Mori Yoshinori, Kataoka Hiromi, Miura Yutaka, Kawaguchi Makoto, Kubota Eiji, Ogasawara Naotaka, Oshima Tadayuki, Tanida Satoshi, Sasaki Makoto, Ohara Hirotaka, Mizoshita Tsutomu, Tatematsu Masae, Asai Kiyofumi, Joh Takashi
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Int J Cancer. 2007 Jul 15;121(2):241-7. doi: 10.1002/ijc.22654.
Human gastric epithelium has a unique mucin gene expression pattern, which becomes markedly altered in gastrointestinal disorder. This alteration in mucin expression, including the mucin MUC5AC, may be related to the development and prognosis of gastric cancers, and MUC5AC-positive gastric cancer has been reported to be poor prognosis. However, the molecular mechanism of MUC5AC transcriptional regulation has not been fully elucidated. AT motif-binding factor 1 (ATBF1) is a homeotic transcriptional regulatory factor recently identified as a tumor suppressor gene, and its subcellular localization suggests a link to cell proliferation and differentiation. We investigated the mechanism of MUC5AC transcriptional regulation by ATBF1. In 123 gastric cancer lesions, ATBF1 expressed in the nucleus significantly suppressed MUC5AC expression, as determined by immunohistochemistry. In addition, analysis of the MUC5AC promoter region revealed an AT motif-like element. This element was found to be essential for ATBF1 suppression of MUC5AC promoter activity as shown in a dual luciferase-reporter assay. Over-expressed ATBF1 also significantly suppressed endogenous MUC5AC protein expression in gastric cancer cells. Chromatin immunoprecipitation demonstrated that ATBF1 binds to the AT motif-like element in the MUC5AC promoter. These results indicate that ATBF1 in the nucleus negatively regulates the MUC5AC gene in gastric cancer by binding to an AT motif-like element in the MUC5AC promoter.
人胃上皮细胞具有独特的黏蛋白基因表达模式，在胃肠道疾病中这种模式会发生显著改变。包括黏蛋白MUC5AC在内的黏蛋白表达变化，可能与胃癌的发生发展及预后相关，且据报道MUC5AC阳性的胃癌预后较差。然而，MUC5AC转录调控的分子机制尚未完全阐明。AT基序结合因子1（ATBF1）是一种最近被鉴定为肿瘤抑制基因的同源异型转录调节因子，其亚细胞定位表明它与细胞增殖和分化有关。我们研究了ATBF1对MUC5AC转录调控的机制。通过免疫组织化学检测发现，在123个胃癌病灶中，细胞核中表达的ATBF1显著抑制了MUC5AC的表达。此外，对MUC5AC启动子区域的分析揭示了一个类似AT基序的元件。如双荧光素酶报告基因检测所示，该元件对于ATBF1抑制MUC5AC启动子活性至关重要。过表达的ATBF1也显著抑制了胃癌细胞中内源性MUC5AC蛋白的表达。染色质免疫沉淀表明，ATBF1与MUC5AC启动子中的类似AT基序的元件结合。这些结果表明，细胞核中的ATBF1通过与MUC5AC启动子中的类似AT基序的元件结合，对胃癌中的MUC5AC基因进行负调控。
