Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
Nat Commun. 2020 Apr 28;11(1):2056. doi: 10.1038/s41467-020-15955-w.
Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5' end of the Trk fused Gene (TFG) fused to the 3' end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.
甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤。通过 RNA 测序分析，我们在一名患者的肿瘤组织中发现了一种 RET 重排，该患者不携带任何已知的 RAS 或 BRAF 突变。这种新的基因融合涉及 Trk 融合基因（TFG）5' 端的外显子 1-4 与 RET 酪氨酸激酶的 3' 端融合，导致 TFG-RET 融合，以激酶依赖的方式转化永生化人甲状腺细胞。TFG-RET 以 PB1 结构域依赖性方式寡聚化，TFG-RET 的寡聚化是致癌转化所必需的。定量蛋白质组学分析显示，E3 泛素连接酶 HUWE1 和 DUBs（如 USP9X 和 UBP7）在肿瘤和转移病灶中上调，在其他患者中也得到了进一步证实。TFG-RET 的表达导致 HUWE1 的上调，而抑制 HUWE1 则显著降低 RET 介导的致癌作用。
