Inhaltszusammenfassung

Papillary thyroid cancer (PTC) is the most common type of endocrine cancer. Partial or complete removal of the thyroid lobe, followed by radioactive iodine treatment (131I) (RAI) is the standard treatment strategy for the treatment of thyroid cancer. But the management of tumors that cannot undergo resection, mostly due to distant metastasis and/or development of resistance to RAI is challenging. Identifying and understanding the molecular pathogenesis underlying thyroid cancer is import...Papillary thyroid cancer (PTC) is the most common type of endocrine cancer. Partial or complete removal of the thyroid lobe, followed by radioactive iodine treatment (131I) (RAI) is the standard treatment strategy for the treatment of thyroid cancer. But the management of tumors that cannot undergo resection, mostly due to distant metastasis and/or development of resistance to RAI is challenging. Identifying and understanding the molecular pathogenesis underlying thyroid cancer is important for the development of better diagnosis and treatment. The main aim of the project is the identification and validation of novel molecular alterations in PTC patient samples by employing genomic and proteomic approaches. From a set of patients whose PTC did not harbour any BRAF or RAS mutations (the most common mutations in PTC), a 35 years old male patient’s normal, primary tumor and metastatic tissues were selected for both genomic and proteomic analysis. We identified a novel RET gene fusion in this patient and the oncogenic ability of this novel gene fusion was tested in transformation assays. Stable expression of the novel RET fusion gene activated several oncogenic signalling pathways and transformed immortalized human thyroid cells. The novel RET fusion exhibited high kinase activity and formed dimers and oligomers partially in a PB1 domain dependent manner. Quantitative proteomic analysis of normal vs tumour vs metastasis of the same patient revealed the upregulation of proteins involved in the ubiquitination machinery including HECT carrying E3 ligase HUWE1 and Deubiquitinating enzymes (DUBs) like USP9X and UBP7 in the tumour and metastatic lesions. Inhibition of RET, HUWE1 and DUBs by small molecule inhibitors significantly reduced RET-mediated oncogenesis. Apart from unveiling a novel oncogenic RET fusion in PTCs, our data opens a novel avenue of targeting ubiquitin signalling machinery in human PTCs.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie