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Wnt pathway reprogramming during human embryonal carcinoma differentiation and potential for therapeutic targeting
BMC Cancer, 11/02/09

Snow GE et al. – During induced differentiation of human EC cells, the Wnt signalling pathway is reprogrammed and canonical Wnt signalling induced. Specific species regulating non-canonical Wnt signalling conferred growth inhibition when targeted for repression in these EC cells. Notably, FZD7 repression significantly inhibited growth of human EC cells and is a promising therapeutic target for TGCTs.

• Human embryonal carcinoma cells stably infected with lentiviral construct carrying canonical Wnt responsive reporter to assess Wnt signalling activity following induced differentiation
• Cells differentiated with all-trans retinoic acid (RA) or by targeted repression of pluripotency factor POU5F1
• Wnt pathway real-time-PCR array used to evaluate changes in gene expression as cells differentiated
• Highlighted Wnt pathway genes specifically repressed using siRNA or stable shRNA and transfected EC cells assessed for proliferation, differentiation status and levels of core pluripotency genes

• Canonical Wnt signalling activity was low basally in undifferentiated EC cells, but substantially increased with induced differentiation
• Wnt pathway gene expression levels compared during induced differentiation and many components altered including ligands (WNT2B), receptors (FZD5, FZD6, FZD10), secreted inhibitors (SFRP4, SFRP1), and other effectors of Wnt signalling (FRAT2, DAAM1, PITX2, Porcupine)
• Independent repression of FZD5, FZD7 and WNT5A using transient as well as stable methods of RNA interference (RNAi) inhibited cell growth of pluripotent NT2/D1 human EC cells, but did not appreciably induce differentiation or repress key pluripotency genes
• Silencing of FZD7 gave greatest growth suppression in all human EC cell lines tested including NT2/D1, NT2/D1-R1, Tera-1 and 833K cells

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