Background: ADAMTS1, a disintegrin and metalloproteinase with thrombospondin motifs-1, is essential for normal biological processes such as inflammation, organogenesis, and ovulation. Its upregulation has been implicated in various cancer development, growth, and progression. This study analysed the expression of ADAMTS1 in epithelial serous ovarian tumours, and ovarian tumours of platinum sensitive (SP) and resistant (RP) origins and ovarian cancer cell lines. The role of ADAMTS1 was evaluated by knocking-down the expression of ADAMTS1 by siRNA.
Methods: The protein levels of ADAMTS1 in primary tumours and ovarian cancer cell lines was assessed by immunohistochemistry and mRNA expression by real-time PCR (qRT-PCR). Cell lines were transiently transfected with ADAMTS1 siRNAs. The expression of different genes after ADAMTS1 knock-down (ADAMTS1-KD) was analysed by qRT-PCR and immunofluorescence. The chemosensitivity (IC50 values) to chemotherapy treatment in the cell lines was evaluated by MTT assay. The expression of angiogenesis and pro-inflammatory cytokines response was evaluated using LEGENDplex™ Assay.
Results: The expression of ADAMTS1 was significantly enhanced in high-grade serous ovarian tumours compared to normal/benign ovarian tissues and specifically in the tumour stroma. Treatment with chemotherapy (platinum and taxane drugs) enhanced significantly the expression of ADAMTS1 in ovarian cancer cell lines as well as expression of secretory IL-6, VEGF, PIGF, MIP1β, ENA-78 and Rantes. The expression of ADAMTS1 was significantly high in RP compared to SP tumours.
Approximately 70-80% knock-down of ADAMTS1 expression by siRNA were confirmed in ADAMTS1-KD ovarian cancer cell lines at the mRNA and protein levels. Suppression of ADAMTS1 expression modulated the expression of several extracellular matrix (ECM) related genes. ADAMTS1-KD in ovarian cancer cell lines induced mesenchymal-to-epithelial-transition (MET), made the cell lines sensitive to paclitaxel and induced the secretion of MIG, IL8, PIGF and ENA-78 in treated cells compared to their treated controls.
Conclusions: Our results indicate that ADAMTS1 is upregulated in tumours as ovarian cancer progresses and is upregulated after chemotherapy treatment. ADAMTS1-KD modulates the expression of several ECM related genes, induces a MET-phenotype and makes the cells sensitive to chemotherapy. These findings suggest that this protein may be potentially a good therapeutic target for ovarian cancer treatment.