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Tumor Biology

, Volume 35, Issue 3, pp 1763–1774 | Cite as

NORE1A sensitises cancer cells to sorafenib-induced apoptosis and indicates hepatocellular carcinoma prognosis

  • Li-Li Liu
  • Mei-Fang Zhang
  • Ying-Hua Pan
  • Jing-Ping Yun
  • Chris Zhiyi Zhang
Research Article

Abstract

NORE1A, identified as a Ras effector, is frequently silenced in human cancers and has been implicated in tumour progression. Reports showing that NORE1A may function as a tumour suppressor have been emerging. However, to date, its expression and relevant significance in hepatocellular carcinoma (HCC) remain elusive. In this study, we examined the expression of NORE1A in HCC cell lines and a cohort of 250 HCC samples. We found that both the mRNA and the protein levels of NORE1A were noticeably downregulated in 14 fresh HCC tissues, compared to corresponding paracarcinoma tissues. Furthermore, NORE1A in tumours was decreased in 72.4 % (181/250) of HCC patients. Low NORE1A expression was significantly associated with poor differentiation (P = 0.003), advanced stage (P = 0.002), high level of serum AFP (P < 0.001), vascular invasion (P = 0.034) and incomplete involucrum (P = 0.018). Multivariate analysis revealed that NORE1A was an independent poor prognostic factor for both overall survival (hazard ratio (HR) 0.622, 95 % confidence interval (95 % CI) 0.405–0.956, P = 0.030) and recurrence-free survival (HR 0.613, 95 % CI 0.390–0.964, P = 0.034). Moreover, low NORE1A expression in advanced-stage HCC predicted disease relapse. In addition, NORE1A overexpression reduced cell viability, inhibited colony formation, and attenuated cell invasion in vitro. Further study demonstrated that NORE1A was capable of sensitising cancer cells to sorafenib-induced apoptosis via the activation of the Mst-1/Akt pathway. Collectively, our data suggest that NORE1A may be a promising prognostic biomarker and therapeutic target in HCC.

Keywords

NORE1A Sorafenib Apoptosis Prognosis Hepatocellular carcinoma 

Notes

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (no. 81201717) and the China Postdoctoral Science Foundation (no. 2012M511867).

Conflicts of interest

None

Supplementary material

13277_2013_1184_MOESM1_ESM.doc (35 kb)
Table S1 Hazard ratios of univariate analysis. (DOC 35 kb)
13277_2013_1184_Fig7_ESM.jpg (361 kb)
Figure S1

NORE1A mRNA expression is downregulated in HCC cell lines. (JPEG 361 kb)

13277_2013_1184_Fig8_ESM.jpg (403 kb)
Figure S2

NORE1A expression correlates with overall survival in subgroups of HCC patients. (JPEG 403 kb)

13277_2013_1184_Fig9_ESM.jpg (406 kb)
Figure S3

NORE1A expression correlates with recurrence-free survival in subgroups of HCC. (JPEG 406 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina
  2. 2.Department of Rheumatology and ImmunologyThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

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