Abstract
BACKGROUND: Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with high recurrence rates. Lymphovascular invasion (LVI) predicts a poor prognosis, yet its molecular drivers remain unclear. BOC cell adhesion-associated, oncogene-regulated (BOC, also known as Brother of CDO [Cell adhesion molecule-Related/Down-regulated by Oncogenes]), a hedgehog-related cell surface receptor, may serve as a biomarker for tumor progression and chemotherapy response. The study aimed to investigate the role of BOC in UTUC and its potential to predict LVI and chemotherapy response. METHODS: Sequencing (RNA-seq) of 10 stage III UTUC, treatment-naïve, fresh tissue samples identified BOC as a candidate biomarker, which was subsequently validated in 2 independent cohorts (n = 74). Functional assays using urothelial carcinoma cell lines assessed the impact of BOC knockdown on cell migration, proliferation, and drug sensitivity. Methylation-specific PCR (MSP) was used to identify potential regulatory sites influencing BOC expression, and immunohistochemistry (IHC) analysis was conducted to compare BOC levels in high- and low-grade bladder cancer. RESULTS: BOC expression was significantly higher in patients with lymphovascular invasion (LVI+, p < 0.01). Knockdown of BOC markedly inhibited cancer cell migration, without affecting proliferation. BOC knockdown enhanced the efficacy of cisplatin and gemcitabine in UTUC cells, although clinical tissue data did not provide direct evidence of its role as a predictor of drug response. Methylation analysis identified key regulatory sites that may control BOC expression, and IHC confirmed increased BOC levels in high-grade bladder cancer, linking it to tumor aggressiveness. CONCLUSION: BOC may serve as a potential biomarker for predicting LVI and chemotherapy response in UTUC. Its involvement in cancer cell migration and association with high-grade tumors suggests its clinical relevance for prognosis and treatment stratification. Further validation in larger, multi-center studies is warranted.