Suppression of Hedgehog signalling promotes pro-tumourigenic integrin expression and function.

摘要: Aberrant Hedgehog (Hh) signalling has been reported in a number of malignancies, particularly basal cell carcinoma (BCC) the skin. Clinical trials Hh inhibitors are underway many cancers, and these have produced significant clinical benefit BCC patients, although regrowth new, or clinically aggressive, variants, as well development secondary reported. ?v?6 integrin is expressed where it shown to correlate with an aggressive tumour phenotype poor prognosis. We previously up-regulation morphoeic modulates stromal response induces invasion. To examine possible link between function, we generated models, overexpressing Gli1 immortalized keratinocytes (NTert1, HaCaT). Unexpectedly, found that suppressing significantly increased expression. This promoted motility also myofibroblast differentiation through integrin-dependent TGF-?1 activation. inhibited expression by TGF-?1-induced Smad2/3 activation, blocking positive feedback loop maintaining high levels. A similar mechanism was observed AsPC1 pancreatic cancer cells expressing endogenous Gli1, suggesting common across types. In vitro findings were supported using human samples, showed inverse correlation different subtypes cancers. summary, show inversely correlates tumours vivo, targeting up-regulates TGF-?1/Smad2/3-dependent expression, promoting pro-tumourigenic functions vitro. These results potential significance, given recurrence variants malignancies patients treated targeting.