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المؤلفون: Abigail Camenisch, Isabella R. Blum, Stefanie A.T. Mitchell, Meng-Han Wu, Christopher M. Cox, Matthew T Ollerton, Pawel R. Kiela, Marco Padilla-Rodriguez, Vanessa Figliuolo da Paz, John Muller, Curtis A. Thorne, Jean M. Wilson, Samina Momtaz
المصدر: Dev Biol
مصطلحات موضوعية: Male, Endosome, Endocytic cycle, Crypt, Endosomes, Biology, Stem cell marker, Article, Mice, Lysosome, medicine, Animals, Intestinal Mucosa, Wnt Signaling Pathway, Molecular Biology, Cell Proliferation, Glycoproteins, Mice, Knockout, Microfilament Proteins, Wnt signaling pathway, LGR5, Cell Differentiation, Cell Biology, Intestinal epithelium, Cell biology, Intestines, Wnt Proteins, Enterocytes, medicine.anatomical_structure, Female, Developmental Biology
الوصف: During postnatal intestinal development, the intestinal epithelium is highly proliferative, and this proliferation is regulated by signaling in the intervillous and crypt regions. This signaling is primarily mediated by Wnt, and requires membrane trafficking. However, the mechanisms by which membrane trafficking regulates signaling during this developmental phase are largely unknown. Endotubin (EDTB, MAMDC4) is an endosomal protein that is highly expressed in the apical endocytic complex (AEC) of villus enterocytes during fetal and postnatal development, and knockout of EDTB results in defective formation of the AEC and giant lysosome. Further, knockout of EDTB in cell lines results in decreased proliferation. However, the role of EDTB in proliferation during the development of the intestine is unknown. Using Villin-CreERT2 in EDTB(fl/fl) mice, we deleted EDTB in the intestine in the early postnatal period, or in enteroids in vitro after isolation of intervillous cells. Loss of EDTB results in decreased proliferation in the developing intestinal epithelium and decreased ability to form enteroids. EDTB is present in cells that contain the stem cell markers LGR5 and OLFM4, indicating that it is expressed in the proliferative compartment. Further, using immunoblot analysis and TCF/LEF-GFP mice as a reporter of Wnt activity, we find that knockout of EDTB results in decreased Wnt signaling. Our results show that EDTB is essential for normal proliferation during the early stages of intestinal development and suggest that this effect is through modulation of Wnt signaling.
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المؤلفون: Elena Prigmore, Louis-François Handfield, Michael R. Stratton, Tong Li, Mercedes Jimenez-Linan, Lucy Gardner, Luz Garcia-Alonso, Tarryn Porter, Krishnaa T. Mahbubani, Vitalii Kleshchevnikov, Anna Arutyunyan, Hassan Massalha, Monika Dabrowska, Paul Ayuk, Kwasi Kwakwa, Ashley Moffett, Benjamin Woodhams, Kourosh Saeb-Parsy, Ridma C. Fernando, Regina Hoo, Elizabeth Tuck, Konstantina Nikolakopoulou, Stijn van Dongen, Valentina Lorenzi, Jong-Eun Park, Kenny Roberts, Cecilia Icoresi Mazzeo, Margherita Y. Turco, Vasyl Vaskivskyi, Martin Prete, Aleksandra Tarkowska, Roser Vento-Tormo, Krzysztof Polanski, Carmen Sancho-Serra, Cecilia Lindskog, Omer Ali Bayraktar, Vladimir Yu. Kiselev, Sarah A. Teichmann, Lia S. Campos, Luiza Moore
المساهمون: Roberts, Kenny [0000-0001-6155-0821], Nikolakopoulou, Konstantina [0000-0003-2306-590X], Woodhams, Benjamin [0000-0003-2801-5733], Arutyunyan, Anna [0000-0003-0453-5443], Polanski, Krzysztof [0000-0002-2586-9576], Li, Tong [0000-0002-8240-4476], Vaskivskyi, Vasyl [0000-0002-4080-4965], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Stratton, Michael R. [0000-0001-6035-153X], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Moffett, Ashley [0000-0002-8388-9073], Moore, Luiza [0000-0001-5315-516X], Bayraktar, Omer A. [0000-0001-6055-277X], Teichmann, Sarah A. [0000-0002-6294-6366], Vento-Tormo, Roser [0000-0002-9870-8474], Apollo - University of Cambridge Repository, Mahbubani, Krishnaa T [0000-0002-1327-2334], Stratton, Michael R [0000-0001-6035-153X], Bayraktar, Omer A [0000-0001-6055-277X], Teichmann, Sarah A [0000-0002-6294-6366], Mahbubani, Krishnaa [0000-0002-1327-2334], Teichmann, Sarah [0000-0002-6294-6366]
المصدر: Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
مصطلحات موضوعية: 631/45, Cell type, Notch signaling pathway, Reproduktionsmedicin och gynekologi, In Vitro Techniques, Cell fate determination, Biology, Endometrium, Tissue Culture Techniques, Transcriptome, Spatio-Temporal Analysis, Downregulation and upregulation, Obstetrics, Gynecology and Reproductive Medicine, Genetics, Organoid, medicine, Humans, Cell Lineage, Gonadal Steroid Hormones, Menstrual Cycle, Receptors, Notch, Uterus, article, Wnt signaling pathway, Cell Differentiation, Endometrial Neoplasms, Cell biology, Organoids, Wnt Proteins, medicine.anatomical_structure, Cellular Microenvironment, Female, 631/80, Signal Transduction
الوصف: The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively. Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6
وصف الملف: application/pdf; application/zip; text/xml
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المؤلفون: Zhenmin Wang, Zhizhong Li, Guozhi Xiao, Canling Long, Songlin Peng, Zhiteng Bao, He Xiaoqin, Chen Gaoyang, Wanze Tang, Xin Chen, Dazhi Yang, Tan Baoyu, William W. Lu, Shang Wang
المصدر: International Journal of Biological Sciences
مصطلحات موضوعية: Stromal cell, Ovariectomy, Bone Marrow Cells, Applied Microbiology and Biotechnology, Bone resorption, Bone remodeling, Pathogenesis, Bone Density, Osteogenesis, medicine, Animals, Humans, RNA, Messenger, RNA, Small Interfering, Piwi-interacting RNAs, Molecular Biology, Ecology, Evolution, Behavior and Systematics, beta Catenin, Aged, Glycoproteins, Bone Development, Chemistry, Stem Cells, Bone marrow stromal cells, Wnt signaling pathway, Cell Biology, Middle Aged, Wnt signaling, Rats, Wnt Proteins, medicine.anatomical_structure, Gene Expression Regulation, Bone formation, Ovariectomized rat, Cancer research, Osteoporosis, Female, Bone marrow, Signal transduction, Developmental Biology, Research Paper
الوصف: Bone remodeling is a dynamic process between bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Disrupted bone remodeling is a key factor in postmenopausal osteoporosis, a metabolic disorder characterized by deteriorated bone microarchitecture and increased risk of fracture. Recent studies have shown that piwi-binding RNA (piRNA) is involved in the pathogenesis of certain diseases at the post-transcriptional level. Here, we analyzed piRNA-63049 (piR-63049), which may play an essential role in bone remodeling. The expression of piR-63049 significantly increased in both bone tissues and plasma of osteoporotic rats and postmenopausal osteoporotic patients. Overexpressing piR-63049 could inhibit the osteoblastogenesis of bone marrow stromal cells (BMSCs) while knocking down piR-63049 could promote the osteoblastogenesis of BMSCs through the Wnt2b/β-catenin signaling pathway. Moreover, knocking-down piR-63049 (piR-63049-antagonist) in vivo could attenuate the bone loss in ovariectomized rats by promoting bone formation. Taken together, the current study shows that piR-63049 inhibits bone formation through the Wnt2b/β-catenin signaling pathway. This novel piRNA may be a potential target to increase bone formation in bone loss disorders such as postmenopausal osteoporosis.
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المؤلفون: Andrew P. Bradford, Elizabeth R. Woodruff, Benjamin G. Bitler, Rebecca J. Wolsky, Lubna Qamar, Marisa R. Moroney, Bradley R. Corr
المصدر: Molecular Carcinogenesis. 60:511-523
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Indazoles, Cell Survival, Pyridines, T cell, Cell, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, In vivo, Cell Line, Tumor, medicine, Humans, Molecular Targeted Therapy, Viability assay, Wnt Signaling Pathway, Molecular Biology, beta Catenin, Imidazoles, Wnt signaling pathway, Disease Management, Deoxyuridine, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, Wnt Proteins, 030104 developmental biology, medicine.anatomical_structure, chemistry, Tumor progression, Cell culture, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Disease Susceptibility, Heterocyclic Compounds, 3-Ring
الوصف: The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5'-bromo-2'-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690. Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC.
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المؤلفون: Yuanhong Xu, Zhongbo Zhang, Chenghai Zhao
المصدر: Cancer Medicine
Cancer Medicine, Vol 10, Iss 10, Pp 3332-3345 (2021)مصطلحات موضوعية: 0301 basic medicine, Male, Cancer Research, Cell, pancreatic cancer, Deoxycytidine, 0302 clinical medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, RC254-282, beta Catenin, Original Research, Cancer Biology, Gene knockdown, biology, Chemistry, CD24, Wnt signaling pathway, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, chemoresistance, Middle Aged, Up-Regulation, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Hyaluronan Receptors, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, Stem cell, 03 medical and health sciences, stemness, Downregulation and upregulation, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Radiology, Nuclear Medicine and imaging, Cell Proliferation, Fzd7/Wnt7b, CD44, CD24 Antigen, medicine.disease, Gemcitabine, Frizzled Receptors, Pancreatic Neoplasms, Wnt Proteins, 030104 developmental biology, Drug Resistance, Neoplasm, biology.protein, Cancer research, sense organs
الوصف: Mining databases and data obtained from assays on human specimens had shown that Fzd7 is closely associated with Wnt7b, that Fzd7/Wnt7b expression is upregulated in pancreatic cancer tissues compared with normal tissues, and its expression is negatively correlated with survival. Fzd7/Wnt7b knockdown in Capan‐2 and Panc‐1 cells reduced the proliferative capacity of pancreatic cancer stem cells (PCSCs), reduced drug resistance, decreased the percentage of CD24+CD44+ subset of cells and the levels of ABCG2, inhibited cell‐sphere formation, and reduced gemcitabine (GEM) resistance. In contrast, Fzd7/Wnt7b overexpression increased the percentage of the CD24+CD44+ subset of cells, and increased the levels of ABCG2 detected in cell spheroids. The gem‐resistant cells exhibited higher levels of Fzd7/Wnt7b expression, an increased percentage of CD24+CD44+ cells, and higher levels of ABCG2 compared with the parental cells. Taken together, Fzd7/Wnt7b knockdown can reduce PDAC cell stemness and chemoresistance by reducing the percentage of CSCs. Mechanistically, Fzd7 binds with Wnt7b and modulates the levels of β‐catenin, and they may exert their role via modulation of the canonical Wnt pathway.
This study aims to elucidate the regulatory mechanism of stemness and chemoresistance in pancreatic cancer, especially the role of Wnt signaling pathway on stemness and chemoresistance of pancreatic cancer. Fzd7/Wnt7b can regulate the proportion of CSC subset, so that they influence stemness and chemoresistance. -
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المؤلفون: Johannes Beckers, Fabian J. Theis, Wolfgang Enard, Maren Büttner, Christoph Ziegenhain, Heiko Lickert, Fien M. Verhamme, Lena Oppenländer, Anika Böttcher, Sophie Tritschler, Oliver Eickelberg, Michael Sterr, Andrea C. Schamberger, Alexandra Aliluev, Martin Irmler, Steffen Sass, Ingo Burtscher
المصدر: Nat. Cell Biol. 23, 23-31 (2021)
مصطلحات موضوعية: inorganic chemicals, Male, Paneth Cells, Lineage (genetic), Enteroendocrine Cells, Enteroendocrine cell, Biology, digestive system, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, Cell polarity, medicine, Animals, Cell Lineage, Cell Self Renewal, Intestinal Mucosa, beta Catenin, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Gene Expression Profiling, Stem Cells, Wnt signaling pathway, LGR5, Cell Polarity, Cell Biology, Cell biology, Mice, Inbred C57BL, Wnt Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Paneth cell, Female, Single-Cell Analysis, Stem cell
الوصف: A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to treat chronic intestinal diseases. However, the different models of ISC lineage hierarchy1–6 and segregation7–12 are subject to debate. Here, we have discovered non-canonical Wnt/planar cell polarity (PCP)-activated ISCs that are primed towards the enteroendocrine or Paneth cell lineage. Strikingly, integration of time-resolved lineage labelling with single-cell gene expression analysis revealed that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors7–12. Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5+ label-retaining cells7. Finally, Wnt/PCP-activated Lgr5+ ISCs are molecularly indistinguishable from Wnt/β-catenin-activated Lgr5+ ISCs, suggesting that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we redefine the mechanisms underlying ISC lineage hierarchy and identify the Wnt/PCP pathway as a new niche signal preceding lateral inhibition in ISC lineage priming and segregation. Polarity cues regulate intestinal stem cell fate. Bottcher et al. demonstrate that mouse intestinal stem cells, which express the Wnt/planar cell polarity reporter Flattop, are primed either towards the enteroendocrine or Paneth cell lineage.
وصف الملف: application/pdf
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المؤلفون: Morgane Le Rolle, Anne-Amandine Chassot, Pam Siggers, Filippo Massa, Marie-Christine Chaboissier, Bon-Kyoung Koo, Andreas Schedl, Hans Clevers, Agnès Loubat, Laurent Turchi, Andy Greenfield
المساهمون: Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), MRC Harwell Institute [UK], Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), ANR-20-CE14-0022,ARDIGERM,Acide rétinoïque dans la différenciation des cellules germinales et la méiose(2020), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Chaboissier, Marie-Christine, Acide rétinoïque dans la différenciation des cellules germinales et la méiose - - ARDIGERM2020 - ANR-20-CE14-0022 - AAPG2020 - VALID, Blanc 2013 - Acide rétinoique et devenir des cellules germinales - - ARGONADS2013 - ANR-13-BSV2-0017 - Blanc 2013 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Hubrecht Institute for Developmental Biology and Stem Cell Research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHASSOT, Anne Amandine
المصدر: Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2021, 118 (30), pp.e2023376118. ⟨10.1073/pnas.2023376118⟩
Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (30), pp.e2023376118. ⟨10.1073/pnas.2023376118⟩
Proceedings of the National Academy of Sciences of the United States of America, 118(30). National Academy of Sciencesمصطلحات موضوعية: Male, Pluripotent Stem Cells, germ cells, beta Catenin/genetics, Pluripotency & Differentiation, [SDV]Life Sciences [q-bio], Biology, Inbred C57BL, 03 medical and health sciences, Mice, 0302 clinical medicine, Meiosis, Primordial germ cell, medicine, Animals, Germ Cells/cytology, Wnt Proteins/genetics, Gametogenesis, beta Catenin, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Wnt signaling pathway, Cell Differentiation, Pluripotent Stem Cells/cytology, WNT/β-catenin, differentiation, Cell cycle, Biological Sciences, POU5F1/OCT4, Embryonic stem cell, Cell biology, Sexual reproduction, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Wnt Proteins, medicine.anatomical_structure, Female, ovary, Signal transduction, Octamer Transcription Factor-3, 030217 neurology & neurosurgery, Germ cell, Octamer Transcription Factor-3/genetics, Developmental Biology
الوصف: Significance In the mammalian ovary, primordial germ cells maintain a genomic program associated with pluripotency until they stop proliferating, move toward oogenesis, and enter meiosis. The molecular mechanisms that enable primordial germ cells to exit pluripotency and enter meiosis in a timely manner are unclear, and their identification represents a major challenge in reproductive biology because the fertility of each individual depends on this. Evidence that cessation of germ cell proliferation is a cell-autonomous event, unrelated to the number of cell divisions, led to a search for an intrinsic timing mechanism that has long remained elusive. We describe here that WNT/β-catenin signaling regulates this timing and coordinates the transition from pluripotent to gametogenesis-competent germ cells.
Germ cells form the basis for sexual reproduction by producing gametes. In ovaries, primordial germ cells exit the cell cycle and the pluripotency-associated state, differentiate into oogonia, and initiate meiosis. Despite the importance of germ cell differentiation for sexual reproduction, signaling pathways regulating their fate remain largely unknown. Here, we show in mouse embryonic ovaries that germ cell–intrinsic β-catenin activity maintains pluripotency and that its repression is essential to allow differentiation and meiosis entry in a timely manner. Accordingly, in β-catenin loss-of-function and gain-of-function mouse models, the germ cells precociously enter meiosis or remain in the pluripotent state, respectively. We further show that interaction of β-catenin and the pluripotent-associated factor POU5F1 in the nucleus is associated with germ cell pluripotency. The exit of this complex from the nucleus correlates with germ cell differentiation, a process promoted by the up-regulation of Znrf3, a negative regulator of WNT/β-catenin signaling. Together, these data identify the molecular basis of the transition from primordial germ cells to oogonia and demonstrate that β-catenin is a central gatekeeper in ovarian differentiation and gametogenesis.وصف الملف: application/pdf
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::32b8b5f82de617033f1b5409e3c126ab
https://hal.archives-ouvertes.fr/hal-03357217/document -
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المؤلفون: Pirjo Nummela, Colin Nixon, William C. Clark, Ella Gilchrist, Simon J. Leedham, Michael C. Hodder, Nalle Pentinmikko, Arafath Kaja Najumudeen, Nathalie Sphyris, E. Yvonne Jones, Jean-Paul Vincent, Hans Clevers, Nicky J. Willis, Alexander Raven, Kristina Kirschner, Dustin J. Flanagan, Paul V. Fish, Emma Minnee, Pekka Katajisto, Ville Hietakangas, Owen J. Sansom, Christine Perret, Lynn McGarry, Nadia Nasreddin, Rachel A. Ridgway, Ann C. Williams, Kathryn Gilroy, Kalle Luopajärvi, Sandra Scharaw, Béatrice Romagnolo, Marianne Lähde, Ari Ristimäki, Johanna Englund, Anna Taylor Webb, Kari Alitalo, Ann Hedley
المساهمون: Hubrecht Institute for Developmental Biology and Stem Cell Research, Institute of Biotechnology (-2009), University of Helsinki, CAN-PRO - Translational Cancer Medicine Program, Centre of Excellence in Stem Cell Metabolism, Helsinki Institute of Life Science HiLIFE, Institute of Biotechnology, Juha Klefström / Principal Investigator, Research Programs Unit, Department of Pathology, Doctoral Programme in Biomedicine, ATG - Applied Tumor Genomics, Doctoral Programme in Integrative Life Science, HUSLAB, Kari Alitalo / Principal Investigator, Molecular and Integrative Biosciences Research Programme, Biosciences, Nutrient sensing laboratory
المصدر: Nature, 594(7863), 430-435. Nature Publishing Group
Flanagan, D J, Williams, A C, Katajisto, P K, Sampson, O J & al., E 2021, ' NOTUM from Apc-mutant cells biases clonal competition to initiate cancer ', Nature, vol. 594, pp. 430–435 (2021) . https://doi.org/10.1038/s41586-021-03525-zمصطلحات موضوعية: 0301 basic medicine, Male, HOMEOSTASIS, Cell, medicine.disease_cause, Cell Transformation, Inbred C57BL, Ligands, BETA-CATENIN, ACTIVATION, PATHWAY, Mice, 0302 clinical medicine, Conditioned, INTESTINE, Stem Cells/cytology, Wnt Signaling Pathway, Cell Competition/genetics, Esterases/antagonists & inhibitors, Mutation, Multidisciplinary, biology, Stem Cells, Cell Transformation, Neoplastic/genetics, Wnt signaling pathway, Esterases, Cell Differentiation, Neoplastic/genetics, Cell biology, Organoids, POLYPOSIS, medicine.anatomical_structure, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Disease Progression, Organoids/cytology, Female, Stem cell, Colorectal Neoplasms, STEM-CELLS, BONE-FORMATION, Adenoma, Beta-catenin, Genes, APC, 3122 Cancers, Crypt, Adenomatous Polyposis Coli Protein, WNT, 03 medical and health sciences, Cancer stem cell, Wnt Proteins/metabolism, medicine, Animals, Humans, Adenomatous Polyposis Coli Protein/genetics, Cell Proliferation, Adenoma/genetics, Colorectal Neoplasms/genetics, Notum, Culture Media, APC, Wnt Proteins, Mice, Inbred C57BL, 030104 developmental biology, Genes, Cell Competition, Culture Media, Conditioned, biology.protein, 1182 Biochemistry, cell and molecular biology
الوصف: Funding Information: Acknowledgements We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287), and particularly the Biological Services Unit, Histology Service and Molecular Technologies; members of the Sansom and Katajisto laboratories for discussions of the data and manuscript; and BRC Oxford for supplying patient material. O.J.S. and his laboratory members were supported by Cancer Research UK (A28223, A21139, A12481 and A17196). D.J.F. and M.C.H. were supported by the UK Medical Research Council (MR/R017247/1 and MR/J50032X/1, respectively). SpecifiCancer CRUK Grand Challenge (C7932/A29055) is funded by Cancer Research UK and the Mark Foundation for Cancer Research. P.K. and his laboratory members were supported by the Academy of Finland Centre of Excellence MetaStem (266869, 304591 and 320185), the ERC Starting Grant 677809, the Swedish Research Council 2018-03078, the Cancerfonden 190634, the Jane and Aatos Erkko Foundation and the Cancer Foundation Finland. N.P. was supported by the Finnish Cultural Foundation, the Biomedicum Helsinki Foundation, the Orion Research Foundation sr and The Paulo Foundation. P.V.F. was supported by Alzheimer’s Research UK and The Francis Crick Institute. The ARUK UCL Drug Discovery Institute receives its core funding from Alzheimer’s Research UK (520909). The Francis Crick Institute receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling(1), but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)(2). Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
وصف الملف: application/pdf
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المؤلفون: Chenyao Li, Xinxin Chen, Guang Chen, Tao Liu
المصدر: Oncology Reports
مصطلحات موضوعية: Male, Cancer Research, Cell, Metastasis, Cell Movement, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Humans, papillary thyroid cancer, MTT assay, Thyroid Neoplasms, Cell Proliferation, Gene knockdown, Oncogene, lncRNA HOTAIRM1, Chemistry, Articles, General Medicine, Transfection, Middle Aged, Cell cycle, medicine.disease, Molecular medicine, Gene Expression Regulation, Neoplastic, Survival Rate, Wnt Proteins, MicroRNAs, miR-148a, medicine.anatomical_structure, Oncology, Lymphatic Metastasis, Cancer research, Female, Wnt10b, Signal Transduction
الوصف: Long non‑coding RNAs play a role in a variety of malignancies, such as thyroid cancer (TC). However, the effects and function of lincRNA HOTAIRM1 (LINC HOTAIRM1) in TC remains obscure. In the present study, the expression of HOTAIRM1 was evaluated in TC tissues and cells by RT‑qPCR and the association between the lncRNA and disease progression was assessed. In vitro, the biological function of HOTAIRM1 was assessed in TC. Moreover, changes in the expression of Wnt10b were measured by western blot analysis. In addition, MTT assay, bioinformatics analysis and luciferase assays were performed to determine the target binding effect between LINC HOTAIRM1 and miR‑148a, as well as that between Wnt10b and miR‑148a. The changes in the metastatic ability of TPC‑1 and BCPAP cells were evaluated by Transwell assay. The pronounced upregulated expression of HOTAIRM1 was evident in TC cells and tissues, and was associated with TNM stage and lymph node metastasis. When HOTAIRM1 was knocked down, this inhibited the proliferative and invasive abilities of TPC‑1 and BCPAP cells in vitro. The knockdown of this lncRNA also increased the expression of microRNA‑148a (miR‑148a) and decreased Wnt10b expression in these cells, whereas transfection with miR‑148a inhibitor was sufficient to overcome this Wnt10b downregulation. In line with these results, the overexpression of miR‑148a markedly suppressed Wnt10b expression, whereas miR‑148a inhibition resulted in the opposite effects. The overexpression of Wnt10b was also sufficient to overcome the effects of miR‑148a mimics on TPC‑1 and BCPAP cells. Taken together, these results suggest that miR‑148a and Wnt10b are downstream effectors of the HOTAIRM1 signaling pathway in TC. This HOTAIRM1/miR‑148a/Wnt10 axis may thus be amenable to therapeutic targeting in order to improve disease outcomes in patients with TC.
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المؤلفون: Gill Holdsworth, Hollie Allison, Laoise M. McNamara
المصدر: BMC Molecular and Cell Biology, Vol 21, Iss 1, Pp 1-15 (2020)
BMC Molecular and Cell Biologyمصطلحات موضوعية: 0301 basic medicine, Osteoclastogenesis, Oscillatory fluid flow, Cathepsin K, Mice, chemistry.chemical_compound, 0302 clinical medicine, Osteogenesis, biology, lcsh:Cytology, Intracellular Signaling Peptides and Proteins, Up-Regulation, Resorption, medicine.anatomical_structure, RANKL, Osteocyte, Female, Signal Transduction, Research Article, musculoskeletal diseases, medicine.medical_specialty, Cell signaling, medicine.drug_class, Sclerostin antibody, 030209 endocrinology & metabolism, Osteocytes, Bone resorption, CCN Intercellular Signaling Proteins, Mechanobiology, 03 medical and health sciences, Osteoclast, Proto-Oncogene Proteins, Internal medicine, medicine, Animals, Bone Resorption, lcsh:QH573-671, Molecular Biology, Adaptor Proteins, Signal Transducing, NFATC Transcription Factors, RANK Ligand, Osteoprotegerin, Membrane Proteins, Estrogen deficiency, Estrogens, Cell Biology, Antibodies, Neutralizing, Chemokine CXCL12, Coculture Techniques, Mice, Inbred C57BL, Wnt Proteins, 030104 developmental biology, Endocrinology, Gene Expression Regulation, chemistry, Estrogen, Culture Media, Conditioned, biology.protein, Sclerostin
الوصف: Background Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. However, how Scl-Ab governs osteocyte regulation of osteoclast differentiation and function is not fully understood. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG expression. Results Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab has the ability to revert osteocyte-mediated osteoclastogenesis and resorption by decreasing RANKL/OPG ratio expression and increasing WISP1 expression in estrogen deficient osteocytes. Conclusions This study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.
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