RET expression is enhanced in vitro by several differentiating agents, including retinoic acid (RA), which up-regulates RET expression in neuroblastoma cell lines.
Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.
Consistent with this result, ZAR1-depleted NB cells showed well-differentiated phenotypes with elongated neurites and upregulated expression of TRKA and RET, which are markers for differentiated NB.
Furthermore, the antibodies detected a unique 190 kd protein as well as 150 kd protein in a cell lysate from THP-1 human monocytic leukemia cell line, suggesting that glycosylated forms of the c-ret protein are different between neuroblastoma and leukemia cells.
Furthermore, there is strong evidence against linkage to two Hirschsprung disease (a condition that can cosegregate with neuroblastoma) susceptibility genes, RET and EDNRB.
Identification and analysis of the ret proto-oncogene promoter region in neuroblastoma cell lines and medullary thyroid carcinomas from MEN2A patients.
In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here.
In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.
In the present work, we have studied the ability of GDNF proteins, each bearing one of the reported mutations, to activate RET by performing a functional test in cultured neuroblastoma cells.
Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy.
NB-39-nu neuroblastoma cells show high expression and elevated tyrosine phosphorylation of RET, although short interfering RNA against RET (RET siRNA) did not significantly inhibit cell proliferation or suppression of basal levels of phosphorylation of extracellular regulated kinase (ERK)1/2 or protein kinase B (AKT).
Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.
Taken together, our results suggest that SPRY2 regulates GDNF-dependent proliferation and differentiation of TGW neuroblastoma cells mediated by RET tyrosine kinase.
Taken together, these results indicate that GDNF up-regulates the expression of the TH gene by promoting the transcription of the TH gene and the stability of TH mRNA with the Ret receptor dependency in some neuroblastoma cell lines.
The anti-RET antibodies were reactive with 64-kDa (p64ptc-1) and 81-kDa (p81ptc-2) proteins from lysates of ptc-1 and ptc-2 transformed cells, respectively, and identified two proteins of 140 kDa and 160 kDa from extracts of SK-N-SH, a neuroblastoma cell line previously shown to express two differently glycosylated forms of the normal RET product.