Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer
Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer
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DOI：
10.1002/path.1928
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发表时间：
2006-04-01
影响因子：
7.3
通讯作者：
Kodama, T
中科院分区：
文献类型：
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作者：
Tanaka, T;Jiang, S;Kodama, T
肝细胞核因子-4 α（HNF 4 α）存在于多种异构体中，这些异构体通过选择性启动子（P1和P2）使用和剪接产生。在这里，我们建立了单克隆抗体（mAb）检测P1和P2启动子驱动的HNF 4 α，并评估其在正常成人组织和手术切除的不同来源的癌症的表达。使用免疫组织化学分析，我们证明，虽然P1启动子驱动的HNF 4 α在肝细胞，小肠，结肠，肾脏和附睾中表达，P2启动子驱动的HNF 4 α在胆管，胰腺，胃，小肠，结肠和附睾中表达。在胃癌、肝细胞癌和结直肠癌中观察到P1和P2启动子驱动的HNF 4 α表达模式的改变。HNF 4 α在肾细胞癌、肝细胞癌和结直肠癌的肺转移中表达，但在肺肿瘤中未观察到。P1和P2启动子驱动的HNF 4 α表达模式的肿瘤转移与原发部位的起源。P1启动子驱动的HNF 4 α也见于胃的肠上皮化生。这些数据为P1和P2启动子驱动的HNF 4 α在蛋白水平的组织分布提供了证据，并表明HNF 4 α可能是未知原发性转移瘤的新诊断标志物。我们认为HNF 4 α的替代启动子使用的失调与某些癌症的发病机制有关。版权所有（c）2006大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Hepatocyte nuclear factor-4 alpha (HNF4 alpha) exists in multiple isoforms that are generated by alternative promoter (PI and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4 alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4 alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4 alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of PI and P2 promoter-driven HNF4 alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4 alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4 alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4 alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4 alpha at the protein level and suggest that HNF4 alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4 alpha is associated with the pathogenesis of certain cancers. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.