Pulmonary preconditioning, injury, and inflammation modulate expression of the candidate tumor suppressor gene ECRG4 in lung.
Pulmonary preconditioning, injury, and inflammation modulate expression of the candidate tumor suppressor gene ECRG4 in lung.
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DOI：
10.3109/01902148.2014.983282
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发表时间：
2015-04
影响因子：
1.7
通讯作者：
Baird A
中科院分区：
文献类型：
--
作者：
Kao S;Shaterian A;Cauvi DM;Dang X;Chun HB;De Maio A;Costantini TW;Coimbra R;Eliceiri BP;Baird A
人类c2 orf 40基因编码一种名为食管癌相关基因-4（ECRG 4）的候选肿瘤抑制基因，ECRG 4是一种在癌症、损伤、炎症和感染中特征性下调的丝氨酸样表观遗传调节蛋白。在这里，我们询问ECRG 4基因表达是否在肺上皮细胞中可检测到，以及其表达是否随炎症、感染和/或保护性预处理而变化。我们使用免疫印迹、PCR和定量PCR来测量ECRG 4以及吸入麻醉预处理、脂多糖注射或剖腹手术来调节肺部炎症。免疫印迹确定小鼠肺中存在全长14 kDa ECRG 4肽。免疫组织化学定位ECRG 4到I型肺泡上皮细胞。基础ECRG 4 mRNA高于TNF-α、IL-1β和IL-6，但在炎性肺损伤后，TNF-α、IL-1β、IL-6和IL-10上调，而ECRG 4基因表达降低。在静脉内施用脂多糖后观察到类似的发现。相反，异氟烷麻醉的肺预处理增加肺ECRG 4基因表达。体外人肺上皮细胞中ECRG 4的过表达降低了细胞增殖，这意味着体内ECRG 4的缺失将允许细胞生长。本研究支持ECRG 4在肺泡上皮细胞中作为前哨生长抑制剂的假设。其下调损伤，感染和炎症和上调预处理支持ECRG 4在调节肺泡上皮细胞对损伤和炎症的反应中的作用。通过扩展，研究结果支持其通过启动子超甲基化（即肺癌）抑制的功能后果，并表明其上调的潜在益处。
The human c2orf40 gene encodes a candidate tumor suppressor called Esophageal Cancer-Related Gene-4 (ECRG4) that is a cytokine-like epigenetically-regulated protein that is characteristically downregulated in cancer, injury, inflammation, and infection. Here, we asked whether ECRG4 gene expression is detectable in lung epithelial cells and if its expression changes with inflammation, infection, and/or protective preconditioning. We used immunoblotting, PCR, and quantitative PCR to measure ECRG4 and either inhalation anesthesia preconditioning, lipopolysaccharide injection, or laparotomy to modulate lung inflammation. Immunoblotting establishes the presence of the full-length 14 kDa ECRG4 peptide in mouse lung. Immunohistochemistry localizes ECRG4 to type l alveolar epithelial cells. Basal ECRG4 mRNA is greater than TNF-α, IL-1β, and IL-6 but following inflammatory lung injury, TNF-α, IL-1β, IL-6, and IL-10 are upregulated while ECRG4 gene expression is decreased. Similar findings are observed after an intravenous administration of lipopolysaccharide. In contrast, lung preconditioning with isoflurane anesthesia increases lung ECRG4 gene expression. Over-expression of ECRG4 in human lung epithelial cells in vitro decreases cell proliferation implying that a loss of ECRG4 in vivo would be permissive to cell growth. This study supports the hypothesis that ECRG4 acts as a sentinel growth inhibitor in lung alveolar epithelial cells. Its downregulation by injury, infection, and inflammation and upregulation by preconditioning supports a role for ECRG4 in regulating the alveolar epithelium response to injury and inflammation. By extension, the findings support a functional consequence to its inhibition by promoter hypermethylation (i.e. lung cancer) and suggest potential benefits to its upregulation.