Description: BACKGROUND Overexpression of serine protease inhibitor Kazal type 1 (SPINK1) defines an aggressive molecular subtype of ETS fusion-negative prostate cancer (PCa) patients in western countries. However, how SPINK1 contributes to PCa invasion and metastasis is largely unknown. METHODS Fluorescence in situ hybridization and immunohistochemistry were utilized to detect ERG rearrangement, SPINK1 expression, and EGFR aberrations in a cohort of 211 PCa patients with radical prostatectomy. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Cellular distribution of E-cadherin and vimentin were observed by immunofluorescence. Cellular function was evaluated by siRNA, transwell, and wound healing assay, respectively. RESULTS SPINK1-induced Epithelial-mesenchymal transition (EMT) in benign prostate RWPE cells, manifested by acquisition of mesenchymal morphology, alternation of EMT markers as well as migration and invasion capabilities. Knockdown of SPINK1 in 22RV1 PCa cells results in up-regulation of E-cadherin and down-regulation of vimentin. SPINK1-induced EMT is mediated by EGFR, in which MAPK/MEK/ERK pathway is mainly involved. Connective tissue growth factor (CTGF) might be an important down-stream molecule of SPINK1–EGFR axis. Clinically, SPINK1 and EGFR were significantly co-overexpressed in a cohort of Chinese PCa patients (n 〉 200). SPINK1 is an unfavorable prognostic factor in Chinese PCas ( P  = 0.025). CONCLUSIONS These findings suggest that SPINK1 promotes EMT through EGFR signaling pathway in PCa and SPINK1 could be a new prognostic marker in Chinese PCas. Prostate © 2014 Wiley Periodicals, Inc.