1] Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan [2] Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Lab Invest. 2013 Oct;93(10):1068-81. doi: 10.1038/labinvest.2013.95. Epub 2013 Aug 12.
Notch signaling has been reported to be involved in several types of malignant tumors; however, the role and activation mechanism of Notch signaling in oral squamous cell carcinoma (OSCC) remains poorly characterized. The purpose of this study was to elucidate the pathological significance of Notch signaling and its activation mechanism in the development and progression of OSCC. In this study, we showed that the expression of Notch1 and intracellular Notch domain (NICD) are upregulated in OSCCs. In addition, Notch1 and NICD were found to be characteristically localized at the invasive tumor front. TNF-α, a major inflammatory cytokine, significantly activated Notch signaling in vitro. In a clinicopathological analysis, Notch1 expression correlated with both the T-stage and the clinical stage. Furthermore, loss of Notch1 expression correlated with the inhibition of cell proliferation and TNF-α-dependent invasiveness in an OSCC cell line. In addition, γ-secretase inhibitor (GSI) prevented cell proliferation and TNF-α-dependent invasion of OSCC cells in vitro. These results indicate that altered expression of Notch1 is associated with increased cancer progression and that Notch1 regulates the steps involved in cell metastasis in OSCC. Moreover, inactivating Notch signaling with GSI could therefore be a useful approach for treating patients with OSCC.
Notch 信号通路已被报道参与多种类型的恶性肿瘤；然而，Notch 信号通路在口腔鳞状细胞癌（OSCC）中的作用和激活机制仍未得到充分阐明。本研究旨在阐明 Notch 信号通路及其在 OSCC 发生和进展中的激活机制的病理意义。在这项研究中，我们表明 Notch1 和细胞内 Notch 结构域（NICD）在 OSCC 中表达上调。此外，Notch1 和 NICD 被发现特征性地定位于侵袭性肿瘤前缘。TNF-α，一种主要的炎症细胞因子，在体外显著激活 Notch 信号通路。在临床病理分析中，Notch1 表达与 T 分期和临床分期相关。此外，在 OSCC 细胞系中，Notch1 表达的缺失与细胞增殖的抑制和 TNF-α依赖性侵袭性相关。此外，γ-分泌酶抑制剂（GSI）可防止 OSCC 细胞在体外的增殖和 TNF-α依赖性侵袭。这些结果表明 Notch1 的异常表达与癌症进展的增加有关，并且 Notch1 调节 OSCC 中细胞转移涉及的步骤。此外，用 GSI 使 Notch 信号失活可能是治疗 OSCC 患者的一种有用方法。
