Biologically, this corresponds to HGF or NK4 binding competitively to the extracellular cMet receptor and activating or repressing an intracellular signaling cascade that controls expression of the MMP-1 promoter.
Only the Δ5KA abolishes binding to PtdIns 3,4,5 P3.
Although SorbA contains a CMeT domain, this appears to be inactive similar to the compactin CMeT domain.
Familial cases have been linked to mutations in the cMET proto-oncogene 37, and mutations in the fumarate hydratase gene, a key enzyme in metabolism 38.
Previous studies have connected the resistance of pancreatic cancer cell lines to gemcitabine, with alterations in EMT (epithelial-to-mesenchymal transition) that include the cMET receptor [ 34].
Moreover, the cMET receptor seems to be functionally active since incubation with HGF induces growth, motility and phosphorylation of intracellular signaling cascades in these cells.
Consistent with the subcutaneous model results, the addition of the cMET inhibitor INC280 to tumours pretreated with gemcitabine was the most efficient therapy.
Hence, phosphorylation of oncogenic signaling cascades in pancreatic cancer cells via paracrine activation of the cMET receptor might contribute to pancreatic cancer aggressiveness.
As predicted from our in vitro data, combination of gemcitabine with the cMET inhibitor INC280 was far superior to single agent therapy in terms of tumour inhibition in the orthotopic model.
45 miR-34a has also been shown to be a direct transcriptional target of the p53 tumor suppressor and to inhibit osteosarcoma cell proliferation and metastasis, possibly via downregulation of the cMet gene.
