Liu Li-Li, Zhang Mei-Fang, Pan Ying-Hua, Yun Jing-Ping, Zhang Chris Zhiyi
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.
Tumour Biol. 2014 Mar;35(3):1763-74. doi: 10.1007/s13277-013-1184-2. Epub 2014 Feb 25.
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.
NORE1A被鉴定为一种Ras效应器，在人类癌症中经常沉默，并与肿瘤进展有关。越来越多的报道表明NORE1A可能作为一种肿瘤抑制因子发挥作用。然而，迄今为止，其在肝细胞癌（HCC）中的表达及相关意义仍不清楚。在本研究中，我们检测了NORE1A在肝癌细胞系和250例肝癌样本中的表达。我们发现，与相应的癌旁组织相比，14例新鲜肝癌组织中NORE1A的mRNA和蛋白水平均明显下调。此外，72.4%（181/250）的肝癌患者肿瘤中的NORE1A降低。NORE1A低表达与低分化（P = 0.003）、晚期（P = 0.002）、血清甲胎蛋白水平高（P < 0.001）、血管侵犯（P = 0.034）和包膜不完整（P = 0.018）显著相关。多因素分析显示，NORE1A是总生存期（风险比（HR）0.622，95%置信区间（95%CI）0.405 - 0.956，P = 0.030）和无复发生存期（HR 0.613，95%CI 0.390 - 0.964，P = 0.034）的独立不良预后因素。此外，晚期肝癌中NORE1A低表达预示疾病复发。此外，NORE1A过表达降低细胞活力，抑制集落形成，并在体外减弱细胞侵袭。进一步研究表明，NORE1A能够通过激活Mst - 1/Akt途径使癌细胞对索拉非尼诱导的凋亡敏感。总体而言，我们的数据表明NORE1A可能是肝癌中有前景的预后生物标志物和治疗靶点。
