ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer

Abstract

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.

<p>The microRNA miR-3174 Suppresses the Expression of ADAM15 and Inhibits the Proliferation of Patient-Derived Bladder Cancer Cells</p>

“…Our results also showed that the inhibited expression of ADAM15 via miR-3174 significantly reduced the proliferation and metastasis of the patient-derived bladder cancer cells. These results were consistent with previous results from Lorenzatti et al 34 Interestingly, our results show that the expression of ADAM23 in the tumor tissue was lower compared to the non-tumor tissue. Also, the expression of ADAM28 and ADAM33 in the tumor tissue was slightly lower compared to the non-tumor tissue, although no statistical significance was found.…”

Actein induces autophagy and apoptosis in human bladder cancer by potentiating ROS/JNK and inhibiting AKT pathways

“…Bladder cancer is a highly prevalent tumor and is related to substantial morbidity, mortality and cost [ 1 , 2 , 49 ]. The environmental or occupational exposures to carcinogens, particularly tobacco, are the major risk factors for promoting the bladder cancer [ 50 , 51 ].…”

“…Human bladder cancer is one of the most common genitourinary malignant cancers, leading to health issue worldwide [ 1 , 2 ]. Presently, the existed therapeutic strategies, including radical cystectomy and chemotherapy, are far from to be satisfied considering the metastases and recurrence of human bladder cancer [ 3 – 5 ].…”

Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers

“…In our study, high throughput functional siRNA screening identified molecules associated with protein degradation, such as Furin, ADAMs, and CAPN ( Supplementary Figure 1 ), as therapeutic targets. For example, ADAM15 is overexpressed in bladder, prostate and breast cancers and its substrate include EGFR ligands and TGF-β that are related to cancer cell proliferation [ 39 ]. These results suggest that protein degradation may be essential for proteins synthesized by deregulated c-Myc to perform their oncogenic functions, as we have indicated with Furin (Figure 4G ).…”