Tissue transglutaminase mediates the pro-malignant effects of oncostatin M receptor over-expression in cervical squamous cell carcinoma.
Tissue transglutaminase mediates the pro-malignant effects of oncostatin M receptor over-expression in cervical squamous cell carcinoma.
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DOI：
10.1002/path.4222
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发表时间：
2013-10
影响因子：
7.3
通讯作者：
Coleman, Nicholas
中科院分区：
文献类型：
--
作者：
Caffarel, Maria M.;Chattopadhyay, Anasuya;Araujo, Angela M.;Bauer, Julien;Scarpini, Cinzia G.;Coleman, Nicholas
关键词：
肿瘤抑制素M受体（OSMR）在晚期宫颈鳞状细胞癌（SCC）中普遍过表达，其临床预后明显较差。过表达OSMR的宫颈SCC细胞对主要配体OSM的反应性增强，从而诱导多种促恶性作用，包括细胞迁移和侵袭性增加。在这里，我们发现组织转谷氨酰胺酶（TGM2）是SCC细胞中OSMR过表达的配体依赖性表型效应的重要介质。在宫颈和口腔鳞状细胞癌的临床样本中，TGM2表达与疾病进展和OSMR水平相关。TGM2在宫颈SCC细胞中的缺失消除了osm诱导的在纤维连接蛋白包被表面的迁移和通过细胞外基质的侵袭性，而TGM2的异位表达增加了细胞的运动性和侵袭性。共聚焦显微镜和共免疫沉淀实验显示，TGM2在纤维连接蛋白存在的情况下与宫颈SCC细胞中的整合素-α5β1相互作用，OSM处理增强了这种相互作用。重要的是，整合素-α5β1和纤维连接蛋白在宫颈和口腔鳞状细胞癌中也过表达，其水平与OSMR和TGM2相关。这项组织和体外联合研究首次证明，刺激宫颈SCC细胞中过表达的OSMR可激活TGM2/整合素-α5β1相互作用并诱导前恶性变化。我们得出结论，OSMR/TGM2/整合素-α5β1/纤维连接蛋白通路在宫颈鳞状细胞癌中具有生物学意义，并且是治疗靶向的候选途径。版权所有©2013英国和爱尔兰病理学会。©2013作者。由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版的病理学杂志。
Oncostatin M receptor (OSMR) is commonly over-expressed in advanced cervical squamous cell carcinoma (SCC), producing a significantly worse clinical outcome. Cervical SCC cells that over-express OSMR show enhanced responsiveness to the major ligand OSM, which induces multiple pro-malignant effects, including increased cell migration and invasiveness. Here, we show that tissue transglutaminase (TGM2) is an important mediator of the ligand-dependent phenotypic effects of OSMR over-expression in SCC cells. TGM2 expression correlated with disease progression and with OSMR levels in clinical samples of cervical and oral SCC. TGM2 depletion in cervical SCC cells abrogated OSM-induced migration on fibronectin-coated surfaces and invasiveness through extracellular matrix, while ectopic expression of TGM2 increased cell motility and invasiveness. Confocal microscopy and co-immunoprecipitation assays showed that TGM2 interacted with integrin–α5β1 in the presence of fibronectin in cervical SCC cells, with OSM treatment strengthening the interaction. Importantly, integrin–α5β1 and fibronectin were also over-expressed in cervical and oral SCC, where levels correlated with those of OSMR and TGM2. This combined tissue and in vitro study demonstrates for the first time that stimulation of over-expressed OSMR in cervical SCC cells activates TGM2/integrin-α5β1 interactions and induces pro-malignant changes. We conclude that an OSMR/TGM2/integrin-α5β1/fibronectin pathway is of biological significance in cervical SCC and a candidate for therapeutic targeting. Copyright © 2013 Pathological Society of Great Britain and Ireland. © 2013 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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