Hypoxia induced overexpression of PrPC in gastric cancer cell lines
Hypoxia induced overexpression of PrPC in gastric cancer cell lines
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DOI：
10.4161/cbt.6.5.4001
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发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Liang, Jie;Bai, Feihu;Fan, Daiming
细胞朊蛋白（Cellular prion protein，PrPC）是一种主要在神经元中表达的铜结合糖基磷脂酰肌醇（GPI）锚定膜蛋白，可在缺血/缺氧脑组织中诱导表达。本实验室还发现它在胃癌中过表达并赋予多药耐药，促进癌转移和抑制凋亡。在实体瘤中，缺氧可促进恶性进展，并通过改变基因表达而赋予化疗抗性。在本研究中，我们研究的分子机制和信号通路参与的诱导PrPC基因在癌细胞系缺氧。PrPC在几种癌细胞系中在mRNA和蛋白水平上均被检测到上调，然后发现缺氧以时间依赖性的方式诱导PrPC。低氧处理后，胃癌MKN 28细胞转染的人PrPC启动子，其中含有HSE的荧光素酶报告基因的构建体，表达更高的荧光素酶活性（4.3倍）比那些细胞转染的构建体不含HSE。此外，MERK/ERK抑制剂（PD 98059）可降低PrPC的上调。siRNA敲低PrPC可使细胞对缺氧诱导的药物敏感性增强。综上所述，我们推测在低氧条件下，某些ERK 1/2磷酸化的转录因子可能与PrPC启动子区的HSE相互作用，导致PrPC在胃癌细胞系MKN 28中表达上调。PrPC表达下调使胃癌细胞对缺氧诱导的药物敏感性增加。然而，其他机制也可能负责缺氧诱导PrPC在胃癌中的过度表达。
Cellular prion protein (PrPC), a copper-binding glycosyl-phosphatidylinositol (GPI)-anchored membrane protein that is expressed predominantly in neurons can be induced in ischemia/hypoxic brain tissues. It was also found to be overexpressed and conferred multidrug resistance, promoting cancer metastasis and inhibiting apoptosis in gastric cancer in our lab. In solid tumors, hypoxia can promote malignant progression and confer resistance to chemotherapy by altering gene expression. In present study, we investigated the molecular mechanisms and signaling pathway involved in the induction of the PrPC gene by hypoxia in cancer cell lines. PrPC was detected to be upregulated in several cancer cell lines at both mRNA and protein level, and then found to be induced by hypoxia in a time-dependent manner. After hypoxia treatment, gastric cancer MKN28 cells transfected with luciferase reporter constructs of the human PrPC promoter, which contained HSE, expressed higher luciferase activities (4.3-fold) than those cells transfected with the constructs containing no HSE. In addition, the upregulation of PrPC was reduced by MERK/ERK inhibitor (PD98059). siRNA knockdown of PrPC could make the cells more sensitive to hypoxia induced drug sensitivity. In conclusion, from these findings, we can propose that some transcriptional factors phosphorylated by ERK1/2, could in turn interact with HSE in the promoter of PrPC resulting in upregulation of PrPC in gastric cancer cell line MKN28 during hypoxia. Downregulation of PrPC makes gastric cancer cells more sensitive to hypoxia induced drug sensitivity. However, other mechanisms might also be responsible for hypoxia induced overexpression of PrPC in gastric cancer.