The role of HAI-1 in Urothelial Bladder Cancer: Tissue Expression, Ectodomain Shedding and Clinical Outcomes

Hepatocyte growth factor activator inhibitor type-1 (HAI-1) plays pivotal roles in epithelial integrity and tumour biology. Although implicated in various malignancies, its expression profile and prognostic value in bladder cancer (BC) remain incompletely defined. High levels of HAI-1 ectodomain in urine have previously been reported to be associated with poor prognosis in BC patients. This study aimed to determine the relationships between tissue and urine levels of HAI-1 and clinical outcomes in BC. This study used immunohistochemistry to measure HAI-1 expression across 770 BCs of all stages and grades. HAI-1 expression was scored on the basis of the percentage of positive cancer cells, subcellular localisation, and staining intensity. Additionally, HAI-1 (SPINT1) mRNA expression was compared with protein levels in tissue and urine. HAI-1 was highly expressed in low-grade, early-stage disease with strong membranous staining. Reduced overall HAI-1 expression, loss of membranous staining and increased cytoplasmic staining correlated with higher stage and grade and shorter survival. SPINT1 mRNA levels were positively correlated with membranous HAI-1 staining intensity (p=0.005). Urinary levels of HAI-1 were negatively associated with the fraction of HAI-1 positive cancer cells and membranous staining intensity (p<0.05).  A positive correlation was observed between SPINT1 expression and urinary HAI-1 levels (p<0.05). The Urobasal A subtype had lower urinary HAI-1 ectodomain levels than other subtypes. HAI-1 expression may serve as a biomarker of tumour differentiation and prognosis in BC. Increased ectodomain shedding into the urine, rather than increased expression, likely explains the higher urine HAI-1 levels seen in more aggressive tumours.