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International Journal of Oncology
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Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

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Article

Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma

  • Authors:
    • Tong-Chun Xue
    • Jing-Huai Zou
    • Rong-Xin Chen
    • Jie-Feng Cui
    • Zhao-You Tang
    • Sheng-Long Ye
  • View Affiliations / Copyright

    Affiliations: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
  • Pages: 1883-1890
    |
    Published online on: August 29, 2014
       https://doi.org/10.3892/ijo.2014.2630
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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 (JAG1Mem) were more likely to undergo extrahepatic metastasis [p<0.001; hazard ratio (HR), 0.166; 95% CI, 0.068-0.402], and JAG1Mem was a strong independent prognostic factor for metastasis (HR, 0.467; 95% CI, 0.271-0.806; p=0.006). JAG1Mem also showed a strong positive correlation with Notch1Mem. In addition, tumors with JAG1Mem expression had more poorly encapsulated membranes (p=0.014). Furthermore, Notch1Mem 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 JAG1Mem 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.
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Copy and paste a formatted citation
Spandidos Publications style
Xue T, Zou J, Chen R, Cui J, Tang Z and Ye S: Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma. Int J Oncol 45: 1883-1890, 2014.
APA
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., & Ye, S. (2014). Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma. International Journal of Oncology, 45, 1883-1890. https://doi.org/10.3892/ijo.2014.2630
MLA
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., Ye, S."Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma". International Journal of Oncology 45.5 (2014): 1883-1890.
Chicago
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., Ye, S."Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma". International Journal of Oncology 45, no. 5 (2014): 1883-1890. https://doi.org/10.3892/ijo.2014.2630
Copy and paste a formatted citation
x
Spandidos Publications style
Xue T, Zou J, Chen R, Cui J, Tang Z and Ye S: Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma. Int J Oncol 45: 1883-1890, 2014.
APA
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., & Ye, S. (2014). Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma. International Journal of Oncology, 45, 1883-1890. https://doi.org/10.3892/ijo.2014.2630
MLA
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., Ye, S."Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma". International Journal of Oncology 45.5 (2014): 1883-1890.
Chicago
Xue, T., Zou, J., Chen, R., Cui, J., Tang, Z., Ye, S."Spatial localization of the JAG1/Notch1/osteopontin cascade modulates extrahepatic metastasis in hepatocellular carcinoma". International Journal of Oncology 45, no. 5 (2014): 1883-1890. https://doi.org/10.3892/ijo.2014.2630
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