A molecular role for lysyl oxidase-like 2 enzyme in Snail regulation and tumor progression
A molecular role for lysyl oxidase-like 2 enzyme in Snail regulation and tumor progression
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DOI：
10.1038/sj.emboj.7600781
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发表时间：
2005-10-05
期刊：
影响因子：
11.4
通讯作者：
Portillo, F
中科院分区：
文献类型：
--
作者：
Peinado, H;Iglesias-de la Cruz, MD;Portillo, F
转录因子Snail通过抑制E-cadherin和其他上皮基因的表达来控制上皮间充质转化（EMT）。然而，蜗牛功能调控的机制尚不完全清楚。本研究发现赖氨酸氧化酶基因家族的两个成员赖氨酸氧化酶样2和3 （LOXL2和LOXL3）与蜗牛相互作用并协同下调E-cadherin的表达。蜗牛赖氨酸残基98和137对蜗牛的稳定性、与LOXL2/3的功能配合以及诱导EMT至关重要。上皮细胞中LOXL2或LOXL3的过表达可诱导EMT过程，支持其在肿瘤进展中的作用。在蜗牛表达的转移癌细胞中，LOXL2的RNA干扰进一步支持了LOXL2的生物学重要性，它导致肿瘤生长的强烈下降，与凋亡增加和间充质和侵袭性/血管生成标志物的表达减少有关。综上所述，这些结果建立了LOXL2和Snail在癌症进展中的直接联系。
The transcription factor Snail controls epithelial mesenchymal transitions (EMT) by repressing E-cadherin expression and other epithelial genes. However, the mechanisms involved in the regulation of Snail function are not fully understood. Here we show that lysyl-oxidase-like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl-oxidase gene family, interact and cooperate with Snail to downregulate E-cadherin expression. Snail's lysine residues 98 and 137 are essential for Snail stability, functional cooperation with LOXL2/3 and induction of EMT. Overexpression of LOXL2 or LOXL3 in epithelial cells induces an EMT process, supporting their implication in tumor progression. The biological importance of LOXL2 is further supported by RNA interference of LOXL2 in Snail-expressing metastatic carcinoma cells, which led to a strong decrease of tumor growth associated to increased apoptosis and reduced expression of mesenchymal and invasive/angiogenic markers. Taken together, these results establish a direct link between LOXL2 and Snail in carcinoma progression.