ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.
ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.
复制标题
DOI：
10.1371/journal.pone.0150138
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Day ML
中科院分区：
文献类型：
--
作者：
Lorenzatti Hiles G;Bucheit A;Rubin JR;Hayward A;Cates AL;Day KC;El-Sawy L;Kunju LP;Daignault S;Lee CT;Liebert M;Hussain M;Day ML
ADAM15是具有催化活性的分解素膜金属蛋白酶家族的一员，其功能是分子信号开关、脱落膜结合生长因子和/或裂解和灭活细胞粘附分子。ADAM15异常的金属蛋白酶功能可能通过释放生长因子或破坏细胞粘附而促进肿瘤进展。在本研究中，我们利用人膀胱癌组织和细胞系来评估ADAM15在人膀胱癌进展中的表达和功能。对基因组和转录组数据库的检查显示，ADAM15在扩增基因中排名前5%，与非侵袭性疾病相比，其mRNA在侵袭性和转移性膀胱癌中显著过表达。用于评估疾病进展的膀胱肿瘤组织阵列的免疫染色显示，ADAM15免疫反应性增加与癌症分期增加相关，并且在转移性样品中显示出明显增强的染色。约一半侵袭性肿瘤和大部分转移性肿瘤的ADAM15染色指数高，而所有低分级和非侵袭性肿瘤的ADAM15染色均为阴性或低。下调ADAM15 mRNA表达可显著抑制膀胱肿瘤细胞通过MatrigelTM和血管内皮单层膜的迁移，降低膀胱肿瘤细胞的侵袭能力。与对照组相比，在膀胱癌异种移植模型中，ADAM15敲低可抑制肿瘤生长45%。催化结构域的结构建模导致了一种新型adam15特异性磺胺抑制剂的设计，该抑制剂在体外和人类膀胱癌异种移植物中显示出生物活性并显着降低膀胱癌细胞的活力。综上所述，这些结果揭示了ADAM15在人类膀胱癌侵袭中的未描述的作用，并表明ADAM15催化结构域可能是晚期疾病患者可行的治疗靶点。
ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in patients with advanced disease.