Li Tong, Wen Hongjin, Brayton Cory, Das Pritam, Smithson Lisa A, Fauq Abdul, Fan Xing, Crain Barbara J, Price Donald L, Golde Todd E, Eberhart Charles G, Wong Philip C
Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
J Biol Chem. 2007 Nov 2;282(44):32264-73. doi: 10.1074/jbc.M703649200. Epub 2007 Sep 7.
Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.
γ-分泌酶是一种独特的天冬氨酸蛋白酶，是Notch和APP膜内蛋白水解调控所必需的，这两条途径分别与癌症和阿尔茨海默病的发病机制有关。然而，γ-分泌酶减少导致鳞状细胞癌（SCC）等肿瘤的机制仍知之甚少。在此，我们证明γ-分泌酶在上皮细胞中以酶活性依赖的方式发挥肿瘤抑制作用。在γ-分泌酶基因敲低导致的SCC中，Notch信号下调，表皮生长因子受体（EGFR）被激活。此外，成纤维细胞中EGFR的水平与γ-分泌酶的水平呈负相关，这表明EGFR的上调刺激了γ-分泌酶基因敲低小鼠上皮细胞的过度增殖。我们的发现支持了这一观点，即与野生型细胞相比，缺乏γ-分泌酶活性的成纤维细胞在受到EGF或EGFR抑制剂刺激时，其增殖反应更敏感。有趣的是，EGFR的上调独立于Notch信号，这表明EGFR途径在SCC的肿瘤发生过程中与Notch平行发挥作用。总的来说，我们的结果建立了一种将EGFR途径与γ-分泌酶的肿瘤抑制作用联系起来的新机制，并且γ-分泌酶基因敲低的小鼠是阐明SCC发病机制和测试改善这类人类癌症治疗策略的优秀啮齿动物模型。
