Impact of Sulfatase‐2 on cancer progression and prognosis in patients with renal cell carcinoma

Heparan sulfate‐specific endosulfatase‐2 (SULF‐2) can modulate the signaling of heparan sulfate proteoglycan‐binding proteins. The involvement of SULF‐2 in cancer growth varies by cancer type. The roles of SULF‐2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF‐2 mRNA and protein in 49 clinical RCC samples were determined by RT‐PCR and immunostaining. The existence of RCC with higher SULF‐2 expression and lower SULF‐2 expression compared to the adjacent normal kidney tissues was suggested. High SULF‐2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF‐2 expression was correlated with an advanced stage and higher invasive factors. Three‐year cancer‐specific survival (CSS) for high SULF‐2 RCC and low SULF‐2 RCC were 100% and 71.4%, respectively (log‐rank P = 0.0019), with a significantly shorter CSS observed in low SULF‐2 RCC patients. The influence of SULF‐2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki‐2, ACHN and 786‐O, using a SULF‐2 suppression model involving siRNA or a SULF‐2 overexpression model involving a plasmid vector. High SULF‐2 expression enhanced Wnt signaling and Wnt‐induced cell viability, but not cell invasion. In contrast, low levels of SULF‐2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCC with lower SULF‐2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.