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// Zhipeng Wang 1, * , Min Shen 2, * , Peng Lu 3, * , Xiao Li 4 , Shaojun Zhu 5 , Shuqiang Yue 4 1 School of Pharmacy, Fourth Military Medical University, Xi’an, China 2 Department of Cardiovascular diseases, Xijing Hospital, Xi’an, China 3 Department of Hepatobiliary Surgery, Hainan Branch of Chinese PLA general Hospital, Sanya, China 4 Department of Hepatobiliary Surgery, Xijing Hospital, Xi’an, China 5 Department of Pathology, Tangdu Hospital, Xian, China * These authors have contributed equally to this work Correspondence to: Shuqiang Yue, email: shuqiangyue@126.com Keywords: hepatocellular carcinoma, cancer stem cell, epithelial-mesenchymal-transition, developmentally downregulated 9 Received: March 21, 2016 Accepted: November 08, 2016 Published: December 10, 2016 ABSTRACT Overexpression of neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a prognostic marker of many cancers, including hepatocellular carcinoma (HCC). However, the functions and mechanisms of NEDD9 are unclear. We found that upregulation of NEDD9 promoted migration, invasion and cell-to-extracellular matrix adhesion of HCC cells. NEDD9 also induced the epithelial-mesenchymal transition (EMT) and expression of matrix metalloprotein 2 (MMP2). Increased aldehyde dehydrogenase (ALDH) activity and CD133-positive cells were observed in HCC cells with high expression of NEDD9, corresponding to greater sphere formation in cancer stem cells (CSCs). NEDD9 deregulated Smad7 expression to inhibit Smad signaling and binding to the FAK-Src-Crk complex. We propose that this is the mechanism by which NEDD9 induced CSC properties.