Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression
Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression
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DOI：
10.15252/embj.201489975
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发表时间：
2015-04-15
期刊：
影响因子：
11.4
通讯作者：
Cano, Amparo
中科院分区：
文献类型：
--
作者：
Martin, Alberto;Salvador, Fernando;Cano, Amparo
赖氨酰氧化酶样2（L0XL2）参与广泛的生理和病理过程，包括纤维化和肿瘤进展，涉及细胞内和细胞外功能。为了探索L0XL2在生理和肿瘤背景中的特异性体内作用，我们产生了条件性功能获得和功能丧失小鼠模型。Loxl2的生殖系缺失促进半数新生小鼠的致死性，主要与先天性心脏缺陷相关，而Loxl2过表达由于上皮组织解体、纤维化和急性炎症引起的附睾功能障碍而引发雄性不育。值得注意的是，当受到化学皮肤致癌作用的挑战时，Loxl2过表达小鼠增加了肿瘤负荷和恶性进展，而Loxl2缺陷小鼠表现出相反的表型。癌前病变中Loxl2水平与表皮分化标志物和Notch1通路组分的表达呈负相关。我们发现LOXL2是NOTCH 1的直接阻遏物。此外，我们确定了一个排他性的表达模式之间的LOXL2和成员的经典的NOTCH1途径在人类HNSCC。我们的数据首次确定了LOXL2在组织稳态中的新作用，并支持其作为SCC治疗的靶点。
Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.