Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation
Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation
复制标题
DOI：
10.1101/gad.1300705
复制
发表时间：
2005-08-15
影响因子：
10.5
通讯作者：
Bugge, TH
中科院分区：
文献类型：
--
作者：
List, K;Szabo, R;Bugge, TH
II 型跨膜丝氨酸蛋白酶基质酶的过度表达是人类上皮肿瘤的高度一致的特征。在这里，我们表明，当 Matriptase 不受其内源性抑制剂 HAI-1 的抵抗时，具有很强的致癌潜力。转基因小鼠皮肤中matriptase的适度原位过度表达引起自发性鳞状细胞癌并显着增强致癌物诱导的肿瘤形成。 Matriptase诱导的恶性转化先于进行性滤泡间增生、发育不良、滤泡转分化、纤维化和真皮炎症。此外，matriptase 诱导促肿瘤 PI3K-Akt 信号通路的激活。在致癌物诱导的肿瘤中，这种激活经常伴随着 H-ras 或 K-ras 突变，而 matriptase 诱导的自发癌形成与 ras 激活无关。表皮 HAI-1 表达的增加完全抵消了 matriptase 的致癌作用。这些数据表明恶性上皮转化中基质酶表达失调。
Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K-Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation.