RET/PTC1-driven neoplastic transformation and proinvasive phenotype of human thyrocytes involve Met induction and beta-catenin nuclear translocation.
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, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, beta-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and beta-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F) devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of beta-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated beta-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes beta-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs.
Cassinelli
Giuliana
G
Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Favini
Enrica
E
Degl'Innocenti
Debora
D
Salvi
Alessandro
A
De Petro
Giuseppina
G
Pierotti
Marco A
MA
Zunino
Franco
F
Borrello
Maria Grazia
MG
Lanzi
Cinzia
C
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism* / Q000502:physiology
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051176:beta Catenin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human