the Akt/PKB, S6K, SGK, and RSK families, undergo phosphorylation and activation downstream of PI3-kinase signaling. This review presents two accepted molecular mechanisms that determine the precise and timely phosphorylation of different substrates by PDK1. The first mechanism involves the colocalization of PDK1 with Akt/PKB in the presence of PIP3. The second mechanism involves the regulated docking interaction between the hydrophobic motif (HM) of substrates and the PIF-pocket of PDK1. This interaction, in trans, is equivalent to the molecular mechanism that governs the activity of AGC kinases through their HMs intramolecularly. PDK1 has been instrumental in illustrating the bi-directional allosteric communication between the PIF-pocket and the ATP-binding site and the potential of the system for drug discovery. PDK1's interaction with substrates is not solely regulated by the substrates themselves. Recent research indicates that full-length PDK1 can adopt various conformations based on the positioning of the PH domain relative to the catalytic domain. These distinct conformations of full-length PDK1 can influence the interaction and phosphorylation of substrates. Finally, we critically discuss recent findings proposing that PIP3 can directly regulate the activity of PDK1, which contradicts extensive in vitro and in vivo studies conducted over the years.
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Affiliation(s)
- Alejandro E Leroux
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina
| | - Ricardo M Biondi
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina
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11
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Rodgers SJ, Mitchell CA, Ooms LM. The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer. Biochem Soc Trans 2023; 51:1459-1472. [PMID: 37471270 PMCID: PMC10586779 DOI: 10.1042/bst20220866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/08/2023] [Accepted: 07/05/2023] [Indexed: 07/22/2023]
Abstract
The class IA PI3K signaling pathway is activated by growth factor stimulation and regulates a signaling cascade that promotes diverse events including cell growth, proliferation, migration and metabolism. PI3K signaling is one of the most commonly hyperactivated pathways in breast cancer, leading to increased tumor growth and progression. PI3K hyperactivation occurs via a number of genetic and epigenetic mechanisms including mutation or amplification of PIK3CA, the gene encoding the p110α subunit of PI3Kα, as well as via dysregulation of the upstream growth factor receptors or downstream signaling effectors. Over the past decade, extensive efforts to develop therapeutics that suppress oncogenic PI3K signaling have been undertaken. Although FDA-approved PI3K inhibitors are now emerging, their clinical success remains limited due to adverse effects and negative feedback mechanisms which contribute to their reduced efficacy. There is an emerging body of evidence demonstrating crosstalk between the PI3K and Wnt/β-catenin pathways in breast cancer. However, PI3K exhibits opposing effects on Wnt/β-catenin signaling in distinct tumor subsets, whereby PI3K promotes Wnt/β-catenin activation in ER+ cancers, but paradoxically suppresses this pathway in ER- breast cancers. This review discusses the molecular mechanisms for PI3K-Wnt crosstalk in breast cancer, and how Wnt-targeted therapies have the potential to contribute to treatment regimens for breast cancers with PI3K dysregulation.
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Affiliation(s)
- Samuel J. Rodgers
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Christina A. Mitchell
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Lisa M. Ooms
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
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12
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Chen J, Dai S, Zhao L, Peng Y, Sun C, Peng H, Zhong Q, Quan Y, Li Y, Chen X, Pan X, Zhong A, Wang M, Zhang M, Yang S, Lu Y, Lian Z, Liu Y, Zhou S, Li Z, Na F, Chen C. A New Type of Endometrial Cancer Models in Mice Revealing the Functional Roles of Genetic Drivers and Exploring their Susceptibilities. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300383. [PMID: 37340596 PMCID: PMC10460855 DOI: 10.1002/advs.202300383] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 04/12/2023] [Indexed: 06/22/2023]
Abstract
Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing-based strategy to generate primary, orthotopic, and driver-defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid-initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high-throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.
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Affiliation(s)
- Jingyao Chen
- Precision Medicine Research CenterState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Siqi Dai
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Lei Zhao
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Yiman Peng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Chongen Sun
- West China Second HospitalSichuan UniversityChengdu610041China
| | - Hongling Peng
- West China Second HospitalSichuan UniversityChengdu610041China
| | - Qian Zhong
- West China Second HospitalSichuan UniversityChengdu610041China
| | - Yuan Quan
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Yue Li
- Department of DermatologyState Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu610041China
| | - Xuelan Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Xiangyu Pan
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Ailing Zhong
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Manli Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Mengsha Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Shengyong Yang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - You Lu
- Division of Thoracic Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengdu610041China
- Laboratory of Clinical Cell Therapy, West China HospitalSichuan UniversityChengdu610041China
| | - Zhong Lian
- Department of DermatologyState Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu610041China
| | - Yu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Shengtao Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
- West China Second HospitalSichuan UniversityChengdu610041China
| | - Zhengyu Li
- West China Second HospitalSichuan UniversityChengdu610041China
| | - Feifei Na
- Division of Thoracic Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengdu610041China
| | - Chong Chen
- Precision Medicine Research CenterState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China
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13
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van Ree JH, Jeganathan KB, Fierro Velasco RO, Zhang C, Can I, Hamada M, Li H, Baker DJ, van Deursen JM. Hyperphosphorylated PTEN exerts oncogenic properties. Nat Commun 2023; 14:2983. [PMID: 37225693 PMCID: PMC10209192 DOI: 10.1038/s41467-023-38740-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumorigenesis remains unclear. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Mice homozygous for a deletion that includes S370, S380, T382 and T383 contain low PTEN levels and hyperactive AKT but are not tumor prone. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a residue hyperphosphorylated in human gastric cancers, reveal that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyperphosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.
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Affiliation(s)
- Janine H van Ree
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Karthik B Jeganathan
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Ismail Can
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Masakazu Hamada
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Darren J Baker
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Jan M van Deursen
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
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14
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Cheung SKK, Kwok J, Or PMY, Wong CW, Feng B, Choy KW, Chang RCC, Burbach JPH, Cheng ASL, Chan AM. Neuropathological signatures revealed by transcriptomic and proteomic analysis in Pten-deficient mouse models. Sci Rep 2023; 13:6763. [PMID: 37185447 PMCID: PMC10130134 DOI: 10.1038/s41598-023-33869-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 04/20/2023] [Indexed: 05/17/2023] Open
Abstract
PTEN hamartoma tumour syndrome is characterised by mutations in the human PTEN gene. We performed transcriptomic and proteomic analyses of neural tissues and primary cultures from heterozygous and homozygous Pten-knockout mice. The somatosensory cortex of heterozygous Pten-knockout mice was enriched in immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis revealed differentially expressed proteins (DEPs) related to dendritic spine development, keratinisation and hamartoma signatures. However, primary astrocytes (ASTs) from heterozygous Pten-knockout mice were enriched in the extracellular matrix GO term, while primary cortical neurons (PCNs) were enriched in immediate-early genes. In ASTs from homozygous Pten-knockout mice, cilium-related activity was enriched, while PCNs exhibited downregulation of forebrain neuron generation and differentiation, implying an altered excitatory/inhibitory balance. By integrating DEPs with pre-filtered differentially expressed genes, we identified the enrichment of traits of intelligence, cognitive function and schizophrenia, while DEPs in ASTs were significantly associated with intelligence and depression.
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Affiliation(s)
- Stanley K K Cheung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Jacinda Kwok
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada
| | - Penelope M Y Or
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Chi Wai Wong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Bo Feng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Kwong Wai Choy
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Raymond C C Chang
- Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China
| | - J Peter H Burbach
- Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Alfred S L Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Andrew M Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.
- Brain and Mind Institute, The Chinese University of Hong Kong, 4/F, Hui Yeung Shing Building, Hong Kong, SAR, China.
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15
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Kim K, Yoon H. Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease. Int J Mol Sci 2023; 24:ijms24054584. [PMID: 36902014 PMCID: PMC10003236 DOI: 10.3390/ijms24054584] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA's beneficial and toxic effects on metabolic disease progression.
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16
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Langdon CG. Nuclear PTEN's Functions in Suppressing Tumorigenesis: Implications for Rare Cancers. Biomolecules 2023; 13:biom13020259. [PMID: 36830628 PMCID: PMC9953540 DOI: 10.3390/biom13020259] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers.
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Affiliation(s)
- Casey G. Langdon
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; ; Tel.: +1-(843)-792-9289
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
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17
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PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. iScience 2023; 26:106070. [PMID: 36824269 PMCID: PMC9942123 DOI: 10.1016/j.isci.2023.106070] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/01/2022] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We demonstrate that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data indicate that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatment of PTEN mutant melanoma.
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18
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Tibarewal P, Rathbone V, Constantinou G, Pearce W, Adil M, Varyova Z, Folkes L, Hampson A, Classen GAE, Alves A, Carvalho S, Scudamore CL, Vanhaesebroeck B. Long-term treatment of cancer-prone germline PTEN mutant mice with low-dose rapamycin extends lifespan and delays tumour development. J Pathol 2022; 258:382-394. [PMID: 36073856 PMCID: PMC9828006 DOI: 10.1002/path.6009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/19/2022] [Accepted: 09/05/2022] [Indexed: 01/19/2023]
Abstract
PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
| | | | | | - Wayne Pearce
- Cancer Institute, University College London, London, UK
| | - Mahreen Adil
- Cancer Institute, University College London, London, UK
| | - Zofia Varyova
- Cancer Institute, University College London, London, UK
| | - Lisa Folkes
- Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Alix Hampson
- Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | | | - Adriana Alves
- Cancer Institute, University College London, London, UK
| | - Sara Carvalho
- Cancer Institute, University College London, London, UK
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19
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Targeting PTEN Regulation by Post Translational Modifications. Cancers (Basel) 2022; 14:cancers14225613. [PMID: 36428706 PMCID: PMC9688753 DOI: 10.3390/cancers14225613] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Phosphatidylinositol-3,4,5-triphosphate (PIP3) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP3 levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP3 is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP3 levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP3 dephosphorylation to PIP2. PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors.
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20
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Hedna R, Kovacic H, Pagano A, Peyrot V, Robin M, Devred F, Breuzard G. Tau Protein as Therapeutic Target for Cancer? Focus on Glioblastoma. Cancers (Basel) 2022; 14:5386. [PMID: 36358803 PMCID: PMC9653627 DOI: 10.3390/cancers14215386] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 08/27/2023] Open
Abstract
Despite being extensively studied for several decades, the microtubule-associated protein Tau has not finished revealing its secrets. For long, Tau has been known for its ability to promote microtubule assembly. A less known feature of Tau is its capability to bind to cancer-related protein kinases, suggesting a possible role of Tau in modulating microtubule-independent cellular pathways that are associated with oncogenesis. With the intention of finding new therapeutic targets for cancer, it appears essential to examine the interaction of Tau with these kinases and their consequences. This review aims at collecting the literature data supporting the relationship between Tau and cancer with a particular focus on glioblastoma tumors in which the pathological significance of Tau remains largely unexplored. We will first treat this subject from a mechanistic point of view showing the pivotal role of Tau in oncogenic processes. Then, we will discuss the involvement of Tau in dysregulating critical pathways in glioblastoma. Finally, we will outline promising strategies to target Tau protein for the therapy of glioblastoma.
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Affiliation(s)
- Rayane Hedna
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
| | - Hervé Kovacic
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
| | - Alessandra Pagano
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
| | - Vincent Peyrot
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
| | - Maxime Robin
- Faculté de Pharmacie, Institut Méditerranéen de Biodiversité et Ecologie marine et continentale (IMBE), UMR 7263, CNRS, IRD 237, Aix-Marseille Université, 13005 Marseille, France
| | - François Devred
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
| | - Gilles Breuzard
- Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
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Basak D, Gregori L, Johora F, Deb S. Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101607. [PMID: 36295041 PMCID: PMC9605520 DOI: 10.3390/life12101607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/11/2022]
Abstract
The incidence and mortality from prostate cancer (PCa) are on the rise which poses a major public health concern worldwide. In this narrative review, we have summarized the characteristics of major in vitro and in vivo PCa models including their utility in developing treatment strategies. Androgens, particularly, testosterone and dihydrotestosterone (DHT) activate the androgen receptor (AR) signaling pathway that facilitates the development and progression of castration resistant PCa. Several enzymes namely, CYP17A1, HSD17B, and SRD5A are essential to furnishing DHT from dehydroepiandrosterone in the classical pathway while DHT is formed from androstanediol in the backdoor pathway. The advancement in delineating the molecular heterogeneity of PCa has been possible through the development of several in vitro and in vivo research models. Generally, tissue culture models are advantageous to understand PCa biology and investigate the efficacy and toxicity of novel agents; nevertheless, animal models are indispensable to studying the PCa etiology and treatment since they can simulate the tumor microenvironment that plays a central role in initiation and progression of the disease. Moreover, the availability of several genetically engineered mouse models has made it possible to study the metastasis process. However, the conventional models are not devoid of limitations. For example, the lack of heterogeneity in tissue culture models and the variation of metastatic characteristics in xenograft models are obviously challenging. Additionally, due to the racial and ethnic disparities in PCa pathophysiology, a new model that can represent PCa encompassing different ethnicities is urgently needed. New models should continue to evolve to address the genetic and molecular complexities as well as to further elucidate the finer details of the steroidogenic pathway associated with PCa.
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22
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PTEN Dual Lipid- and Protein-Phosphatase Function in Tumor Progression. Cancers (Basel) 2022; 14:cancers14153666. [PMID: 35954330 PMCID: PMC9367293 DOI: 10.3390/cancers14153666] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a multifunctional tumor suppressor with protein- and lipid-phosphatase activities. The inactivation of PTEN is commonly found in all human cancers and is correlated with tumor progression. PTEN-lipid-phosphatase activity has been well documented to dephosphorylate phosphatidylinositol-3, 4, 5-phosphate (PIP3), which hinders cell growth and survival by dampening the PI3K and AKT signaling activity. PTEN-protein-phosphatase activity is less well studied and understood. Recent studies have reported that PTEN-protein-phosphatase activity dephosphorylates the different proteins and acts in various cell functions. We here review the PTEN mutations and protein-phosphatase substrates in tumor progression. We aim to address the gap in our understanding as to how PTEN protein phosphatase contributes to its tumor-suppression functions. Abstract PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities.
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23
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Mai CW, Chin KY, Foong LC, Pang KL, Yu B, Shu Y, Chen S, Cheong SK, Chua CW. Modeling prostate cancer: What does it take to build an ideal tumor model? Cancer Lett 2022; 543:215794. [PMID: 35718268 DOI: 10.1016/j.canlet.2022.215794] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 06/10/2022] [Indexed: 11/17/2022]
Abstract
Prostate cancer is frequently characterized as a multifocal disease with great intratumoral heterogeneity as well as a high propensity to metastasize to bone. Consequently, modeling prostate tumor has remained a challenging task for researchers in this field. In the past decades, genomic advances have led to the identification of key molecular alterations in prostate cancer. Moreover, resistance towards second-generation androgen-deprivation therapy, namely abiraterone and enzalutamide has unveiled androgen receptor-independent diseases with distinctive histopathological and clinical features. In this review, we have critically evaluated the commonly used preclinical models of prostate cancer with respect to their capability of recapitulating the key genomic alterations, histopathological features and bone metastatic potential of human prostate tumors. In addition, we have also discussed the potential use of the emerging organoid models in prostate cancer research, which possess clear advantages over the commonly used preclinical tumor models. We anticipate that no single model can faithfully recapitulate the complexity of prostate cancer, and thus, propose the use of a cost- and time-efficient integrated tumor modeling approach for future prostate cancer investigations.
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Affiliation(s)
- Chun-Wai Mai
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, 43000, Malaysia
| | - Kok-Yong Chin
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, 56000, Malaysia
| | - Lian-Chee Foong
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, 43000, Malaysia
| | - Kok-Lun Pang
- Newcastle University Medicine Malaysia, Iskandar Puteri, 79200, Malaysia
| | - Bin Yu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Yu Shu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Sisi Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Soon-Keng Cheong
- Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, 43000, Malaysia
| | - Chee Wai Chua
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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24
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Chai C, Wu HH, Abuetabh Y, Sergi C, Leng R. Regulation of the tumor suppressor PTEN in triple-negative breast cancer. Cancer Lett 2022; 527:41-48. [PMID: 34902523 DOI: 10.1016/j.canlet.2021.12.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 01/01/2023]
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BCa) in which estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) are not expressed. Although TNBC cases account for approximately 15% of all BCa cases, TNBC patients' prognosis is poor compared with that of other BCa subtypes. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and migration by negatively regulating the PI3K/Akt pathway. PTEN is one of the most commonly inactivated tumor suppressors in BCa. PTEN inactivity is associated with larger tumor sizes, multiple lymph node metastases, and an aggressive triple-negative phenotype. This review primarily focuses on two key points: (1) PTEN and its function. (2) The regulation of tumor suppressor PTEN in TNBC. We provide a summary of genomic alterations of PTEN in BCa. We further discuss the transcriptional regulation of PTEN and how PTEN is regulated by posttranscription and posttranslational modification, as well as by protein interactions. Finally, we discuss the perspectives of the PTEN protein in TNBC.
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Affiliation(s)
- Chengsen Chai
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Key Laboratory of Clinical Laboratory Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - H Helena Wu
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Yasser Abuetabh
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Consolato Sergi
- Division of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
| | - Roger Leng
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
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25
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Yan Y, Shi H, Zhao Z, Wang S, Zhou S, Mu Y, Ding N, Lai Y, Zhao AZ, Cheng L, Li F. Adiponectin Deficiency Promotes Endometrial Carcinoma Pathogenesis and Development via Activation of
Mitogen‐Activated
Protein Kinase. J Pathol 2022; 257:146-157. [PMID: 35072951 DOI: 10.1002/path.5874] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 12/06/2021] [Accepted: 01/21/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Yunjing Yan
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Hui Shi
- Department of Pathology Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing Jiangsu Province China
| | - Zhenggang Zhao
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Shuai Wang
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Sujin Zhou
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Yunping Mu
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Ning Ding
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Yimei Lai
- Department of Pathology First Affiliated Hospital of Gannan Medical University Ganzhou Jiangxi Province China
| | - Allan Z. Zhao
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
| | - Lixian Cheng
- Key laboratory of Functional and Clinical Translational Medicine Xiamen Key Laboratory of Respiratory Diseases, Xiamen Medical College Xiamen Fujian Province China
| | - Fanghong Li
- The School of Biomedical and Pharmaceutical Sciences Guangdong University of Technology Guangzhou Guangdong Province China
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26
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Clipperton-Allen AE, Swick H, Botero V, Aceti M, Ellegood J, Lerch JP, Page DT. Pten haploinsufficiency causes desynchronized growth of brain areas involved in sensory processing. iScience 2022; 25:103796. [PMID: 35198865 PMCID: PMC8844819 DOI: 10.1016/j.isci.2022.103796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/25/2021] [Accepted: 01/18/2022] [Indexed: 01/16/2023] Open
Abstract
How changes in brain scaling relate to altered behavior is an important question in neurodevelopmental disorder research. Mice with germline Pten haploinsufficiency (Pten +/-) closely mirror the abnormal brain scaling and behavioral deficits seen in humans with macrocephaly/autism syndrome, which is caused by PTEN mutations. We explored whether deviation from normal patterns of growth can predict behavioral abnormalities. Brain regions associated with sensory processing (e.g., pons and inferior colliculus) had the biggest deviations from expected volume. While Pten +/- mice showed little or no abnormal behavior on most assays, both sexes showed sensory deficits, including impaired sensorimotor gating and hyporeactivity to high-intensity stimuli. Developmental analysis of this phenotype showed sexual dimorphism for hyporeactivity. Mapping behavioral phenotypes of Pten +/- mice onto relevant brain regions suggested abnormal behavior is likely when associated with relatively enlarged brain regions, while unchanged or relatively decreased brain regions have little predictive value.
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Affiliation(s)
| | - Hannah Swick
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Valentina Botero
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA,Doctoral Program in Chemical and Biological Sciences, The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL 33458, USA
| | - Massimiliano Aceti
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Jacob Ellegood
- Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
| | - Jason P. Lerch
- Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON M5T 3H7, Canada,Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK
| | - Damon T. Page
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA,Doctoral Program in Chemical and Biological Sciences, The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL 33458, USA,Corresponding author
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27
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Papa A, Pandolfi PP. PTEN in Immunity. Curr Top Microbiol Immunol 2022; 436:95-115. [DOI: 10.1007/978-3-031-06566-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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28
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Claridge SE, Cavallo JA, Hopkins BD. Patient-Derived In Vitro and In Vivo Models of Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1361:215-233. [DOI: 10.1007/978-3-030-91836-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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29
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Maru Y, Hippo Y. Two-Way Development of the Genetic Model for Endometrial Tumorigenesis in Mice: Current and Future Perspectives. Front Genet 2021; 12:798628. [PMID: 34956336 PMCID: PMC8696168 DOI: 10.3389/fgene.2021.798628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/23/2021] [Indexed: 12/23/2022] Open
Abstract
Endometrial cancer (EC) is the most common malignancy of the female reproductive tract worldwide. Although comprehensive genomic analyses of EC have already uncovered many recurrent genetic alterations and deregulated signaling pathways, its disease model has been limited in quantity and quality. Here, we review the current status of genetic models for EC in mice, which have been developed in two distinct ways at the level of organisms and cells. Accordingly, we first describe the in vivo model using genetic engineering. This approach has been applied to only a subset of genes, with a primary focus on Pten inactivation, given that PTEN is the most frequently altered gene in human EC. In these models, the tissue specificity in genetic engineering determined by the Cre transgenic line has been insufficient. Consequently, the molecular mechanisms underlying EC development remain poorly understood, and preclinical models are still limited in number. Recently, refined Cre transgenic mice have been created to address this issue. With highly specific gene recombination in the endometrial cell lineage, acceptable in vivo modeling of EC development is warranted using these Cre lines. Second, we illustrate an emerging cell-based model. This hybrid approach comprises ex vivo genetic engineering of organoids and in vivo tumor development in immunocompromised mice. Although only a few successful cases have been reported as proof of concept, this approach allows quick and comprehensive analysis, ensuring a high potential for reconstituting carcinogenesis. Hence, ex vivo/in vivo hybrid modeling of EC development and its comparison with corresponding in vivo models may dramatically accelerate EC research. Finally, we provide perspectives on future directions of EC modeling.
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Affiliation(s)
- Yoshiaki Maru
- Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yoshitaka Hippo
- Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
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30
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Eritja N, Navaridas R, Ruiz-Mitjana A, Vidal-Sabanés M, Egea J, Encinas M, Matias-Guiu X, Dolcet X. Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation. Cancers (Basel) 2021; 13:cancers13194990. [PMID: 34638474 PMCID: PMC8507901 DOI: 10.3390/cancers13194990] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/01/2021] [Accepted: 10/01/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary PTEN is a protein highly altered in endometrial cancer. PTEN mutation or deficiency leads to the activation of other downstream proteins that are important to the development of cancers. In this study, we have identified the SMAD2/3 proteins as targets of PTEN deficiency. We have found that loss of PTEN in endometrial cells leads to SMAD2/3 activation. To investigate the role of SMAD2/3 activation downstream of PTEN deficiency, we have used endometrial cells lacking both PTEN and SMAD2/3 proteins. These cells display even more tumorigenic potential than cells lacking only PTEN. These results suggest that SMAD2/3 acts as an obstacle for cancer development triggered by PTEN loss. Abstract TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways’ contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency.
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Affiliation(s)
- Núria Eritja
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
| | - Raúl Navaridas
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
| | - Anna Ruiz-Mitjana
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
| | - Maria Vidal-Sabanés
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
| | - Joaquim Egea
- Molecular Developmental Neurobiology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, 25198 Lleida, Spain;
| | - Mario Encinas
- Developmental and Oncogenic Signalling Group, Departament de Medicina Experimental, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, 25198 Lleida, Spain;
| | - Xavier Matias-Guiu
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
- Department of Pathology, Hospital Universitari de Bellvitge, 08908 Barcelona, Spain
| | - Xavier Dolcet
- Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Institut de Recerca Biomèdica de Lleida, IRBLleida, Universitat de Lleida, Centro de Investigación Biomédica en Red Cáncer CIBERONC, 25198 Lleida, Spain; (N.E.); (R.N.); (A.R.-M.); (M.V.-S.); (X.M.-G.)
- Correspondence:
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31
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Clipperton-Allen AE, Zhang A, Cohen OS, Page DT. Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice. Genes (Basel) 2021; 12:1366. [PMID: 34573348 PMCID: PMC8468545 DOI: 10.3390/genes12091366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/20/2021] [Accepted: 08/26/2021] [Indexed: 01/16/2023] Open
Abstract
Pten germline haploinsufficient (Pten+/-) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical-subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/- mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal "hard-wired" connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/- mice and their wild-type littermates from weaning under either standard (4-5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9-10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/- mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/- mice and partially rescued increased repetitive behavior in Pten+/- males. We found that Pten+/- mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/- mice, possibly through normalizing the excitatory synaptic protein abundance.
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Affiliation(s)
| | | | | | - Damon Theron Page
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; (A.E.C.-A.); (A.Z.); (O.S.C.)
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32
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Zhai J, Zhang J, Zhang L, Liu X, Deng W, Wang H, Zhang Z, Liu W, Chen B, Wu C, Long H, Xu B, Ying X, Zou H, He J, Li P, Hu T, Xiang W, Li J. Autotransplantation of the ovarian cortex after in-vitro activation for infertility treatment: a shortened procedure. Hum Reprod 2021; 36:2134-2147. [PMID: 34268564 DOI: 10.1093/humrep/deab143] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 05/10/2021] [Indexed: 12/26/2022] Open
Abstract
STUDY QUESTION Is it possible to establish a new in-vitro activation (IVA) protocol for infertility treatment? SUMMARY ANSWER A new IVA procedure is an efficient and easily performed approach for infertility treatment of patients with diminished ovarian reserve (DOR). WHAT IS KNOWN ALREADY IVA of primordial follicles with or without stimulators has been developed to treat patients with primary ovarian insufficiency (POI) successfully. However, the efficiency of the procedure is still very low. There is a requirement to optimize the protocol with increased efficiency for clinical application. STUDY DESIGN, SIZE, DURATION Newborn mouse ovaries were used to establish a new 1-h IVA protocol with the mechanistic target of rapamycin (mTOR) stimulator phosphatidic acid (PA, 200 µM) and the phosphatidylinositol-3-kinase (PI3K) stimulator 740Y-P (250 µg/ml); a prospective observational cohort study in POI patients was performed on 15 POI patients and 3 poor ovarian response (POR) patients in three different centers of reproductive medicine in China. PARTICIPANTS/MATERIALS, SETTING, METHODS One-third of ovarian cortex was removed and processed into bigger strips (1 × 1 cm2, 1-2 mm thickness). Strips were then sutured back after treatment. The new approach only requires one laparoscopic surgery. MAIN RESULTS AND THE ROLE OF CHANCE Follicular activation and development increased in cultured mouse and human ovarian tissues after 1 h of stimulator treatment. Compared with tiny ovarian cortex pieces (1 × 1 mm2), large ovarian strips (1 × 1 cm2) showed the lowest apoptotic signals after incubation. We applied the orthotropic transplantation procedure with large strips in the clinic, and 9 of 15 POI patients showed at least one-wave follicular growth during the monitoring period. One patient was reported with one healthy delivery after natural conception and another patient with a healthy singleton delivery after IVF. All the contacted patients (n = 13) responded with no side effects on their health 2-4 years after IVA procedure. LIMITATIONS, REASONS FOR CAUTION Further clinical trials with a large number of well-defined patients are required to compare different IVA protocols. A long-term follow-up system should be set up to monitor patient's health in the future cohort study. WIDER IMPLICATIONS OF THE FINDINGS By using stimulators, the findings in the study provide a more efficient IVA protocol for the treatment of patients with DOR. It requires only one laparoscopic surgery and thus minimizes patients' discomfort and costs. This strategy could be useful for patients diagnosed with POI and desire pregnancy as soon as possible after the operation. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Key Research and Development Program of China (2018YFC1003703 and 2018YFC1004203); the National Natural Science Foundation of China (81871221); Co-construction of Provincial Department (201601006). The authors have no conflict of interest to disclose. TRIAL REGISTRATION NUMBER ChiCTR2000030872.
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Affiliation(s)
- Jun Zhai
- Institute of Reproductive Health, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Zhang
- Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Zhang
- Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaochun Liu
- Shenzhen IVF Gynecological Hospital, Shenzhen, China
| | - Weifen Deng
- Reproductive Medicine Center, Shenzhen Hengsheng Hospital, Shenzhen, China
| | - Hong Wang
- Beijing Jiaen Hospital, Bejing, China
| | - Zhiguo Zhang
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wei Liu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Beili Chen
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chongbo Wu
- Shenzhen IVF Gynecological Hospital, Shenzhen, China
| | - Huidong Long
- Shenzhen IVF Gynecological Hospital, Shenzhen, China
| | - Boqun Xu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyan Ying
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huijuan Zou
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jun He
- Nanjing Ovahealth Biotechnology, Nanjing, China
| | - Pei Li
- Beijing Jiaen Hospital, Bejing, China
| | - Tiling Hu
- Beijing Jiaen Hospital, Bejing, China
| | - Wenpei Xiang
- Institute of Reproductive Health, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Nascimento-Gonçalves E, Seixas F, Ferreira R, Colaço B, Parada B, Oliveira PA. An overview of the latest in state-of-the-art murine models for prostate cancer. Expert Opin Drug Discov 2021; 16:1349-1364. [PMID: 34224283 DOI: 10.1080/17460441.2021.1943354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Prostate cancer (PCa) is a complex, heterogenous and multifocal disease, which is debilitating for patients and often fatal - due to bone metastasis and castration-resistant cancer. The use of murine models that mimic human disease has been crucial in the development of innovative therapies and for better understanding the mechanisms associated with initiation and progression of PCa. AREAS COVERED This review presents a critical analysis of murine models for the study of PCa, highlighting their strengths, weaknesses and applications. EXPERT OPINION In animal models, disease may not occur exactly as it does in humans, and sometimes the levels of efficacy that certain treatments obtain in animal models cannot be translated into clinical practice. To choose the most appropriate animal model for each research work, it is crucial to understand the anatomical and physiological differences between the mouse and the human prostate, while it is also important to identify biological similarities and differences between murine and human prostate tumors. Although significant progress has already been made, thanks to many years of research and study, the number of new challenges and obstacles to overcome mean there is a long and difficult road still to travel.
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Affiliation(s)
- Elisabete Nascimento-Gonçalves
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, UTAD, Vila Real, Portugal.,Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology (Laqv-requimte),department of Chemistry, University of Aveiro (UA), Portugal
| | - Fernanda Seixas
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,Animal and Veterinary Research Centre (CECAV), UTAD, Vila Real, Portugal
| | - Rita Ferreira
- Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology (Laqv-requimte),department of Chemistry, University of Aveiro (UA), Portugal
| | - Bruno Colaço
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, UTAD, Vila Real, Portugal.,Department of Zootechnics, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Belmiro Parada
- Faculty of Medicine, University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (Icbr), Coimbra, Portugal.,University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.,Urology and Renal Transplantation Department, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal
| | - Paula A Oliveira
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, UTAD, Vila Real, Portugal
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Tissue distribution and developmental changes of PTEN in the immune organs of chicken and effect of IBDV infection on it. Poult Sci 2021; 100:101356. [PMID: 34358959 PMCID: PMC8350381 DOI: 10.1016/j.psj.2021.101356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/30/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, functions in antiviral innate immunity and regulates the development and function of T cells and B cells. However, limited information about PTEN is available in poultry. In the present study, quantitative real-time polymerase chain reaction and immunohistochemistry staining were used to study the tissue distribution and developmental changes of PTEN in the main immune organs of chicken. The effects of infectious bursal disease virus (IBDV) infection on PTEN mRNA expression in the bursa of Fabricius (BF) of chickens were also investigated. The results are as follows. 1) The order of PTEN mRNA expression levels at the 18th d of hatching (E18) was: muscle and immune organs (spleen and thymus) > visceral organs (heart, lung, kidney, and liver) > hypothalamus and digestive tracts (duodenum, jejunum, ileum, cecum, proventriculus, BF [originates from cloaca], and cecum tonsil [locates at the lamina propria of cecum]). However, at the 15th d of raising (D15), the PTEN mRNA expression in the heart was the highest among all the tissues, followed by those in the liver, proventriculus, and kidney. The PTEN mRNA expression levels in the rest tissues were very low and were only 1.20 to 19.47% as much as that in the heart (P < 0.05). 2) The changes in the expression of PTEN mRNA in the BF, spleen, and thymus from E15 to D15 had no obvious regularity. PTEN-immunopositive (PTEN-ip) cells in the BF were distributed in epithelium mucosa, bursal follicles and interfollicles before hatching, but only in bursal follicles after hatching. PTEN-ip cells in the spleen were expressed in the periarterial lymphatic sheath from E18 to D15. Most of PTEN-ip cells distributed in the thymic medulla and only a few distributed in the thymic cortex during the whole experiment. 3) Chicken with IBDV infection had a remarkable decrease in PTEN mRNA expression from 1 d postinfection (dpi) to 7 dpi. Although PTEN mRNA level was reversed at 7 dpi, it was still significantly lower than that at 0 dpi (P < 0.05). These findings suggest that the PTEN of chicken might play important roles in the development of embryos and T/B lymphocytes, and the downregulation of PTEN in chickens infected with IBDV might be a mechanism of IBDV evasion from host immunity. Strategies designed to restore PTEN expression may be a therapy for preventing chickens from IBDV infection.
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Maru Y, Tanaka N, Tatsumi Y, Nakamura Y, Itami M, Hippo Y. Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition. Oncogenesis 2021; 10:46. [PMID: 34172714 PMCID: PMC8233399 DOI: 10.1038/s41389-021-00337-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/04/2021] [Accepted: 06/10/2021] [Indexed: 01/06/2023] Open
Abstract
KRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.
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Affiliation(s)
- Yoshiaki Maru
- Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Naotake Tanaka
- Department of Gynecology, Chiba Cancer Center, Chiba, Japan
| | - Yasutoshi Tatsumi
- Division of Oncogenomics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yuki Nakamura
- Division of Oncogenomics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Makiko Itami
- Division of Surgical Pathology, Chiba Cancer Center, Chiba, Japan
| | - Yoshitaka Hippo
- Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan.
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Regua AT, Arrigo A, Doheny D, Wong GL, Lo HW. Transgenic mouse models of breast cancer. Cancer Lett 2021; 516:73-83. [PMID: 34090924 DOI: 10.1016/j.canlet.2021.05.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 11/26/2022]
Abstract
Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling of abnormal genetic events frequently found in human breast cancers. Genetically engineered mouse models (GEMMs) of breast cancer employ tissue-specific genetic manipulation for tumorigenic induction within the mammary tissue. Under the transcriptional control of mammary-specific promoters, transgenic mouse models can simulate spontaneous mammary tumorigenesis by expressing one or more putative oncogenes, such as MYC, HRAS, and PIK3CA. Alternatively, the Cre-Lox system allows for tissue-specific deletion of tumor suppressors, such as p53, Rb1, and Brca1, or specific knock-in of putative oncogenes. Thus, GEMMs can be designed to implement one or more genetic events to induce mammary tumorigenesis. Features of GEMMs, such as age of transgene expression, breeding quality, tumor latency, histopathological characteristics, and propensity for local and distant metastasis, are variable and strain-dependent. This review aims to summarize currently available transgenic breast cancer mouse models that undergo spontaneous mammary tumorigenesis upon genetic manipulation, their varying characteristics, and their individual genetic manipulations that model aberrant signaling events observed in human breast cancers.
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Affiliation(s)
- Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
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Igarashi A, Kato T, Sesaki H, Iijima M. Nuclear PTEN deficiency and heterozygous PTEN loss have distinct impacts on brain and lymph node size. Biochem Biophys Res Commun 2021; 555:81-88. [PMID: 33813280 PMCID: PMC8085137 DOI: 10.1016/j.bbrc.2021.03.081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 01/08/2023]
Abstract
Defects in PTEN, a critical tumor suppressor, are associated with tumorigenesis and aberrant organ sizes. It has been shown that heterozygous PTEN loss increases brains and neuron size, while the specific loss of nuclear PTEN has the opposite effect. Here, we investigate the impact of a combination of heterozygous PTEN loss and nuclear PTEN loss on the size of various organs, including the brain, liver, thymus, spleen, and inguinal lymph node. We found that the effect of the combination varies among organs. Notably, the combination of heterozygous PTEN loss and nuclear PTEN loss restored the normal size of brains and neurons. In contrast, the liver's size was unaffected by either single PTEN defects or their combination. Strikingly, the size of the inguinal lymph node was greatly increased due to lymphoma by the combination of the two PTEN defects. These data suggest that nuclear PTEN and non-nuclear PTEN function in an antagonistic manner in the brain while acting synergistically in the inguinal lymph node.
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Affiliation(s)
- Atsushi Igarashi
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Takashi Kato
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Miho Iijima
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Lottini T, Iorio J, Lastraioli E, Carraresi L, Duranti C, Sala C, Armenio M, Noci I, Pillozzi S, Arcangeli A. Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses. Sci Rep 2021; 11:8847. [PMID: 33893331 PMCID: PMC8065064 DOI: 10.1038/s41598-021-87492-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 03/18/2021] [Indexed: 11/26/2022] Open
Abstract
The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.
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Affiliation(s)
- Tiziano Lottini
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | | | - Claudia Duranti
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Cesare Sala
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Miriam Armenio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Ivo Noci
- Department of Biochemical, Experimental and Clinical Science, University of Florence, Florence, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni, 50, 50134, Florence, Italy.
- CSDC-Center for the Study of Complex Dynamics, 50019, Sesto Fiorentino, Florence, Italy.
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Prolonged atrazine exposure beginning in utero and adult uterine morphology in mice. J Dev Orig Health Dis 2021; 13:39-48. [PMID: 33781367 DOI: 10.1017/s2040174421000106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Through drinking water, humans are commonly exposed to atrazine, a herbicide that acts as an endocrine and metabolic disruptor. It interferes with steroidogenesis, including promoting oestrogen production and altering cell metabolism. However, its precise impact on uterine development remains unknown. This study aimed to determine the effect of prolonged atrazine exposure on the uterus. Pregnant mice (n = 5/group) received 5 mg/kg body weight/day atrazine or DMSO in drinking water from gestational day 9.5 until weaning. Offspring continued to be exposed until 3 or 6 months of age (n = 5-9/group), when uteri were collected for morphological and molecular analyses and steroid quantification. Endometrial hyperplasia and leiomyoma were evident in the uteri of atrazine-exposed mice. Uterine oestrogen concentration, oestrogen receptor expression, and localisation were similar between groups, at both ages (P > 0.1). The expression and localisation of key epithelial-to-mesenchymal transition (EMT) genes and proteins, critical for tumourigenesis, remained unchanged between treatments, at both ages (P > 0.1). Hence, oestrogen-mediated changes to established EMT markers do not appear to underlie abnormal uterine morphology evident in atrazine exposure mice. This is the first report of abnormal uterine morphology following prolonged atrazine exposure starting in utero, it is likely that the abnormalities identified would negatively affect female fertility, although mechanisms remain unknown and require further study.
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Qi Y, Liu J, Chao J, Greer PA, Li S. PTEN dephosphorylates Abi1 to promote epithelial morphogenesis. J Cell Biol 2021; 219:151941. [PMID: 32673396 PMCID: PMC7480098 DOI: 10.1083/jcb.201910041] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 04/08/2020] [Accepted: 06/08/2020] [Indexed: 12/20/2022] Open
Abstract
The tumor suppressor PTEN is essential for early development. Its lipid phosphatase activity converts PIP3 to PIP2 and antagonizes the PI3K–Akt pathway. In this study, we demonstrate that PTEN’s protein phosphatase activity is required for epiblast epithelial differentiation and polarization. This is accomplished by reconstitution of PTEN-null embryoid bodies with PTEN mutants that lack only PTEN’s lipid phosphatase activity or both PTEN’s lipid and protein phosphatase activities. Phosphotyrosine antibody immunoprecipitation and mass spectrometry were used to identify Abi1, a core component of the WASP-family verprolin homologous protein (WAVE) regulatory complex (WRC), as a new PTEN substrate. We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. This leads to down-regulation of the WRC and reorganization of the actin cytoskeleton. The latter is critical to the transformation of nonpolar pluripotent stem cells into the polarized epiblast epithelium. Our findings establish a link between PTEN and WAVE-Arp2/3–regulated actin cytoskeletal dynamics in epithelial morphogenesis.
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Affiliation(s)
- Yanmei Qi
- Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ
| | - Jie Liu
- Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ
| | - Joshua Chao
- Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ
| | - Peter A Greer
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Shaohua Li
- Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ
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Yip HYK, Papa A. Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments. Cells 2021; 10:659. [PMID: 33809714 PMCID: PMC8002322 DOI: 10.3390/cells10030659] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/12/2021] [Accepted: 03/13/2021] [Indexed: 12/13/2022] Open
Abstract
Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.
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Affiliation(s)
| | - Antonella Papa
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia;
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Hofving T, Elias E, Rehammar A, Inge L, Altiparmak G, Persson M, Kristiansson E, Johansson ME, Nilsson O, Arvidsson Y. SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors. BMC Cancer 2021; 21:101. [PMID: 33509126 PMCID: PMC7841913 DOI: 10.1186/s12885-021-07786-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 01/02/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. METHODS Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC. RESULTS Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. CONCLUSIONS Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.
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Affiliation(s)
- Tobias Hofving
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Erik Elias
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anna Rehammar
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
| | - Linda Inge
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Gülay Altiparmak
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Marta Persson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Erik Kristiansson
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
| | - Martin E Johansson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Ola Nilsson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Yvonne Arvidsson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden.
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Deng R, Guo Y, Li L, He J, Qiang Z, Zhang H, Chen R, Wang Y, Zhao X, Yu J. BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN. Mol Oncol 2021; 15:279-298. [PMID: 33155366 PMCID: PMC7782096 DOI: 10.1002/1878-0261.12844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/17/2020] [Accepted: 10/21/2020] [Indexed: 01/25/2023] Open
Abstract
Deubiquitinase BAP1 is an important tumor suppressor in several malignancies, but its functions and critical substrates in prostate cancer (PCa) remain unclear. Here, we report that the mRNA and protein expression levels of BAP1 are downregulated in clinical PCa specimens. BAP1 can physically bind to and deubiquitinate PTEN, which inhibits the ubiquitination-mediated degradation of PTEN and thus stabilizes PTEN protein. Ectopically expressed BAP1 in PCa cells increases PTEN protein level and subsequently inhibits the AKT signaling pathway, thus suppressing PCa progression. Conversely, knockdown of BAP1 in PCa cells leads to the decrease in PTEN protein level and the activation of the Akt signaling pathway, therefore promoting malignant transformation and cancer metastasis. However, these can be reversed by the re-expression of PTEN. More importantly, we found that BAP1 protein level positively correlates with PTEN in a substantial fraction of human cancers. These findings demonstrate that BAP1 is an important deubiquitinase of PTEN for its stability and the BAP1-PTEN signaling axis plays a crucial role in tumor suppression.
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Affiliation(s)
- Rong Deng
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yanmin Guo
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lian Li
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jianfeng He
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhe Qiang
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hailong Zhang
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ran Chen
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yanli Wang
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xian Zhao
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
- Basic Clinical Research CenterRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jianxiu Yu
- Department of Biochemistry and Molecular Cell BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghaiChina
- Basic Clinical Research CenterRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
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Sinha D, Nag P, Nanayakkara D, Duijf PHG, Burgess A, Raninga P, Smits VAJ, Bain AL, Subramanian G, Wall M, Finnie JW, Kalimutho M, Khanna KK. Cep55 overexpression promotes genomic instability and tumorigenesis in mice. Commun Biol 2020; 3:593. [PMID: 33087841 PMCID: PMC7578791 DOI: 10.1038/s42003-020-01304-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 09/17/2020] [Indexed: 12/16/2022] Open
Abstract
High expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53+/− induced tumours in vivo. At the cellular level, using mouse embryonic fibroblasts (MEFs), we demonstrate that Cep55 overexpression induces proliferation advantage by modulating multiple cellular signalling networks including the hyperactivation of the Pi3k/Akt pathway. Notably, Cep55 overexpressing MEFs have a compromised Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, resulting in a prolonged aberrant mitotic division. Importantly, this phenotype was rescued by pharmacological inhibition of Pi3k/Akt or expression of mutant Chk1 (S280A) protein, which is insensitive to regulation by active Akt, in Cep55 overexpressing MEFs. Moreover, we report that Cep55 overexpression causes stabilized microtubules. Collectively, our data demonstrates causative effects of deregulated Cep55 on genome stability and tumorigenesis which have potential implications for tumour initiation and therapy development. Sinha et al. demonstrate that overexpression of centrosomal protein Cep55 in mice is sufficient to cause a wide-spectrum of cancer via multiple mechanisms including hyperactivation of the Pi3k/Akt pathway, stabilized microtubules and a defective replication checkpoint response. These findings are relevant to human cancers as high CEP55 expression is associated with worse prognosis across multiple cancer types.
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Affiliation(s)
- Debottam Sinha
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.,School of Environment and Sciences, Griffith University, Nathan, 4111, QLD, Australia
| | - Purba Nag
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.,School of Environment and Sciences, Griffith University, Nathan, 4111, QLD, Australia.,Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland and Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, 4029, QLD, Australia
| | - Devathri Nanayakkara
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, 4102, QLD, Australia.,Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Andrew Burgess
- ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia
| | - Prahlad Raninga
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Veronique A J Smits
- Unidad de Investigación, Hospital Universitario de Canarias, Tenerife, Spain.,Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Tenerife, Spain.,Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
| | - Amanda L Bain
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Goutham Subramanian
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia
| | - Meaghan Wall
- Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, Melbourne, Australia
| | - John W Finnie
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide and SA Pathology, Adelaide, Australia
| | - Murugan Kalimutho
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006, QLD, Australia.
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45
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Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research. Cancers (Basel) 2020; 12:cancers12092651. [PMID: 32957478 PMCID: PMC7563251 DOI: 10.3390/cancers12092651] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 02/08/2023] Open
Abstract
Simple Summary The molecular progression of prostate cancer is complex and elusive. Biological research relies heavily on in vitro and in vivo models that can be used to examine gene functions and responses to the external agents in laboratory and preclinical settings. Over the years, several models have been developed and found to be very helpful in understanding the biology of prostate cancer. Here we describe these models in the context of available information on the cellular and molecular progression of prostate cancer to suggest their potential utility in basic and preclinical prostate cancer research. The information discussed herein should serve as a hands-on resource for scholars engaged in prostate cancer research or to those who are making a transition to explore the complex biology of prostate cancer. Abstract We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to be complex, and histological findings often do not provide an accurate assessment of disease aggressiveness and future course. Moreover, we also witness tremendous racial disparity in prostate cancer incidence and clinical outcomes necessitating a deeper understanding of molecular and mechanistic bases of prostate cancer. Biological research heavily relies on model systems that can be easily manipulated and tested under a controlled experimental environment. Over the years, several cancer cell lines have been developed representing diverse molecular subtypes of prostate cancer. In addition, several animal models have been developed to demonstrate the etiological molecular basis of the prostate cancer. In recent years, patient-derived xenograft and 3-D culture models have also been created and utilized in preclinical research. This review is an attempt to succinctly discuss existing information on the cellular and molecular progression of prostate cancer. We also discuss available model systems and their tested and potential utility in basic and preclinical prostate cancer research.
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Greidinger A, Miller-Samuel S, Giri VN, Woo MSA, Akumalla S, Zeigler-Johnson C, Keith SW, Silver DP. Neuroendocrine Tumors Are Enriched in Cowden Syndrome. JCO Precis Oncol 2020; 4:1900241. [PMID: 32923874 DOI: 10.1200/po.19.00241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2020] [Indexed: 11/20/2022] Open
Affiliation(s)
- Alison Greidinger
- Department of Medicine, Thomas Jefferson University, Philadelphia, PA
| | - Susan Miller-Samuel
- Cancer Risk Assessment and Clinical Cancer Genetics Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
| | - Veda N Giri
- Department of Medical Oncology and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.,Department of Urology, Thomas Jefferson University, Philadelphia, PA
| | | | | | | | - Scott W Keith
- Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA
| | - Daniel P Silver
- Department of Medical Oncology and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
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47
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Xia Q, Ali S, Liu L, Li Y, Liu X, Zhang L, Dong L. Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance. Front Oncol 2020; 10:1569. [PMID: 32984016 PMCID: PMC7492558 DOI: 10.3389/fonc.2020.01569] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.
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Affiliation(s)
- Qin Xia
- School of Life Sciences, Beijing Institute of Technology, Beijing, China
| | - Sakhawat Ali
- School of Life Sciences, Beijing Institute of Technology, Beijing, China
| | - Liqun Liu
- School of Life Sciences, Beijing Institute of Technology, Beijing, China
| | - Yang Li
- School of Life Sciences, Beijing Institute of Technology, Beijing, China
| | - Xuefeng Liu
- School of Electronic and Optical Engineering, Nanjing University of Science and Technology, Nanjing, China
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Lei Dong
- School of Life Sciences, Beijing Institute of Technology, Beijing, China
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48
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Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis. Proc Natl Acad Sci U S A 2020; 117:20538-20548. [PMID: 32788364 DOI: 10.1073/pnas.2002964117] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.
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49
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Parsons R. Discovery of the PTEN Tumor Suppressor and Its Connection to the PI3K and AKT Oncogenes. Cold Spring Harb Perspect Med 2020; 10:a036129. [PMID: 31932465 PMCID: PMC7397838 DOI: 10.1101/cshperspect.a036129] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PTEN (phosphatase and tensin homolog on chromosome 10) was discovered over 20 years ago in 1997 and linked to the phosphatidylinositol 3-kinase (PI3K) and AKT oncogenes the following year. The discovery of PTEN emerged from the linked concepts of oncogenes and tumor suppressor genes that cause and prevent cancer and the fields of tumor viruses and human cancer genetics from which these two concepts arose. While much has been learned since, the initial discovery and characterization, including the discovery that PTEN is a regulator of PI3K and AKT, provide the foundation on which we continue to build our knowledge. To provide the context in which these cancer genes were discovered, background information that led to their discovery will also be discussed, which will hopefully be a useful guide for readers seeking to build on the work of others.
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Affiliation(s)
- Ramon Parsons
- Department of Oncological Sciences, Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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50
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Overexpression of PTEN regulated by miR-19b and miR-494 in the villous of recurrent spontaneous abortion patients. J Reprod Immunol 2020; 140:103133. [DOI: 10.1016/j.jri.2020.103133] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 03/07/2020] [Accepted: 04/09/2020] [Indexed: 11/19/2022]
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