Division of Gastroenterology, Tohoku Graduate School of Medicine, Sendai, Japan.
Mol Carcinog. 2011 Oct;50(10):781-90. doi: 10.1002/mc.20699. Epub 2011 Jul 12.
Oxidative stress might participate in the carcinogenesis of human esophageal squamous cell carcinomas (hESCC). 4-Hydroxynonenal (HNE) is a major product of membrane lipid peroxidation with short life. It might act as an important mediator through the generation of adducts and activate epidermal growth factor receptor (EGFR) signaling. It is mainly trapped with glutathione (GSH) and catalyzed by glutathione S-transferases (GSTs). This study aimed to elucidate the possible participation of HNE, GSH/GST system, and EGFR signaling in hESCC development. Immunohistochemistry of HNE adducts, EGFR, and phosphorylated EGFR (pEGFR) was performed with hESCC specimens. The effect of HNE on the phosphorylation of EGFR and its downstream PhospholipaseCγ1 (PLCγ1) was investigated with KYSE30 cell-line. Pretreatment with GSH inducer N-acetylcysteine (NAC) or GSH inhibitor Buthionine sulfoximine (BSO) and mandatory transfection of hGSTA4 gene in KYSE30 were conducted to investigate the relationship between HNE and GSH/GST system. Immunoreactants of HNE adducts, EGFR, and pEGFR were increased in hESCC compared to non-cancerous epithelium with positive correlations. The treatment of HNE ligand-independently induced the phosphorylation of EGFR and PLCγ1 accompanying the diminishment of intracellular GSH level. NAC increased GSH contents but BSO decreased in dose-dependent manners. Reflecting changes in GSH, HNE-induced EGFR phosphorylation was suppressed by NAC, whereas it was promoted by BSO. Mandatory expression of hGSTA4 suppressed HNE-induced events. We first demonstrated that the ligand-independent activation of EGFR by the balance between the stimulation of HNE and the prevention of intrinsic GSH/GST system might participate in the development of hESCC.
氧化应激可能参与人类食管鳞状细胞癌（hESCC）的癌变。4-羟基壬烯醛（HNE）是膜脂质过氧化的主要产物，寿命短。它可能通过加合物的生成作为重要的介质，并激活表皮生长因子受体（EGFR）信号。它主要与谷胱甘肽（GSH）结合，并由谷胱甘肽 S-转移酶（GSTs）催化。本研究旨在阐明 HNE、GSH/GST 系统和 EGFR 信号在 hESCC 发展中的可能参与。对 hESCC 标本进行 HNE 加合物、EGFR 和磷酸化 EGFR（pEGFR）的免疫组织化学检测。用 KYSE30 细胞系研究 HNE 对 EGFR 磷酸化及其下游磷脂酶 Cγ1（PLCγ1）的影响。用 GSH 诱导剂 N-乙酰半胱氨酸（NAC）或 GSH 抑制剂丁硫氨酸亚砜（BSO）预处理 KYSE30，并强制性转染 hGSTA4 基因，以研究 HNE 与 GSH/GST 系统的关系。与非癌上皮相比，hESCC 中 HNE 加合物、EGFR 和 pEGFR 的免疫反应物增加，且呈正相关。HNE 配体非依赖性诱导 EGFR 和 PLCγ1 的磷酸化，同时伴随细胞内 GSH 水平降低。NAC 以剂量依赖的方式增加 GSH 含量，而 BSO 则减少。反映 GSH 的变化，HNE 诱导的 EGFR 磷酸化被 NAC 抑制，而被 BSO 促进。hGSTA4 的强制性表达抑制 HNE 诱导的事件。我们首次证明，通过 HNE 的刺激和内在 GSH/GST 系统的预防之间的平衡，EGFR 的配体非依赖性激活可能参与 hESCC 的发展。
