【作者】 王秦川； 刘希永； 陈文军； 王林波； 阎云；

【机构】 浙江大学医学院附属邵逸夫医院；

【摘要】 胃癌是我国常见的消化系统恶性肿瘤,其发病率和死亡率在各大恶性肿瘤中均居前列。如何有效的预测胃癌患者预后及治疗效果,是胃癌目前诊疗面临的主要问题。核糖核苷酸还原酶(RNR)是将核糖核苷酸转化为脱氧核糖核苷酸的唯一酶,在细胞DNA合成及修复中具有重要的作用,也是肿瘤治疗的重要靶点之一。RRM1是组成RNR的唯一调节大亚基,在肺癌和胰腺癌中被认为与吉西他滨化疗耐药相关,在进展期患者中预示不良预后;而也有研究显示在早期肺癌患者中,RRM1提示良好的预后。在胃癌的研究中,尚无关于RRM1的作用及机制的报道。本文对RRM1在胃癌诊治中的作用和分子机制进行了研究。首先,我们通过免疫组化染色方法研究了RRM1表达在希望城医学中心(COH)和浙江大学(ZJU)两个中心胃癌患者中的作用。我们发现RRM1与淋巴结转移、肿瘤大小、Ki67表达水平和肿瘤分化水平密切相关,Kaplan-Meier生存分析提示RRM1高表达的胃癌患者生存较低表达患者明显降低,多因素Cox风险模型分析则提示RRM1是胃癌患者不良预后的风险因素,风险比分别为2.55(COH,95%CI 1.27-5.15)和1.51(ZJU,95%CI 1.07-2.13),进一步的分层分析则显示RRM1对进展期、低分化水平和高生长能力的胃癌患者具有更好的预测作用。然后,我们在胃癌细胞模型中对RRM1对胃癌细胞的生长与转移的影响及分子机制进行了分析,发现RRM1主要通过Ras/Raf/MAPK通路显著的影响了胃癌细胞的生长与侵袭,并且与EMT通路也有一定的关联。通过siRNA靶向抑制RRM1表达之后,胃癌细胞dNTP池水平明显下降,MMP-9分泌水平、生长能力和侵袭能力随之明显降低,提示RRM1可能是胃癌治疗的潜在靶点。更多还原

【Abstract】 Objectives:We aimed to investigate the prognostic value of RRM1 in GC patients. Methods:A total of assessable 389 GC patients with clinicopathological and survival information were enrolled from City of Hope(COH,n=67) and Zhejiang University(ZJU,n=322).RRM1 protein expression was determined by immunohistochemistry on FFPE tissue samples.Kaplan-Meier and Cox analyses were used to measure survival.Ras/ Rat activity and invasion assays were used to evaluate the role of RRM1 in GC cell lines. Results:In vitro experiments demonstrated RRM1 activated Ras/Raf/MAPK signal transduction and promoted GC cell proliferation.Meanwhile,RRM1 expression was significantly associated with lymph node involvement,tumor size,Ki67 expression,histological subtype and histological grade in the GC tissue samples(p<0.05).Kaplan-Meier analysis illustrated that high RRM1 expression predicted poor survival in GC patients in the COH and ZJU cohorts (log-rank p<0.01).In multivariate Cox analysis,the hazard ratios of RRM1 for overall survival were 2.55(95%CI 1.27-5.15) and 1.51(95%CI 1.07-2.13) in the COH and ZJU sets,respectively.In particular,RRM1 specifically predicted the outcome of advanced GCs with poor differentiation and high proliferative ability.Furthermore, inhibition of RRM1 by siRNA significantly reduced the dNTP pool,Ras/Raf and MMP-9 activities and the levels of p-MEK,p-ERK and NF-κB,resulting in growth retardation and reduced invasion in AGS and NCI-N87 cells. Conclusions:RRM1 overexpression predicts poor survival in GC patients with advanced TNM stage.RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.更多还原