Expression of MUC17 is regulated by HIF1α-mediated hypoxic responses and requires a methylation-free hypoxia responsible element in pancreatic cancer.
Expression of MUC17 is regulated by HIF1α-mediated hypoxic responses and requires a methylation-free hypoxia responsible element in pancreatic cancer.
复制标题
DOI：
10.1371/journal.pone.0044108
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yonezawa S
中科院分区：
文献类型：
--
作者：
Kitamoto S;Yokoyama S;Higashi M;Yamada N;Matsubara S;Takao S;Batra SK;Yonezawa S
MUC 17是主要在消化道中表达的1型膜结合糖蛋白。最近的研究表明，MUC 17的异常过表达与胰腺导管腺癌（PDAC）的恶性潜能相关;然而，MUC 17表达的确切调控机制尚未确定。在这里，我们首次报道了MUC 17在缺氧条件下的调节机制，这是肿瘤微环境的一个基本特征，也是癌症进展的驱动力。我们的数据显示，MUC 17在某些胰腺癌细胞中通过低氧诱导因子1α（HIF 1 α）依赖性途径被低氧刺激显著诱导（例如，AsPC 1），而其他胰腺癌细胞（例如，BxPC 3）对缺氧反应不明显。有趣的是，这些低反应细胞在缺氧反应元件（HRE，5 '-RCGTG-3'）（HIF 1 α的结合位点）内具有高度甲基化的CpG基序。因此，我们研究了CpG在HRE上对MUC 17缺氧诱导的去甲基化作用。用5-氮杂-2 ′-脱氧胞苷处理低反应细胞，随后进行额外的低氧孵育，导致低氧MUC 17诱导的恢复。此外，PDAC患者胰腺组织中HRE的DNA甲基化水平高于非癌组织，且低甲基化水平与MUC 17 mRNA表达相关。综上所述，这些结果表明HIF 1 α介导的低氧信号通路有助于MUC 17的表达，并且HRE的DNA甲基化可能是胰腺癌细胞中MUC 17低氧诱导的决定因素。
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.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
29.4
作者：
Ho, Samuel B.;Dvorak, Leah A.;Shekels, Laurie L.
通讯作者：
Shekels, Laurie L.
影响因子：
4.8
作者：
Vincent, Audrey;Ducourouble, Marie-Paule;Van Seuningen, Isabelle
通讯作者：
Van Seuningen, Isabelle
影响因子：
5.7
作者：
Hirono, Seiko;Yamaue, Hiroki;Noda, Tetsuo
通讯作者：
Noda, Tetsuo
影响因子：
78.5
作者：
Kufe, Donald W.
通讯作者：
Kufe, Donald W.