RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation

摘要: Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC). We have previously shown that, human primary thyrocytes, RET/PTC1 induces transcriptional program including MET proto-oncogene. In PTCs, β-catenin frequently mislocated to cytoplasm nucleus. investigated interplay between Ret/ptc1 signaling Met regulating proinvasive phenotype localization cellular models PTC. Here, we show that protein expressed constitutively active thyrocytes exogenously expressing as well mutant (Y451F) devoid main multidocking site. Both transformed PTC cell line TPC-1, Ret/ptc1-Y451-dependent cooperated promote phenotype. Accordingly, gene/functional silencing either or abrogated early branching morphogenesis TPC-1 cells. The same effect was obtained blocking common downstream effector Akt. Y451 required proliferation nuclear translocation β-catenin, suggesting these oncogene-driven effects are Met-independent. Pharmacologic inhibition tyrosine kinases multitarget small molecule RPI-1 blocked invasive ability dislocated from Altogether, results support cross talks with at levels promotes activity drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation acquisition phenotype, highlights new options design therapeutic strategies for PTCs.