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Hedgehog is a regulatory protein during embryonic development and its abnormal activation in adult tissues has been implicated in tumorigenesis within sites where epithelial–mesenchymal interactions take place. In the prostate, Hedgehog signaling activation was observed during advanced cancer progression and metastasis, but whether Hedgehog overexpression can initiate prostate tumorigenesis remains unknown. We introduced a Hedgehog-expressing vector by intra-prostate injection and electroporation to address the effects of Hedgehog overexpression. The manipulation caused lesions with characteristic prostatic intraepithelial neoplasia or even prostatic cancer (CaP) phenotypes within 30 days, with Hedgehog overexpression demonstrated by immunohistochemistry and Western blot detections. The tumorigenic phenotypes were confirmed by discontinuity of basal cell marker p63, mix-up of CK-8/CK-18 positive epithelial cells in the stoma as well as absence of α-SMA positive fibro-muscular sheath. Comparable Hedgehog overexpression was found in human CaP specimen. Thus, Hedgehog overexpression induced prostate tumorigenesis starting from the normal status. Furthermore, a mouse prostate cancer model induced by Hedgehog overexpression was established and may be used for testing novel therapeutical approaches targeting at Hedgehog signaling pathway. [ABSTRACT FROM AUTHOR]