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The sonic hedgehog (SHH) pathway is an early and late mediator of tumorgenesis in pancreatic and other epithelial cancers. GLI-1 is a transcription factor that mediates hedgehog pathway signals and presents an excellent target for novel cancer treatment. Inhibition of cancer cell proliferation by targeting GLI-1 with chemotherapeutic agents or short-interfering RNA (siRNA) is difficult to achieve. We hypothesized that targeting the 3’ untranslated region of GLI-1 mRNA will result in effective inhibition of tumor cell proliferation. To test this hypothesis, we designed a synthetic microRNA and corresponding duplex/small temporal RNAs by introducing 3nt loops in the 3’ UTR GLI-1 sequence with high GU content. We found that microRNAs (miRNA-GLI-1-3548) and its corresponding duplex (duplex 3548) significantly inhibited proliferation and expression of the GLI-1+ ovarian (SKOV3) and pancreatic (MiaPaCa-2) cell lines. The inhibiting effects of miRNAs were manifested by delayed mitosis and by activation of apoptosis in MiaPaCa-2 cells. This is the first demonstration of inhibition of GLI-1 protein expression in cancer cells and provides a novel approach for rational design of novel treatments for pancreatic cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]