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MYO5B mutations in ...
MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
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- Tomic, Tajana Tesan (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden
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- Olausson, Josefin, 1983 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden
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- Rehammar, Anna, 1978 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för samhällsmedicin och folkhälsa,Institutionen för matematiska vetenskaper,Institute of Medicine, School of Public Health and Community Medicine,Department of Mathematical Sciences,Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
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- Deland, Lily (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden
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- Muth, Andreas, 1974 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,Department of Surgery, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Section of endocrine and sarcoma surgery, Gothenburg, Sweden
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- Ejeskär, Katarina, 1969- (författare)
- Högskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine,University of Skövde
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- Nilsson, Staffan, 1956 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden / Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
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- Kristiansson, Erik, 1978 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för samhällsmedicin och folkhälsa,Institute of Medicine, School of Public Health and Community Medicine,Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
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- Wassén, Ola Nilsson (författare)
- Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden,Göteborgs universitet,University of Gothenburg
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- Abel, Frida, 1974 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden
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- Nilsson Wassén, Olof (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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(creator_code:org_t)
- 2020-06-08
- 2020
- Engelska.
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
- Relaterad länk:
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
Nyckelord
- myosin Va
- Article
- cancer growth
- cell adhesion
- cell migration
- cell proliferation
- cellular homeostasis
- controlled study
- female
- gene expression
- gene mutation
- glucose metabolism
- HEK293 cell line
- homeostasis
- human
- human cell
- human tissue
- immunohistochemistry
- in vitro study
- major clinical study
- male
- missense mutation
- MYO5A gene
- MYO5B gene
- paraganglioma
- paralogy
- pathogenicity
- pheochromocytoma
- protein localization
- site directed mutagenesis
- SK-N-AS cell line
- somatic mutation
- stable transfection
- tumor gene
- Translationell medicin TRIM
- Translational Medicine TRIM
- microvillus inclusion disease
- myosin vb
- malignant pheochromocytoma
- clinical-experience
- cell-metabolism
- adrenal-gland
- growth-factor
- gene
- expression
- metformin
- Genetics & Heredity
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