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

Xue,Tong-Chun; Zou,Jing-Huai; Chen,Rong-Xin; Cui,Jie-Feng; Tang,Zhao-You; Ye,Sheng-Long

doi:10.3892/ijo.2014.2630

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

Affiliations: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
Published online on: August 29, 2014 https://doi.org/10.3892/ijo.2014.2630
Pages: 1883-1890

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Ranganathan P, Weaver KL and Capobianco AJ: Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 11:338–351. 2011. View Article : Google Scholar : PubMed/NCBI
2	Zhou L, Wang DS, Li QJ, Sun W, Zhang Y and Dou KF: The down-regulation of Notch1 inhibits the invasion and migration of hepatocellular carcinoma cells by inactivating the cyclo-oxygenase-2/Snail/E-cadherin pathway in vitro. Dig Dis Sci. 58:1016–1025. 2013. View Article : Google Scholar : PubMed/NCBI
3	Lim SO, Park YM, Kim HS, et al: Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma. Hepatology. 53:1352–1362. 2011. View Article : Google Scholar : PubMed/NCBI
4	Liu M, Lee DF, Chen CT, et al: IKKalpha activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell. 45:171–184. 2012. View Article : Google Scholar : PubMed/NCBI
5	Qi R, An H, Yu Y, et al: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 63:8323–8329. 2003.PubMed/NCBI
6	Viatour P, Ehmer U, Saddic LA, et al: Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 208:1963–1976. 2011. View Article : Google Scholar : PubMed/NCBI
7	Zong Y, Panikkar A, Xu J, et al: Notch signaling controls liver development by regulating biliary differentiation. Development. 136:1727–1739. 2009. View Article : Google Scholar : PubMed/NCBI
8	Mazzone M, Selfors LM, Albeck J, et al: Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci USA. 107:5012–5017. 2010. View Article : Google Scholar : PubMed/NCBI
9	D’Souza B, Meloty-Kapella L and Weinmaster G: Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 92:73–129. 2010.
10	Artavanis-Tsakonas S and Muskavitch MA: Notch: the past, the present, and the future. Curr Top Dev Biol. 92:1–29. 2010. View Article : Google Scholar : PubMed/NCBI
11	Kovall RA and Blacklow SC: Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol. 92:31–71. 2010. View Article : Google Scholar : PubMed/NCBI
12	Le Bras S, Loyer N and Le Borgne R: The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic. 12:149–161. 2011.PubMed/NCBI
13	Fortini ME: Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 16:633–647. 2009. View Article : Google Scholar : PubMed/NCBI
14	De la Pompa JL and Epstein JA: Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev Cell. 22:244–254. 2012.PubMed/NCBI
15	Wang Z, Li Y, Kong D and Sarkar FH: The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets. 11:745–751. 2010. View Article : Google Scholar : PubMed/NCBI
16	Leong KG, Niessen K, Kulic I, et al: Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 204:2935–2948. 2007. View Article : Google Scholar : PubMed/NCBI
17	Santagata S, Demichelis F, Riva A, et al: JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64:6854–6857. 2004. View Article : Google Scholar : PubMed/NCBI
18	Villanueva A, Alsinet C, Yanger K, et al: Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 143:1660–1669.e7. 2012. View Article : Google Scholar : PubMed/NCBI
19	Chen RX, Xia YH, Xue TC, Zhang H and Ye SL: Downregulation of osteopontin inhibits metastasis of hepatocellular carcinoma cells via a mechanism involving MMP-2 and uPA. Oncol Rep. 25:803–808. 2011.PubMed/NCBI
20	Xue TC, Han D, Chen RX, et al: High expression of CXCR7 combined with alpha fetoprotein in hepatocellular carcinoma correlates with extra-hepatic metastasis to lung after hepatectomy. Asian Pac J Cancer Prev. 12:657–663. 2011.PubMed/NCBI
21	Simon R, Mirlacher M and Sauter G: Immunohistochemical analysis of tissue microarrays. Methods Mol Biol. 664:113–126. 2010. View Article : Google Scholar : PubMed/NCBI
22	Wang M, Xue L, Cao Q, et al: Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma. Neoplasma. 56:533–541. 2009. View Article : Google Scholar : PubMed/NCBI
23	Lim SO, Kim HS, Quan X, et al: Notch1 binds and induces degradation of Snail in hepatocellular carcinoma. BMC Biol. 9:832011. View Article : Google Scholar : PubMed/NCBI
24	Andersen P, Uosaki H, Shenje LT and Kwon C: Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. 22:257–265. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wang XQ, Zhang W, Lui EL, et al: Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma. Int J Cancer. 131:E163–E172. 2012. View Article : Google Scholar : PubMed/NCBI
26	Zhou L, Wang DS, Li QJ, Sun W, Zhang Y and Dou KF: Downregulation of the Notch signaling pathway inhibits hepatocellular carcinoma cell invasion by inactivation of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor. Oncol Rep. 28:874–882. 2012.
27	Ye QH, Qin LX, Forgues M, et al: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 9:416–423. 2003. View Article : Google Scholar
28	Dong QZ, Zhang XF, Zhao Y, et al: Osteopontin promoter polymorphisms at locus −443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma. Hepatology. 57:1024–1034. 2012.