Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma
Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma
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DOI：
10.1093/neuonc/not315
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发表时间：
2014-07-01
期刊：
影响因子：
15.9
通讯作者：
Tanaka, Shinya
中科院分区：
文献类型：
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作者：
Kohsaka, Shinji;Hinohara, Kunihiko;Tanaka, Shinya
多形性胶质母细胞瘤（GBM）是最具侵袭性的人类肿瘤之一，建立有效的治疗试剂是当务之急。通过在小鼠皮下传代GBM细胞系LN 443和U373，我们已经开发出这些细胞的高度侵袭性变体，命名为LN 443X，U373X1和U373X2，它们显示出增加的肿瘤生长，集落形成潜力，成球潜力和入侵能力。我们进一步研究了使用微阵列分析比较恶性细胞与其亲本细胞和mRNA表达分析在II级至IV级胶质瘤samples.Adipocyte增强子结合蛋白1，epiregulin（EREG），和微纤维相关蛋白5被确定为候选基因与较高的肿瘤分级和预后不良。免疫组化分析也表明EREG的强表达与短的总生存期相关。此外，EREG刺激和EREG引入GBM细胞系被发现增加表皮生长因子受体（EGFR）和细胞外信号调节激酶的磷酸化，并导致促进集落形成、球体形成和体内肿瘤形成。Gefitinib治疗可抑制EGFR和细胞外信号调节激酶的磷酸化，并导致U373过表达的EREG肿瘤消退。这些结果表明EREG是参与胶质瘤恶性的分子之一，EGFR抑制剂可能是EREG过表达的GBM患者的候选治疗药物。
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target.Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples.Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG.These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients.