DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by α3β1 integrin-Rho GTPase signaling

// Ying Fu 1,* , Ming-Xuan Feng 2,* , Jian Yu 1 , Ming-Ze Ma 1 , Xiao-Jin Liu 1,3 , Jun Li 1 , Xiao-Mei Yang 1 , Ya-Hui Wang 1 , Yan-Li Zhang 1 , Jun-Ping Ao 1 , Feng Xue 2 , Wenxin Qin 1 , Jianren Gu 1 , Qiang Xia 2 and Zhi-Gang Zhang 1 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 3 Department of Plastic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China * These authors contributed equally to this work Correspondence: Zhi-Gang Zhang, email: // Qiang Xia, email: // Keywords : Dermatopontin; Hepatocellular Carcinoma; Patient prognosis; Methylation; Metastasis; α3β1 integrin Received : March 17, 2014 Accepted : July 20, 2014 Published : July 21, 2014 Abstract Dermatopontin (DPT), a tyrosine-rich, acidic matricellular protein, has been implicated in several human cancers. However, its biological functions and molecular mechanisms in cancer progression, particular hepatocellular carcinoma (HCC), remain unknown. We demonstrated that DPT was significantly down-regulated in 202 HCC clinical samples and that its expression level was closely correlated with cancer metastasis and patient prognosis. The overexpression of DPT dramatically suppressed HCC cell migration in vitro and intrahepatic metastasis in vivo . We further revealed that the down-regulation of DPT in HCC was due to epigenetic silencing by promoter DNA methylation. And the inhibitory effects of DPT on HCC cell motility were associated with dysregulated focal adhesion assembly, decreased RhoA activity and reduced focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src) phosphorylation, and all of these alterations required the involvement of integrin signaling. Furthermore, we determined that the inhibitory effects of DPT on HCC cell motility were primarily mediated through α3β1 integrin. Our study provides new evidence for epigenetic control of tumor microenvironment, and suggests matricellular protein DPT may serve as a novel prognostic marker and act as a HCC metastasis suppressor.