口腔癌細胞における新規低酸素誘導遺伝子EFEMP2機能解析

肿瘤缺氧通过缺氧诱导的转录因子改变多种基因的表达，导致与生物侵袭性表型相关的许多变化。我们利用寡核苷酸芯片技术鉴定了一个新的低氧诱导基因EFEMP 2，并证明该基因可以降低癌细胞中p53的活性。EFEMP 2在结肠癌和食管癌组织中的表达水平显著高于癌旁正常组织。启动子报告基因在几种癌细胞中表现出明显的活性，并且在低氧条件下（1%pO_2）或共转染HIF-1α后活性增强。EFEMP 2的强制表达降低了癌细胞中p53蛋白水平及其活性，并且还减弱了Notch信号传导。综上所述，我们证明EFEMP 2是由HIF-1和其蛋白通过p53调节调节癌细胞增殖的转录诱导。

Tumor hypoxia alters expression of various genes via hypoxia-inducible transcription factors, resulting causes numerous changes linked to the biologically aggressive phenotype. We identified EFEMP2 as a novel hypoxia-inducible gene by using oligonucleotide array, and demonstrated that the gene could decrease p53 activity in cancer cells. The expression levels of EFEMP2 were significantly higher in both colon and esophageal cancers compared to the adjacent normal tissues. Promoter reporters showed significant activities in several cancer cells and the activities were increased under hypoxic conditions (1% pO_2) or by cotransfection of HIF-1α. Forced expression of EFEMP2 decreased p53 protein levels and its activity in cancer cells, and also attenuated Notch signaling. Taken together, we demonstrated that EFEMP2 was transcriptionally induced by HIF-1 and its protein regulated cancer cell proliferation via p53 regulations.