Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).
Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).
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DOI：
10.18632/oncotarget.3978
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Cao J
中科院分区：
文献类型：
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作者：
Evensen NA;Li Y;Kuscu C;Liu J;Cathcart J;Banach A;Zhang Q;Li E;Joshi S;Yang J;Denoya PI;Pastorekova S;Zucker S;Shroyer KR;Cao J
低氧应激通过引起转录重编程来驱动癌症进展。最近，KIAA 1199被发现是一种细胞迁移诱导蛋白（重命名为CEMIP），在人类癌症中上调。然而，迄今为止，CEMIP在癌症中的诱导机制尚不清楚。在这里，我们证明，缺氧诱导CEMIP表达，导致增强细胞迁移。人结肠癌组织的免疫组织化学显示，CEMIP在位于浸润前沿或粘膜下层的癌细胞中上调。CEMIP定位与E-钙粘蛋白表达呈负相关，这是上皮向间质转化的特征。从机制上讲，缺氧诱导因子-2 α（HIF-2α）而不是HIF-1α直接与CEMIP启动子区域内的缺氧反应元件结合，导致CEMIP表达增加。功能表征表明CEMIP是HIF-2α介导的细胞迁移的下游效应子。CEMIP的表达被证明与Jarid 1A的表达呈负相关，Jarid 1A是一种组蛋白脱甲基酶，可从H3 K4 me 3（转录的活化标记物）中去除甲基，导致基因阻遏改变。低氧张力抑制Jarid 1A的功能，导致CEMIP启动子内H3 K4 me 3的存在增加。这些结果提供了对癌症中CEMIP上调的深入了解，并可能导致针对这种癌细胞迁移促进基因的新治疗策略。
Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a cell-migration inducing protein (renamed CEMIP) that is upregulated in human cancers. However, the mechanism of induction of CEMIP in cancer was hitherto unknown. Here we demonstrate that hypoxia induces CEMIP expression leading to enhanced cell migration. Immunohistochemistry of human colon cancer tissues revealed that CEMIP is upregulated in cancer cells located at the invasive front or in the submucosa. CEMIP localization inversely correlated with E-cadherin expression, which is characteristic of the epithelial-to-mesenchymal transition. Mechanistically, hypoxia-inducible-factor-2α (HIF-2α), but not HIF-1α binds directly to the hypoxia response element within the CEMIP promoter region resulting in increased CEMIP expression. Functional characterization reveals that CEMIP is a downstream effector of HIF-2α-mediated cell migration. Expression of CEMIP was demonstrated to negatively correlate with the expression of Jarid1A, a histone demethylase that removes methyl groups from H3K4me3 (an activation marker for transcription), resulting in altered gene repression. Low oxygen tension inhibits the function of Jarid1A, leading to increased presence of H3K4me3 within the CEMIP promoter. These results provide insight into the upregulation of CEMIP within cancer and can lead to novel treatment strategies targeting this cancer cell migration-promoting gene.