Orimo Tatsuya, Ojima Hidenori, Hiraoka Nobuyoshi, Saito Shigeru, Kosuge Tomoo, Kakisaka Tatsuhiko, Yokoo Hideki, Nakanishi Kazuaki, Kamiyama Toshiya, Todo Satoru, Hirohashi Setsuo, Kondo Tadashi
Proteome Bioinformatics Project, National Cancer Center Hospital, Tokyo, Japan.
Hepatology. 2008 Dec;48(6):1851-63. doi: 10.1002/hep.22552.
Histological differentiation is a major pathological parameter associated with poor prognosis in patients with hepatocellular carcinoma (HCC) and the molecular signature underlying HCC differentiation may involve key proteins potentially affecting the malignant characters of HCC. To develop prognostic biomarkers for HCC, we examined the global protein expression profiles of 45 surgically resected tissues, including 27 HCCs with different degree of histological differentiation, 11 adjacent nontumor tissues, and seven normal liver tissues. Unsupervised classification grouped the 45 samples according to their histological classification based on the protein expression profiles created by laser microdissection and two-dimensional difference gel electrophoresis (2D-DIGE). Statistical analysis and mass spectrometry identified 26 proteins with differential expression, of which 14 were functionally linked to c-Myc, AP-1, HIF1A, hepatocyte nuclear factor 4 alpha, or the Ras superfamily (RhoA, CDC42, and Rac1). Among the proteins identified, we focused on APC-binding protein EB1 (EB1) because it was dominantly expressed in poorly differentiated HCCs, which generally correlate with the poor prognosis in patients with HCC. In addition, EB1 is controlled by c-Myc, RhoA, and CDC42, which have all been linked to HCC malignancy. Immunohistochemistry in a further 145 HCC cases revealed that EB1 significantly correlated with the degree of histological differentiation (P < 0.001), and univariate and multivariate analyses indicated that EB1 is an independent prognostic factor for recurrence (hazard ratio, 2.740; 95% confidence interval, 1.771-4.239; P < 0.001) and survival (hazard ratio, 2.256; 95% confidence interval, 1.337-3.807; P = 0.002) of patients with HCC after curative surgery.
Proteomic profiling revealed the molecular signature behind the progression of HCC, and the prognostic value of EB1 in HCC.
组织学分化是肝细胞癌（HCC）患者预后不良的主要病理参数，HCC分化背后的分子特征可能涉及潜在影响HCC恶性特征的关键蛋白。为了开发HCC的预后生物标志物，我们检测了45例手术切除组织的整体蛋白质表达谱，包括27例不同组织学分化程度的HCC、11例癌旁非肿瘤组织和7例正常肝组织。无监督分类根据激光显微切割和二维差异凝胶电泳（2D-DIGE）创建的蛋白质表达谱，将45个样本按照其组织学分类进行分组。统计分析和质谱鉴定出26种差异表达蛋白，其中14种在功能上与c-Myc、AP-1、HIF1A、肝细胞核因子4α或Ras超家族（RhoA、CDC42和Rac1）相关。在鉴定出的蛋白中，我们重点关注APC结合蛋白EB1（EB1），因为它在低分化HCC中高表达，而低分化HCC通常与HCC患者的不良预后相关。此外，EB1受c-Myc、RhoA和CDC42调控，这些都与HCC的恶性程度有关。对另外145例HCC病例进行免疫组织化学分析显示，EB1与组织学分化程度显著相关（P<0.001），单因素和多因素分析表明，EB1是根治性手术后HCC患者复发（风险比，2.740；95%置信区间，1.771 - 4.239；P<0.001）和生存（风险比，2.256；95%置信区间，1.337 - 3.807；P = 0.002）的独立预后因素。
蛋白质组学分析揭示了HCC进展背后的分子特征以及EB1在HCC中的预后价值。
