Low GCNT2/I-Branching Glycan Expression Is Associated with Bladder Cancer Aggressiveness

Background/Objectives: Abnormal glycan formation on the cancer cell surface plays a crucial role in regulating tumor functions in bladder cancer. In this study, we investigated the roles of glucosaminyl (N-acetyl) transferase 2 (GCNT2) in bladder cancer progression and immune evasion. GCNT2 synthesizes I-branched polylactosamine chains on cell surface glycoproteins. Understanding its functions will provide insights into tumor-immune interactions, facilitating the development of effective immunotherapeutic strategies. Methods: GCNT2 expression levels in bladder cancer cell lines and patient tumor samples were analyzed via quantitative polymerase chain reaction and immunohistochemistry. GCNT2 functions were assessed via overexpression and knockdown experiments. Its effect on natural killer (NK) cell-mediated cytotoxicity was evaluated via in vitro assay. Cytotoxic granule release from NK cells was measured via enzyme-linked immunosorbent assay. Results: GCNT2 expression was inversely correlated with bladder cancer aggressiveness in both cell lines and patient samples. Low GCNT2 levels were associated with advanced tumor stage and grade, suggesting the tumor-suppressive roles of GCNT2. Notably, GCNT2 overexpression enhanced the susceptibility of bladder cancer cells to NK cell-mediated killing, whereas its knockdown promoted immune evasion. GCNT2-overexpressing cells strongly induced the release of cytotoxic granules from NK cells, indicating enhanced immune recognition. Conclusions: Our findings suggest that aggressive bladder tumors evade NK cell immunity by decreasing the GCNT2 levels and that I-antigen glycans synthesized by GCNT2 are crucial for NK cell recognition by tumor cells. Our findings provide insights into the tumor-immune interactions in bladder cancer and GCNT2 and its associated pathways as potential targets for novel immunotherapeutic strategies.