MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
Autoři:
Tajana Tešan Tomić aff001; Josefin Olausson aff001; Anna Rehammar aff002; Lily Deland aff001; Andreas Muth aff003; Katarina Ejeskär aff005; Staffan Nilsson aff001; Erik Kristiansson aff002; Ola Nilsson Wassén aff006; Frida Abel aff001
Působiště autorů:
Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
aff001; Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
aff002; 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, Gothenburg, Sweden
aff002; Department of Surgery, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
aff003; Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Section of endocrine and sarcoma surgery, Gothenborg, Sweden
aff004; School of Health and Education, University of Skövde, Skövde, Sweden
aff005; Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
aff006
Vyšlo v časopise:
MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008803
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008803
Souhrn
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.
Klíčová slova:
Cytoplasm – Gene expression – Glucose metabolism – Membrane proteins – Metastatic tumors – Microarrays – Neurofibromatosis type 1 – Somatic mutation
Zdroje
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