Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog

摘要: Hedgehog (HH) signaling proteins mediate inductive events during animal development1–11. Mutation of the only known HH receptor gene, Patched (PTC), has recently been implicated in inherited and sporadic forms most common human cancer, basal cell carcinoma (BCC)12–14. In Drosophila, acts by inactivating PTC function1,3, raising possibility that overexpression Sonic (SHH) epidermis might have a tumorigenic effect equivalent to loss function. We used retroviral transduction normal keratinocytes constitutively express SHH. SHH-expressing cells demonstrated increased expression both target, BMP-2B, as well bcl-2, protein prominently expressed BCCs. These were then regenerate skin transgenic for long terminal repeat-driven SHH (LTR-SHH) on immune-deficient mice. LTR-SHH consistently displays abnormal specific histologic features seen BCCs, including downgrowth epithelial buds into dermis, palisading separation from underlying dermis. addition, gene abnormalities previously described decreased BP180/BPAG2 laminin 5 adhesion epidermal keratins. data indicate recapitulates BCC vivo, suggest activation this conserved pathway contributes development neoplasia describe new tissue model neoplasia.