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LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity.
Cancer Letters ( IF 9.7 ) Pub Date : 2020-01-03 , DOI: 10.1016/j.canlet.2019.12.040
Olga Almacellas-Rabaiget 1 , Paola Monaco 1 , Juan Huertas-Martinez 1 , Silvia García-Monclús 1 , Mariona Chicón-Bosch 1 , Susana Maqueda-Marcos 1 , Isabel Fabra-Heredia 1 , David Herrero-Martín 2 , Santiago Rello-Varona 1 , Enrique de Alava 3 , Roser López-Alemany 1 , Paloma H Giangrande 4 , Oscar M Tirado 5
Affiliation  

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities.

中文翻译:

LOXL2促进肺泡横纹肌肉瘤的致癌进展,而与其催化活性无关。

横纹肌肉瘤(RMS)是儿童和青春期最常见的软组织恶性肿瘤。具有高侵袭性组织学变异的患者由于高转移发生率而预后不良。类赖氨酰氧化酶2(LOXL2)是一种赖氨酰氧化酶,是细胞外基质(ECM)交联酶家族的成员,该酶最近已成为肿瘤进展和转移的重要调节剂。我们报告LOXL2在RMS中过表达,表明LOXL2在RMS致癌进展中的潜在作用。一致地,瞬时稳定的LOXL2敲低降低了两种ARMS细胞系的细胞迁移和侵袭能力。此外,使用野生型或突变的(催化失活的)构建体将XL2导入RMS非表达细胞会导致细胞迁移增加,细胞的侵袭以及体内自发肺转移的数量和发生率,与其催化活性无关。为了进一步研究与LOXL2表达相关的分子机制,对LOXL2转染的细胞进行了下拉测定,并通过质谱分析。中间丝蛋白波形蛋白被证实是LOXL2相互作用体。因此,我们的结果表明通过调节细胞骨架动力学和细胞运动能力,LOXL2在RMS中具有致癌作用。
更新日期:2020-01-04
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