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MUC17 的表达受 HIF1α 介导的缺氧反应调控,需要在胰腺癌中存在无甲基化的缺氧反应元件。

Expression of MUC17 is regulated by HIF1α-mediated hypoxic responses and requires a methylation-free hypoxia responsible element in pancreatic cancer.

机构信息

Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

出版信息

PLoS One. 2012;7(9):e44108. doi: 10.1371/journal.pone.0044108. Epub 2012 Sep 10.

Abstract

MUC17 is a type 1 membrane-bound glycoprotein that is mainly expressed in the digestive tract. Recent studies have demonstrated that the aberrant overexpression of MUC17 is correlated with the malignant potential of pancreatic ductal adenocarcinomas (PDACs); however, the exact regulatory mechanism of MUC17 expression has yet to be identified. Here, we provide the first report of the MUC17 regulatory mechanism under hypoxia, an essential feature of the tumor microenvironment and a driving force of cancer progression. Our data revealed that MUC17 was significantly induced by hypoxic stimulation through a hypoxia-inducible factor 1α (HIF1α)-dependent pathway in some pancreatic cancer cells (e.g., AsPC1), whereas other pancreatic cancer cells (e.g., BxPC3) exhibited little response to hypoxia. Interestingly, these low-responsive cells have highly methylated CpG motifs within the hypoxia responsive element (HRE, 5'-RCGTG-3'), a binding site for HIF1α. Thus, we investigated the demethylation effects of CpG at HRE on the hypoxic induction of MUC17. Treatment of low-responsive cells with 5-aza-2'-deoxycytidine followed by additional hypoxic incubation resulted in the restoration of hypoxic MUC17 induction. Furthermore, DNA methylation of HRE in pancreatic tissues from patients with PDACs showed higher hypomethylation status as compared to those from non-cancerous tissues, and hypomethylation was also correlated with MUC17 mRNA expression. Taken together, these findings suggested that the HIF1α-mediated hypoxic signal pathway contributes to MUC17 expression, and DNA methylation of HRE could be a determinant of the hypoxic inducibility of MUC17 in pancreatic cancer cells.

摘要

黏蛋白 17(MUC17)是一种 1 型跨膜糖蛋白,主要在消化道中表达。最近的研究表明,MUC17 的异常过表达与胰腺导管腺癌(PDAC)的恶性潜能相关;然而,MUC17 表达的确切调控机制尚未确定。在这里,我们首次报道了缺氧条件下 MUC17 的调控机制,缺氧是肿瘤微环境的一个重要特征,也是癌症进展的驱动力。我们的数据显示,在一些胰腺癌细胞(如 AsPC1)中,MUC17 受到缺氧刺激的显著诱导,这是通过缺氧诱导因子 1α(HIF1α)依赖途径实现的,而其他胰腺癌细胞(如 BxPC3)对缺氧的反应很小。有趣的是,这些低反应性细胞在缺氧反应元件(HRE,5'-RCGTG-3')内具有高度甲基化的 CpG 基序,这是 HIF1α 的结合位点。因此,我们研究了 HRE 上 CpG 的去甲基化效应对 MUC17 缺氧诱导的影响。用 5-氮杂-2'-脱氧胞苷处理低反应性细胞,然后进行缺氧孵育,导致缺氧诱导的 MUC17 诱导恢复。此外,与非癌组织相比,来自 PDAC 患者的胰腺组织中 HRE 的 DNA 甲基化显示出更高的低甲基化状态,并且低甲基化也与 MUC17 mRNA 表达相关。总之,这些发现表明 HIF1α 介导的缺氧信号通路有助于 MUC17 的表达,而 HRE 的 DNA 甲基化可能是胰腺癌细胞中 MUC17 缺氧诱导性的决定因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbca/3438193/3b7d92e8f526/pone.0044108.g001.jpg

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