Initiation of malignancy by duodenal contents reflux and the role of ezrin in developing esophageal squamous cell carcinoma
Initiation of malignancy by duodenal contents reflux and the role of ezrin in developing esophageal squamous cell carcinoma
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DOI：
10.1111/j.1349-7006.2009.01470.x
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发表时间：
2010-03-01
期刊：
影响因子：
5.7
通讯作者：
Hattori, Takanori
中科院分区：
文献类型：
--
作者：
Ling, Zhi-Qiang;Mukaisho, Ken-ichi;Hattori, Takanori
胃食道反流最近被认为是上呼吸道癌变的一个致病因素。食道鳞状细胞癌(ESCCs)发生在十二指肠内容物反流动物身上，没有任何已知的致癌物存在。我们建立了一个细胞系，命名为ESCC-DR，来自一只反流动物的胸部转移瘤。为了深入了解与十二指肠内容物反流诱导的癌变相关的基因组变化，我们首先在ESCC-DR中使用Agilent鼠244K阵列进行了比较基因组杂交，并确定了许多染色体的获得和丢失。在已鉴定的许多基因中，我们检测到了一个有趣的Ezrin扩增子，这是最近在人类ESCC中报道的。Ezrin是细胞骨架和质膜的交联体，参与癌细胞的生长和转移潜能。Western blotting证实Ezrin蛋白在ESCC-DR中高表达。我们还用免疫组织化学方法比较了Ezrin蛋白在两种不同反流模型中发生的增生性、非增生性、ESCC和转移部位的表达水平和模式。Ezrin免疫组织化学染色显示Ezrin在ESCC细胞的胞核、胞浆和质膜中均有高表达。磷酸化ERM(Ezrin、Radioxin、moesin)在较大转移部位的前沿或侵袭性前沿表达。综上所述，十二指肠反流具有启动恶变的巨大潜力，因此可能在ESCC的发生发展中起作用。Ezrin可能影响ESCC细胞的生长和侵袭性，只有在肿瘤细胞的前沿和侵袭前沿的转移行为中才需要磷酸化。(《癌症科学》2010；101：624-630)
Gastroesophageal reflux has recently been implicated as a causative factor in upper aerodigestive tract carcinogenesis. Esophageal squamous cell carcinomas (ESCCs) have developed in duodenal-content reflux animals without any known carcinogen present. We established a cell line, designated ESCC-DR, from a thoracic metastatic tumor in a reflux animal. To gain insight into the genomic alterations associated with duodenal content reflux-induced carcinogenesis, we first performed comparative genomic hybridization using an Agilent rat 244K array in ESCC-DR and identified many chromosomal gains and losses. Of the many genes identified, we detected an interesting ezrin amplicon that has been recently reported in human ESCC. Ezrin, which cross-links the cytoskeleton and plasma membrane, is involved in the growth and metastatic potential of cancer cells. Overexpression of ezrin protein in ESCC-DR was confirmed by Western blotting. We also compared ezrin protein expression levels and patterns in hyperplastic, dysplastic, ESCC, and metastatic sites developed in two distinct reflux models using immunohistochemistry. Immunohistochemical staining of ezrin revealed overexpression in the nucleus, and the cytoplasm as well as plasma membrane of ESCC cells. Phosphorylated ERM (ezrin, radixin, moesin) was expressed at the leading edge, or invasive front, of larger metastatic sites. Taken together, duodenal reflux has a great potential for initiating malignancy, and thus likely plays a role in development of ESCC. Ezrin probably influences the growth and invasiveness of ESCC cells, and phosphorylation is only required in metastatic behavior of tumor cells at the leading edge and invasive front. (Cancer Sci 2010; 101: 624-630)