Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma
Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma
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DOI：
10.1002/ijc.20860
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发表时间：
2005-06-10
影响因子：
6.4
通讯作者：
Oka, M
中科院分区：
文献类型：
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作者：
Matoba, K;Iizuka, N;Oka, M
由于肝内复发 (IHR) 频率高，尤其是肝切除术后 1 年内的早期 IHR，肝细胞癌 (HCC) 患者的预后仍然较差。为了寻找与早期 IHR 相关的基因，我们在 33 个 HCC 的训练集中进行了 DNA 微阵列分析，并通过监督学习方法从大约 6,000 个基因中选择了与早期 IHR 相关的 46 个基因。基因选择通过错误发现率或 0.37% 进行验证。这 46 个基因包括许多与免疫反应相关的基因，这些基因在早期 IHR 的 HCC 中均下调。其中四个编码 MHC II 类抗原的基因（HLA-DRA、HLA-DRB1、HLA-DG 和 HLA-DQA）在早期 IHR 的 HCC 中与未复发的 HCC 中的水平协调下调。聚类分析重现了 27 个盲法 HCC 样本中 4 个 MHC 11 类基因的表达模式。为了定位肿瘤中 HLA-DR 蛋白的主要产生位点，我们使用了来自 50 个 HCC 的 50 个冷冻标本。免疫荧光染色显示，肿瘤细胞中的 HLA-DR 蛋白水平与通过 DNA 微阵列分析和实时定量逆转录 -PCR 测定的 HLA-DRA 转录水平相关，而基质细胞中则不然。单变量分析显示肿瘤HLA-DR蛋白表达、pTNM分期和静脉侵犯与早期IHR相关。多变量分析显示肿瘤 HLA-DR 蛋白表达是早期 IHR 的独立危险因素之一，表明 HLA-DR 蛋白作为生物标志物和治疗干预的分子靶点的潜力。 (c) 2005 年 Wiley-Liss, Inc.
The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of the high frequency of intrahepatic recurrence (IHR), particularly early IHR within 1 year of hepatectomy. To search for genes involved in early IHR, we performed DNA microarray analysis in a training set of 33 HCCs and selected 46 genes linked to early IHR from approximately 6,000 genes by means of a supervised learning method. Gene selection was validated by a false discovery rate or 0.37%. The 46 genes included many immune response-related genes, which were all down-regulated in HCCs with early IHR. Four of these genes (HLA-DRA, HLA-DRB1, HLA-DG and HLA-DQA), encoding MHC class II antigens, were coordinately downregulated in HCCs with early IHR compared to levels in HCCs with nonrecurrence. A cluster analysis reproduced expression patterns of the 4 MHC class 11 genes in 27 blinded HCC samples. To localize the major site of production of HLA-DR protein in the tumor, we used 50 frozen specimens from 50 HCCs. Immunofluoreseence staining showed that HLA-DR protein levels in tumor cells, but not in stromal cells, were associated with the transcription levels of HLA-DRA determined by both DNA microarray analysis and real-time quantitative reverse transcription -PCR. Univariate analysis showed that tumor HLA-DR protein expression, pTNM stage and venous invasion were associated with early IHR. Multivariate analysis showed that tumor HLA-DR protein expression was one of the independent risk factors for early IHR, suggesting HLA-DR protein potential as a biomarker and a molecular target for therapeutic intervention. (c) 2005 Wiley-Liss, Inc.