It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21.
In tumours with disomy 3, we found none or very few TIMP-3-positive cells though the mRNA level was high which indirectly postulates posttranscriptional problems in protein biosynthesis in this entity of uveal melanomas.
Taken together, these results show that TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8.
Escalation of the adenoviral dose to three rounds of three daily consecutive injections with 1.4x10(9) pfu of RAdTIMP-3 every 6 days entirely inhibited growth of injected melanomas for 32 days.
These results propose a novel role for TIMP-3 in regulation of invasion and survival of malignant cells and suggest potential use for TIMP-3 in adenovirus-mediated gene therapy of malignant melanoma.