title: NORE1A sensitises cancer cells to sorafenib-induced apoptosis and indicates hepatocellular carcinoma prognosis.
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.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No 651, Dongfeng Road East, Guangzhou, 510060, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Liu
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Zhang
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Pan
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Yun
authors.forename: Chris Zhiyi
authors.initials: CZ
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; C454042:RASSF5 protein, human; D009536:Niacinamide; D000077157:Sorafenib; D020559:Monomeric GTP-Binding Proteins