Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California, United States of America.
PLoS One. 2013 Apr 23;8(4):e61394. doi: 10.1371/journal.pone.0061394. Print 2013.
We report an inverse relationship between expression of the orphan candidate tumor suppressor gene esophageal cancer related gene 4 (Ecrg4), and the mucosal epithelial cell response to infection in the middle ear (ME). First, we found constitutive Ecrg4 mRNA expression in normal, quiescent ME mucosa that was confirmed by immunostainning of mucosal epithelial cells and immunoblotting of tissue lysates for the 14 kDa Ecrg4 protein. Upon experimental ME infection, Ecrg4 gene expression rapidly decreased by over 80%, between 3 to 48 hrs, post infection. When explants of this infected mucosa were placed in culture and transduced with an adenovirus (AD) encoding Ecrg4 gene (ADEcrg4), the proliferative and migratory responses of mucosal cells were significantly inhibited. ADEcrg4 transduction of control explants from uninfected MEs had no effect on basal growth and migration. Over-expression of Ecrg4 in vivo, by pre-injecting MEs with ADEcrg4 48 hrs prior to infection, prevented the natural down-regulation of Ecrg4, reduced mucosal proliferation and prevented inflammatory cell infiltration normally observed after infection. Taken together, these data support a hypothesis that Ecrg4 plays a role in coordinating the inflammatory and proliferative response to infection of mucosal epithelium suggesting a possible mechanism for its putative anti-tumor activity.
我们报告了孤儿候选肿瘤抑制基因食管癌细胞相关基因 4（Ecrg4）的表达与中耳（ME）黏膜上皮细胞对感染的反应之间呈反比关系。首先，我们发现正常、静止的 ME 黏膜中存在组成型 Ecrg4 mRNA 表达，这通过黏膜上皮细胞的免疫染色和组织裂解物中 14 kDa Ecrg4 蛋白的免疫印迹得到证实。在实验性 ME 感染后，Ecrg4 基因表达在感染后 3 至 48 小时内迅速下降超过 80%。当将感染的黏膜外植体置于培养中并用编码 Ecrg4 基因的腺病毒（AD）（ADEcrg4）转导时，黏膜细胞的增殖和迁移反应受到显著抑制。从未感染 ME 的对照外植体中转导 ADEcrg4 对基础生长和迁移没有影响。在感染前 48 小时用 ADEcrg4 预先注射 ME 来体内过表达 Ecrg4，可防止 Ecrg4 的自然下调，减少黏膜增殖并防止感染后通常观察到的炎症细胞浸润。总之，这些数据支持了这样一种假设，即 Ecrg4 在协调黏膜上皮细胞对感染的炎症和增殖反应中发挥作用，这表明其潜在的抗肿瘤活性可能存在一种机制。
