Lorenzatti Hiles Guadalupe, Bucheit Amanda, Rubin John R, Hayward Alexandra, Cates Angelica L, Day Kathleen C, El-Sawy Layla, Kunju L Priya, Daignault Stephanie, Lee Cheryl T, Liebert Monica, Hussain Maha, Day Mark L
Division of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan, United States of America.
Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS One. 2016 Mar 1;11(3):e0150138. doi: 10.1371/journal.pone.0150138. eCollection 2016.
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.
ADAM15是具有催化活性的解聚素金属蛋白酶家族的成员，该家族作为分子信号开关发挥作用，可释放膜结合生长因子和/或切割并使细胞粘附分子失活。ADAM15异常的金属蛋白酶功能可能通过生长因子的释放或细胞粘附的破坏促进肿瘤进展。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。对旨在评估疾病进展的膀胱肿瘤组织阵列进行免疫染色，结果显示ADAM15免疫反应性增加与癌症分期增加相关，且在转移样本中染色明显更强。约一半的侵袭性肿瘤和大多数转移病例表现出高ADAM15染色指数，而所有低级别和非侵袭性病例表现为阴性或低染色。敲低ADAM15 mRNA表达显著抑制膀胱肿瘤细胞迁移，并降低膀胱肿瘤细胞通过基质胶和血管内皮单层的侵袭能力。在人膀胱癌异种移植模型中敲低ADAM15，与对照组相比，肿瘤生长受到45%的抑制。对催化结构域进行结构建模，设计出一种新型的ADAM15特异性磺酰胺抑制剂，该抑制剂具有生物活性，并在体外和人膀胱癌异种移植模型中显著降低膀胱癌细胞的活力。综上所述，这些结果揭示了ADAM15在人膀胱癌侵袭中一个未被描述的作用，并表明ADAM15催化结构域可能是晚期疾病患者的一个可行治疗靶点。
