食管鳞癌和 Barrett 腺癌中 STAT3 的表达、活性及其抑制的功能后果。
STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett's adenocarcinomas.
机构信息
Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
1] Institute of Clinical Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
出版信息
Oncogene. 2014 Jun 19;33(25):3256-66. doi: 10.1038/onc.2013.298. Epub 2013 Aug 5.
Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n=49) and Barrett's adenocarcinomas (BAC, n=61) revealed similar STAT3 expression in ESCCs and BACs (P=0.109), but preferentially activated P-STAT3 in ESCCs (P=0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P=0.0148) and OE33 (P=0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P=0.073, P=0.015), but not in OE21 cells (P=0.1079, P=0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (P<0.0001) and OE33 (P=0.01) cells. In contrast, genes promoting cell migration (CTHRC1) were markedly upregulated in OE21 cells, whereas a gene linked to tight-junction stabilization and restricted cell motility (SHROOM2) was downregulated in OE21 but upregulated in OE33 cells. This study shows frequent, but distinct, patterns of STAT3 expression and activation in ESCCs and BACs. STAT3 knockdown reduces cell proliferation in ESCC and BAC cells, inhibits migration of BAC cells and may support cell migration of ESCC cells. Thereby, novel STAT3-regulated genes involved in ESCC and BAC cell proliferation and cell migration were identified. Thus, STAT3 may be further exploited as a potential novel therapeutic target, however, by careful distinction between the two histotypes of esophageal cancers.
信号转导和转录激活因子 3（STAT3）在几种上皮癌中发生改变，代表了一个潜在的治疗靶点。在这里，研究了两种主要的食管癌组织类型中 STAT3 的表达、活性和细胞功能。在原位，对食管鳞状细胞癌（ESCC，n=49）和 Barrett 腺癌（BAC，n=61）中的 STAT3 和 STAT3-Tyr705 磷酸化（P-STAT3）的免疫组织化学显示，ESCC 和 BAC 中的 STAT3 表达相似（P=0.109），但 ESCC 中更倾向于激活 P-STAT3（P=0.013）。在体外，表皮生长因子（EGF）刺激 OE21（ESCC）细胞时观察到强烈的 STAT3 激活，而 OE33（BAC）细胞则表现出组成性较弱的 STAT3 激活。STAT3 敲低显著降低了 OE21（P=0.0148）和 OE33（P=0.0243）细胞的增殖。重要的是，STAT3 敲低使 OE33 细胞在两种类型的迁移实验中的迁移减少了 2.5 倍（P=0.073，P=0.015），但在 OE21 细胞中没有（P=0.1079，P=0.386）。对 STAT3 敲低的转录组分析表明，STAT3 水平降低与两种 OE21（P<0.0001）和 OE33（P=0.01）细胞中细胞周期基因的显著下调有关。相比之下，促进细胞迁移的基因（CTHRC1）在 OE21 细胞中明显上调，而与紧密连接稳定和限制细胞迁移相关的基因（SHROOM2）在 OE21 细胞中下调，而在 OE33 细胞中上调。这项研究表明，ESCC 和 BAC 中 STAT3 的表达和激活存在频繁但不同的模式。STAT3 敲低降低了 ESCC 和 BAC 细胞的增殖，抑制了 BAC 细胞的迁移，并可能支持 ESCC 细胞的迁移。因此，确定了涉及 ESCC 和 BAC 细胞增殖和细胞迁移的新的 STAT3 调节基因。因此，STAT3 可能被进一步开发为一个潜在的新的治疗靶点，然而，需要仔细区分两种食管癌的组织类型。
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