The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma
The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma
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DOI：
10.1136/gut.2007.129544
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发表时间：
2008-02-01
期刊：
影响因子：
24.5
通讯作者：
Bosserhoff, A-K
中科院分区：
文献类型：
--
作者：
Hellerbrand, C.;Amann, T.;Bosserhoff, A-K
背景：黑色素瘤抑制活性2（Melanoma inhibitory activity 2，MIA 2）是MIA基因家族中的一个新基因。MIA 2在肝细胞中的选择性表达由MIA 2启动子中的肝细胞核因子（HNF）1结合位点控制。相反，在大多数肝细胞癌（HCC）MIA 2的表达下调或loss.Aim：在这项研究中，我们研究了MIA 2在hepatocancerogenesis.Methods和结果的调节和功能作用：在肝癌细胞系和组织HNF-1的表达低于原代人肝细胞（PHH）和相应的非肿瘤组织，分别，并与MIA 2的表达下调显着相关。HCC细胞中HNF-1的重新表达重新诱导HCC细胞中的MIA 2达到与PHH中发现的相似水平。此外，通过稳定转染，MIA 2在HCC细胞系中重新表达，并且所产生的细胞克隆揭示了体外侵袭潜力和增殖速率的强烈降低。与这些发现一致，用重组MIA 2处理HCC细胞抑制增殖和侵袭。在裸鼠中，MIA 2再表达的HCC细胞生长明显较慢，并显示出侵袭性较低的生长模式。对85例患者的包含HCC和相应非癌肝组织的组织微阵列的免疫组织化学分析证实了HCC中MIA 2表达的降低。此外，MIA 2阴性肝癌组织表现出显着较高的Ki 67标记指数和损失MIA 2表达相关的显着更先进的肿瘤stages.Conclusion：这项研究提出MIA 2作为肝癌生长和侵袭的抑制剂在体外和体内，因此，作为肝癌的肿瘤抑制剂。此外，我们的研究结果表明了一种新的机制，即HCC中HNF-1表达的缺失如何通过下调MIA 2影响致瘤性。
Background: Melanoma inhibitory activity 2 (MIA2) is a novel gene of the MIA gene family. The selective expression of MIA2 in hepatocytes is controlled by hepatocyte nuclear factor (HNF) 1 binding sites in the MIA2 promotor. In contrast, in most hepatocellular carcinomas (HCC) MIA2 expression is down-regulated or lost.Aim: In this study we examined the regulation and functional role of MIA2 in hepatocancerogenesis.Methods and results: In HCC cell lines and tissues HNF-1 expression was lower than in primary human hepatocytes (PHH) and corresponding non-tumorous tissue, respectively, and correlated significantly with the down-regulation of MIA2 expression. Re-expression of HNF-1 in HCC cells reinduced MIA2 in HCC cells to similar levels as found in PHH. Further, MIA2 was re-expressed in HCC cell lines by stable transfection, and the generated cell clones revealed a strongly reduced invasive potential and proliferation rate in vitro. In line with these findings treatment of HCC cells with recombinant MIA2 inhibited proliferation and invasion. In nude mice MIA2 re-expressing HCC cells grew significantly slower and revealed a less invasive growth pattern. Immunohistochemical analysis of a tissue microarray containing HCC and corresponding non-cancerous liver tissue of 85 patients confirmed reduced MIA2 expression in HCC. Furthermore, MIA2 negative HCC tissue showed a significantly higher Ki67 labelling index and loss of MIA2 expression correlated significantly with more advanced tumour stages.Conclusion: This study presents MIA2 as an inhibitor of HCC growth and invasion both in vitro and in vivo, and consequently, as a tumour suppressor of HCC. Further, our findings indicate a novel mechanism, how loss of HNF-1 expression in HCC affects tumorigenicity via down-regulation of MIA2.