Kallikrein-Related Peptidase 7 Promotes Multicellular Aggregation via the α5β1 Integrin Pathway and Paclitaxel Chemoresistance in Serous Epithelial Ovarian Carcinoma
Kallikrein-Related Peptidase 7 Promotes Multicellular Aggregation via the α5β1 Integrin Pathway and Paclitaxel Chemoresistance in Serous Epithelial Ovarian Carcinoma
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DOI：
10.1158/0008-5472.can-09-3415
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Clements, Judith A.
中科院分区：
文献类型：
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作者：
Dong, Ying;Tan, Olivia L.;Clements, Judith A.
激肽释放酶相关肽酶7（KLK 7）在上皮性卵巢癌（EOC）中上调，高水平与不良预后相关。然而，这种关系的机制和KLK 7在EOC进展中的作用尚不清楚。我们报道了两种不同的KLK 7转录本，KLK 7 -253和KLK 7 -181，在高级别浆液性卵巢上皮癌中同时表达。多细胞聚集体（MCA），促进细胞存活和耐药性，特别是在稳定过表达KLK 7 -253的SKOV-3细胞中观察到。重要的是，这些MCA侵入单层间皮细胞并形成癌细胞灶。使用针对KLK 7和α（5）β（1）和β（1）整联蛋白的抗体阻断MCA证实了KLK 7和整联蛋白调节的细胞粘附的参与。还观察到α（5）/β（1）整联蛋白水平增加，与纤连蛋白和玻连蛋白的附着增强，其被抗β（1）整联蛋白抗体阻断。最后，免疫印迹和免疫组化显示，在来自腹水的浆液性EOC细胞和来自化疗无应答者的肿瘤样本中，生存后时间较短，KLK 7和α（5）/β（1）整合素水平较高。此外，KLK 7 -253和KLK 7 -181克隆在体外对紫杉醇治疗更具抗性。这些发现表明，高KLK 7水平与浆液性EOC患者的化疗耐药性和不良预后相关的机制是通过增加MCA和α（5）β（1）整合素依赖性细胞粘附促进腹膜播散和再侵袭。Cancer Res; 70（7）; 2624-33. (C)2010年AACR。
Kallikrein-related peptidase 7 (KLK7) is upregulated in epithelial ovarian carcinoma (EOC) with high levels correlated with poor prognosis. However, the mechanisms underlying this relationship and the role of KLK7 in EOC progression are unknown. We report that two different KLK7 transcripts, KLK7-253 and KLK7-181, are simultaneously expressed in high-grade serous EOC. Multicellular aggregates (MCA), which promote cell survival and chemoresistance, were observed in SKOV-3 cells stably overexpressing KLK7-253 in particular. Importantly, these MCAs invade into a monolayer of mesothelial cells and form cancer cell foci. Blocking MCA using antibodies against KLK7 and alpha(5)beta(1) and beta(1) integrins confirmed the involvement of KLK7 and integrin-regulated cell adhesion. Increased levels of alpha(5)/beta(1) integrins and enhanced attachment to fibronectin and vitronectin, which was blocked with an anti-beta(1) integrin antibody, were also observed. Finally, Western blot and immunohistochemistry showed higher KLK7 and alpha(5)/beta(1) integrin levels in serous EOC cells from ascites and tumor samples from chemotherapy nonresponders with short postsurvival times. Additionally, both KLK7-253 and KLK7-181 clones were more resistant to paclitaxel treatment in vitro. These findings suggest a mechanism for the association of high KLK7 levels with chemoresistance and poor prognosis for serous EOC patients by promotion of peritoneal dissemination and reinvasion via increased MCA and alpha(5)beta(1) integrin-dependent cell adhesion. Cancer Res; 70(7); 2624-33. (C) 2010 AACR.