Background/Aims: human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is highly expressed in multiple solid malignant tumors, making it a potential biomarker for tumorigenesis and invasion. However, the expression and clinical significance of HHLA2 in bladder urothelial carcinoma (BUC) have not been extensively studied. This study aimed to investigate the relationship between HHLA2 expression and clinicopathological characteristics of BUC. Methods: A total of 212 patients pathologically diagnosed with BUC were included in this study. HHLA2 expression was analyzed by immunohistochemical staining and qRT-polymerase chain reaction. Correlations of HHLA2 expression and pathological characteristics, including 5-year recurrence-free survival (RFS) and overall survival (OS) were examined, and the diagnostic value of HHLA2 was estimated by using the receiver operating characteristic (ROC) curve. Results: Immunohistochemical staining showed that the expression of HHLA2 was significantly upregulated in BUC tissues compared with normal bladder tissues. In BUC tissues, HHLA2 expression was significantly associated with tumor size, tumor stage, tumor grade, and lymph node metastasis (all p < 0.05). HHLA2 expression was an independent prognostic factor of tumor metastasis (p < 0.05). The Kaplan-Meier survival curve revealed that high HHLA2 expression was significantly correlated with the poor RFS and OS of BUC patients (both p < 0.05), and the ROC curve showed HHLA2 could be a good diagnostic marker. Conclusions: HHLA2 can independently predict unfavorable prognosis in BUC.

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