Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells
Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells
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DOI：
10.4161/cc.10.1.14362
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发表时间：
2011-01-01
期刊：
影响因子：
4.3
通讯作者：
Geliebter, Jan
中科院分区：
文献类型：
--
作者：
Nowicki, Theodore S.;Zhao, Hong;Geliebter, Jan
甲状腺乳头状癌是最常见的内分泌和甲状腺恶性肿瘤。尿激酶型纤溶酶原激活物受体（uPAR）在肿瘤的发病机制中起重要作用，包括细胞外基质的破坏、侵袭和转移。此外，越来越多的证据表明，uPAR还通过调节多种信号通路促进肿瘤发生。BRAF（V600 E）是PT C中最常见的初始基因突变，其导致ERK 1/2过度磷酸化，其已在许多癌症中显示诱导uPAR。用MEK/ERK抑制剂U 0126处理BRAF（V600 E）阳性PTC细胞系BCPAP，使uPAR RNA水平降低90%。在BCPAP细胞中siRNA介导的uPAR下调导致粘着斑激酶（FAK）/磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路的活性大大降低。这种现象是同时急剧降低的增殖率和减少克隆存活，以及表现出衰老相关的核形态和β-半乳糖苷酶活性的诱导。uPAR敲低的BCPAP细胞还显示出迁移和侵袭率大大降低，以及在纤溶酶原补充后细胞增强其侵袭力的能力完全丧失。总之，这些数据提供了新的证据，uPAR诱导（作为组成性ERK 1/2激活的结果）作为PTC发病机制的核心组成部分的新作用，并强调了uPAR作为治疗靶点的潜力。
Papillary thyroid carcinoma (PT C) is the most common endocrine and thyroid malignancy. The urokinase plasminogen activator receptor (uPAR) plays an important role in cancer pathogenesis, including breakdown of the extracellular matrix, invasion and metastasis. Additionally, there is increasing evidence that uPAR also promotes tumorigenesis via the modulation of multiple signaling pathways. BRAF(V600E), the most common initial genetic mutation in PT C, leads to ERK1/2 hyperphosphorylation, which has been shown in numerous cancers to induce uPAR. Treatment of the BRAF(V600E)-positive PT C cell line, BCPAP, with the MEK/ERK inhibitor U0126 reduced uPAR RNA levels by 90%. siRNA-mediated downregulation of uPAR in BCPAP cells resulted in greatly decreased activity in the focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. This phenomenon was concurrent with drastically reduced proliferation rates and decreased clonigenic survival, as well as demonstrated senescence-associated nuclear morphology and induction of beta-galactosidase activity. uPAR-knockdown BCPAP cells also displayed greatly reduced migration and invasion rates, as well as a complete loss of the cells' ability to augment their invasiveness following plasminogen supplementation. Taken together, these data provide new evidence of a novel role for uPAR induction (as a consequence of constitutive ERK1/2 activation) as a central component in PT C pathogenesis, and highlight the potential of uPAR as a therapeutic target.