Hypoxia-induced HIF-1α and ZEB1 are critical for the malignant transformation of ameloblastoma via TGF-β-dependent EMT
Hypoxia-induced HIF-1α and ZEB1 are critical for the malignant transformation of ameloblastoma via TGF-β-dependent EMT
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DOI：
10.1002/cam4.2667
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发表时间：
2019-11-01
期刊：
影响因子：
4
通讯作者：
Hashimoto, Shuichi
中科院分区：
文献类型：
--
作者：
Yoshimoto, Shohei;Tanaka, Fumie;Hashimoto, Shuichi
成釉细胞癌（ameloblasticcarcinoma，AC）是一种罕见的原发性牙源性上皮性恶性肿瘤，是成釉细胞瘤（ameloblastoma，AB）的良性上皮性牙源性肿瘤的恶性对应物。AC在大约三分之一的患者中发生肺转移，并且显示预后不良。然而，AC肿瘤发生的机制仍不清楚。在这篇报告中，我们的目的是阐明AB或AC癌变的恶性转化机制。应用基因芯片技术筛选与AB恶性转化相关的基因，并应用免疫组化技术检测AB和继发AC中相关蛋白的表达和定位。低氧诱导因子1 α亚基（HIF 1A）和锌指E盒结合同源盒1（ZEB 1）基因在AC中的表达显著高于AB。这两个基因在缺氧和上皮间质转化（EMT）中密切相关。此外，AC中HIF-1 α和ZEB 1蛋白的表达显著强于AB。在使用成釉细胞瘤细胞系AM-1的细胞测定中，缺氧条件上调转化生长因子-β（TGF-β）的表达并诱导EMT。抗过敏药曲尼司特可抑制缺氧引起的细胞形态学改变和细胞迁移能力。最后，我们得出结论，缺氧诱导的HIF-1 α和ZEB 1是通过TGF-β依赖性EMT的AB恶性转化的关键。因此，HIF-1 α和ZEB 1可能是预测AB恶变的潜在生物标志物。
Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic malignant neoplasm and the malignant counterpart of benign epithelial odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops pulmonary metastasis in about one third of the patients and reveals a poor prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this report, we aimed to clarify the mechanisms of malignant transformation of AB or AC carcinogenesis. The relatively important genes in the malignant transformation of AB were screened by DNA microarray analysis, and the expression and localization of related proteins were examined by immunohistochemistry using samples of AB and secondary AC. Two genes of hypoxia-inducible factor 1 alpha subunit (HIF1A) and zinc finger E-box-binding homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in AB. Both genes were closely related in hypoxia and epithelial-mesenchymal transition (EMT). In addition, expressions of HIF-1 alpha and ZEB1 proteins were significantly stronger in AC than in AB. In the cell assays using ameloblastoma cell line, AM-1, hypoxia condition upregulated the expression of transforming growth factor-beta (TGF-beta) and induced EMT. Furthermore, the hypoxia-induced morphological change and cell migration ability were inhibited by an antiallergic medicine tranilast. Finally, we concluded that hypoxia-induced HIF-1 alpha and ZEB1 were critical for the malignant transformation of AB via TGF-beta-dependent EMT. Then, both HIF-1 alpha and ZEB1 could be potential biomarkers to predict the malignant transformation of AB.