Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma
Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-10-3096
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发表时间：
2011-08-15
影响因子：
11.5
通讯作者：
Gao, Dong-Mei
中科院分区：
文献类型：
--
作者：
Xiang, Zuo-Lin;Zeng, Zhao-Chong;Gao, Dong-Mei
目的：肝细胞癌最常发生于感染了乙型或丙型肝炎病毒的患者。差异基因表达谱有助于研究与淋巴转移相关的基因。实验设计：从36例淋巴结阳性或36例阴性的肝癌患者的瘤内和瘤周组织中提取经福尔马林固定的RNA。对一组502个已知的癌症相关基因进行了cDNA介导的退火法、选择法、延伸法和连接试验，以确定20对有或没有LNM患者的差异表达基因。通过免疫组织化学和组织微阵列对309例接受肝切除的肝癌患者的独立队列中的候选生物标志物进行评估。309例患者中，235例(76.1%)感染乙肝。结果：与淋巴结阴性患者相比，淋巴结阳性患者瘤内组织中有17个基因高表达，19个基因低表达，瘤周组织中有25个基因高表达，22个基因低表达。对309例肝细胞癌患者进行了缺氧诱导因子-1α、血管内皮生长因子和基质金属蛋白酶-2的检测。我们发现HIF-1α、血管内皮生长因子和基质金属蛋白酶-2的瘤内蛋白水平是发生LNM的独立危险因素。结论：我们发现了83个在淋巴结阳性和淋巴结阴性的肝癌中差异表达的癌基因。我们的研究结果表明，肿瘤内HIF-1α、血管内皮生长因子和基质金属蛋白酶-2的联合检测可作为预测淋巴结转移的分子模型。临床癌症研究中心；17(16)；5463-72。(C)2011年AACR。
Purpose: Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC.Experimental Design: RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n = 36) or negative (n = 36) HCC. A cDNA-mediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancer-related genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B.Results: Compared with lymph node-negative patients, lymph node-positive patients had 17 over-expressed genes and 19 underexpressed genes in intratumoral tissues, and 25 over-expressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1 alpha, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1 alpha, VEGF, and MMP-2 were independent risk factors for developing LNM.Conclusion: We identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC. Our findings show that the combination of intratumoral HIF-1 alpha, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM. Clin Cancer Res; 17(16); 5463-72. (C)2011 AACR.