Investigating the role of the protease ADAMTS5 in ovarian cancer

Ovarian cancer (OC) is the fifth most lethal gynaecologic malignancy in the UK. At the advanced stages (III and IV), there are peritoneal or distant metastases outside the peritoneal cavity, and the 5-year survival rate is less than 35%. Therefore, it is essential to identify the mechanisms controlling OC metastasis to prevent it. The extracellular matrix (ECM) is a dynamic structure which is remodelled under both normal and pathological conditions by modifying enzymes. Changes in the composition and structure of the ECM were previously detected in several types of tumours, including ovarian carcinoma. ADAMTS5 (a disintegrin and metalloproteinase domain with thrombospondin motifs 5) is a member of the ADAMTS family of proteases involved in ECM degradation. Previously, high ADAMTS5 expression was found to correlate with reduced overall survival in OC patients. Additionally, the expression of the ADAMTS5 substrate versican has also been shown to be upregulated in OC metastasis. However, the role of ADAMTS5 in OC progression remains unclear. Here I showed that ADAMTS5 expression is promoted in OC cells over-expressing the small GTPase Rab25 grown on 3D matrices, through a NF-κB dependent mechanism. We also found that ADAMTS5 inhibition and knockdown strongly reduced Rab25-dependent OC cell migration and invasion through 3D matrices. Furthermore, when in co-culture with cancer-associated fibroblasts, OC cells showed increased 3D invasion, which can be suppressed by ADAMTS5 downregulation. Altogether, this research investigated the upregulation mechanism of ADAMTS5 and demonstrated the tumour-promoting role of ADAMTS5 in OC, which could be considered a potential therapy target for OC metastasis.