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RET/PTC3  junction oncogene is typical of radiation-induced childhood papillary thyroid carcinoma (PTC) with a short latency period. Since,  RET/PTC3  is only present in the tumour cells, thus represents an interesting target for specific therapy by small interfering RNA (siRNA). Our aim is to demonstrate  in vitro  and  in vivo  molecular and cellular effects of siRNA on  RET/PTC3  knockdown for therapeutic application.First, we established a novel cell line stably expressing  RET/PTC3  junction oncogene, named RP3 which was found tumorigenic in nude mice compared to NIH/3T3 mouse fibroblasts. Among four siRNAs and five concentrations tested against  RET/PTC3 , an efficient siRNA  RET/PTC3  and an appropriate dose (50 nM) were selected which showed significant inhibition ( p <0.001) of gene (RT-qPCR) and protein (Western blot) expressions. This siRNA was found efficient in RP3 cells (harbouring  RET/PTC3 ) but non-efficient in BHP10-3 SCmice cell line (harbouring RET/PTC1) showing that a specific siRNA against fusion sequence is required to target the junction oncogene.  In vitro  siRNA  RET/PTC3  showed significant ( p <0.001) inhibitory effects on RP3 cell viability (MTT assay) and on invasion/migration (IncuCyte scratch test) with blockage of cell cycle at G0/G1 phase (flow cytometry) and induced apoptosis by caspase-3 and PARP1 cleavage (WB). After intravenous injection in nude mice, respective squalene (SQ) nanoparticles (NPs) of siRNA  RET/PTC3  significantly ( p <0.001) reduced RP3 tumour growth, oncogene and oncoprotein expressions, induced apoptosis and partially restored differentiation (decrease in Ki67). Hence, our findings highly support the use of siRNA  RET/PTC3 -SQ NPs as a new promising treatment for patients affected by PTC expressing  RET/PTC3 .

Effects of siRNA on RET/PTC3 Junction Oncogene in Papillary Thyroid Carcinoma: From Molecular and Cellular Studies to Preclinical Investigations