title: Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma.
abstract: The model of Notch-driven carcinogenesis and development of hepatocellular carcinoma remains controversial and is based on observations of developmental stage- and dose-dependent Notch activation. In this study, the relevance of the spatial distribution of Notch cascade members to the promotion of hepatocellular carcinoma metastasis was evaluated. The spatial expression patterns of the members of the Jagged1 (JAG1)/Notch1 cascade in HCC were evaluated in a tissue microarray of 112 tumors and 46 peri-tumors. Regulation of JAG1/Notch1 on osteopontin (OPN) was evaluated by RNA interference. Tumor cells with JAG1 expressed on the membrane (JAG1(Mem)) were more likely to undergo extrahepatic metastasis [p<0.001; hazard ratio (HR), 0.166; 95% CI, 0.068-0.402], and JAG1(Mem) was a strong independent prognostic factor for metastasis (HR, 0.467; 95% CI, 0.271-0.806; p=0.006). JAG1(Mem) also showed a strong positive correlation with Notch1(Mem). In addition, tumors with JAG1(Mem) expression had more poorly encapsulated membranes (p=0.014). Furthermore, Notch1(Mem) expression correlated with HCC metastasis and was the strongest predictive factor for metastasis. However, in peri-tumoral tissues, most JAG1 (45/46) and Notch1 (41/46) was localized to the cytoplasm. The expression of OPN, one of the main targets of JAG1/Notch1 signaling and a crucial metastasis-related gene in HCC, correlated significantly with JAG1(Mem) expression. Knockdown of JAG1 expression or Notch1 expression induced the downregulation of OPN in HCC cells. Taken together, protein localization is a critical factor affecting the activity of the Notch cascade in the development of hepatocellular carcinoma. Furthermore, our results suggest that the JAG1/Notch1/OPN cascade represents a potential therapeutic target for hepatocellular carcinoma metastasis.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Tong-Chun
authors.initials: TC
authors.lastname: Xue
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Jing-Huai
authors.initials: JH
authors.lastname: Zou
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Rong-Xin
authors.initials: RX
authors.lastname: Chen
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Jie-Feng
authors.initials: JF
authors.lastname: Cui
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China.
authors.forename: Sheng-Long
authors.initials: SL
authors.lastname: Ye
mesh_terms: D000368:Aged; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072100:Jagged-1 Protein; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D053495:Osteopontin / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D053495:Osteopontin