Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma
Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma
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DOI：
10.1038/sj.onc.1208050
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发表时间：
2005-01-27
期刊：
影响因子：
8
通讯作者：
Goggins, M
中科院分区：
文献类型：
--
作者：
Sato, N;Parker, AR;Goggins, M
利用微阵列，我们已经筛选出由药物重新激活的基因，这些药物改变了胰腺癌细胞的表观遗传机制。已鉴定的基因之一是组织因子途径抑制物2(TFPI-2)，它编码一种广谱丝氨酸蛋白酶抑制物，负向调节细胞外基质的降解，这是肿瘤侵袭和转移的关键步骤。因此，我们研究了TFPI-2基因在胰腺癌中的表达和甲基化模式，并确定了它在肿瘤生长和侵袭中的作用。TFPI-2在正常胰腺组织中大量表达，而在高比例胰腺癌细胞系和原发胰腺导管肿瘤(IPMN)中检测不到TFPI-2mRNA。TFPI-2表达缺失与其启动子CpG岛异常甲基化有关。佛波酯(PMA)可以刺激TFPI-2启动子的活性，但在含有未甲基化或部分甲基化的TFPI-2的细胞系中，TFPI-2的表达增强，但在含有完全甲基化的TFPI-2的细胞系中未能诱导表达。73%的胰腺癌移植瘤和胰腺癌组织中存在TFP I-2基因异常甲基化，老年胰腺癌患者TFP I-2基因异常甲基化发生率较高，且与IPMN的进展显著相关(P=0.0002)。在非表达的胰腺癌细胞中恢复TFPI-2基因的表达，可显著抑制其增殖、迁移和体外侵袭能力。因此，我们得出结论，TFPI-2的表观遗传失活是导致胰腺导管腺癌侵袭性表型的常见机制。
Using microarrays, we have screened for genes reactivated by drugs that modify epigenetic mechanisms in pancreatic cancer cells. One of the genes identified was tissue factor pathway inhibitor 2 (TFPI-2), which encodes for a broad-spectrum serine proteinase inhibitor that negatively regulates the extracellular matrix degradation, an essential step in tumor invasion and metastasis. We therefore investigated the expression and methylation patterns of the TFPI-2 gene in pancreatic adenocarcinoma, and determined its role in tumor growth and invasion. In contrast to its abundant expression in normal pancreas, TFPI-2 mRNA was undetectable in a high fraction of pancreatic cancer cell lines and in primary pancreatic ductal neoplasms (IPMNs). Loss of TFPI-2 expression was associated with aberrant hypermethylation of its promoter CpG island. Treatment with the phorbol ester (PMA), known to stimulate the TFPI-2 promoter activity, augmented the TFPI-2 expression in cell lines with unmethylated or partially methylated TFPI-2, but failed to induce the expression in cell lines that harbored fully methylated TFPI-2. Aberrant methylation of TFPI-2 was also detected in 73% (102/140) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas, was more likely in older patients with pancreatic cancer, and significantly correlated with progression of IPMNs (P = 0.0002). Restored expression of the TFPI-2 gene in nonexpressing pancreatic cancer cells resulted in marked suppression in their proliferation, migration, and invasive potential in vitro. We thus conclude that epigenetic inactivation of TFPI-2 is a common mechanism that contributes to the aggressive phenotype of pancreatic ductal adenocarcinoma.