白细胞介素-6通过磷酸化信号转导子和转录激活子3而非磷酸化信号转导子和转录激活子1激活肝癌发生并影响肝细胞癌患者的生存：一项队列研究
IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study.
作者信息
Kao Jung-Ta, Feng Chun-Lung, Yu Cheng-Ju, Tsai Shu-Mei, Hsu Ping-Ning, Chen Yao-Li, Wu Yi-Ying
机构信息
School of Medicine, China Medical University, Taichung, Taiwan.
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
出版信息
BMC Gastroenterol. 2015 Apr 25;15:50. doi: 10.1186/s12876-015-0283-5.
BACKGROUND
Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited.
METHODS
Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain.
RESULTS
Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1.
CONCLUSIONS
Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.
背景
功能性介质的生物活性激活调节炎症和致癌作用的下游转导子。在肝细胞癌（HCC）不同临床病理阶段，介质（IL-6、IL-27、TNF-α和VEGF）与信号转导和转录激活因子（STAT）蛋白之间的相关性仍然有限。
方法
检测147例未经治疗的HCC病例（HCC总组）的血清介质，其中包括70例HBV感染患者（HCC-HBV组）、64例HCV感染患者（HCC-HCV组）和13例无HBV/HCV感染患者（HCC-NBNC组）。另156例非HCC个体组成对照组，包括54例健康个体（HG）和102例慢性肝炎患者（CH总组）。为了与血清介质进行相关性分析，86对肝组织（CH组：52例；HCC组：34例）用于p-STATs蛋白免疫染色。
结果
虽然四种介质（IL-6、IL-27、TNF-α和VEGF）均显著过表达，但IL-6在HCC总组与CH总组或HG组之间呈现出最强的相关性（HCC总组与CH总组：P<0.001；HCC总组与HG组：P<0.001）。过表达的IL-6浓度与肝功能不良相关（白蛋白：r=-0.383，P<0.001；胆红素：r=0.280，P=0.001；国际标准化比值：r=0.299，P<0.001；谷草转氨酶：0.212，P=0.016）、肿瘤进展（TNM分期系统：r=0.370；P<0.001）、临床病情严重程度（巴塞罗那临床肝癌分期系统：r=0.471；P<0.001；晚期与早期HCC，P=0.001；进展期与早期HCC，P=0.007；晚期与中期HCC，P=0.003；进展期与中期HCC，P=0.019）以及6个月死亡率（P=0.024）。同样，与IL-27（r=0.052，P=0.770）、TNF-α（r=0.019，P=0.917）和VEGF（r=0.096，P=0.595）表达相比，血清IL-6（r=0.501，P=0.003）与组织p-STAT3而非p-STAT1的激活呈正相关。
结论
血清IL-6通过p-STAT3而非p-STAT1信号通路，影响肝功能、肿瘤进展，并决定HCC患者的生存。
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