DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma

Urothelial carcinoma includes upper urinary tract cancer (UTUC) and bladder cancer. Although nephroureterectomy is the standard treatment for UTUC, the recurrence rate is approximately half and the tumor is associated with poor prognoses. Metastases are the most devastating and lethal clinical situation in urothelial carcinoma. Despite its clinical importance, few potential diagnostic biomarkers are suitable for early UC detection. We compared high-stage/high-grade urothelial carcinoma tissues to adjacent normal urothelial tissues using methyl-CpG binding domain protein capture for genome-wide DNA methylation analysis. Based on our findings, inhibin beta A (INHBA) might be associated with carcinogenesis and metastasis. Further, clinical UC specimens had significant INHBA hypomethylation based on pyrosequencing. INHBA was detected by real-time PCR and immunohistochemistry staining, and was found to be highly expressed in clinical tissues and cell lines of urothelial carcinoma. Further, INHBA depletion was found to significantly reduce BFTC-909 cell growth and migration by INHBA-specific small interfering RNA. Interestingly, a positive correlation was found between SMAD binding and extracellular structure organization with INHBA using gene set enrichment analysis and gene ontology analysis. Together, these results are the first evidence of INHBA promoter hypomethylation and INHBA overexpression in UTUC. INHBA may affect urothelial carcinoma migration by reorganizing the extracellular matrix through the SMAD pathway.

Automated summary

Urothelial carcinoma, a type of malignant tumor commonly found in the upper urinary tract and bladder, is associated with high recurrence and poor prognosis. This study identified INHBA as a potential diagnostic biomarker for urothelial carcinoma, showing its role in carcinogenesis and metastasis. INHBA was found to be hypomethylated and overexpressed in clinical samples of urothelial carcinoma. Further experiments demonstrated that INHBA depletion reduced cell growth and migration, potentially through the SMAD pathway. These findings provide insights into the molecular mechanisms of urothelial carcinoma and suggest a potential target for early detection and treatment.