UPK2 (uroplakin 2) is a membrane-spanning protein component of the asymmetric unit membrane (AUM) in terminally differentiated urothelial cells, where it associates with other uroplakins to form urothelial plaques 1. The protein provides essential barrier function to prevent urine passage across the urothelium in the renal pelvis, ureters, and bladder 1. UPK2 belongs to the tetraspanin-associated UPK2/3 protein family, which evolved from protoPTPRQ-like ancestor genes through duplication and domain loss 2. In normal tissues, UPK2 expression is highly specific to urothelium 3. However, aberrant UPK2 expression occurs in malignancies. UPK2 is a diagnostic marker for urothelial carcinoma with excellent specificity, detectable by both immunohistochemistry and RNAscope methods 4. Notably, UPK2 is also overexpressed in a distinct subset of colorectal cancers (~12% of cases) 5. UPK2-positive colorectal cancers exhibit aggressive features including advanced stage, lymphovascular invasion, micropapillary growth pattern, TP53 mutations, and reduced anti-tumor immune infiltration 65. UPK2 positivity independently predicts poor prognosis with significantly higher colorectal cancer-specific mortality (hazard ratio 2.31) 5, establishing UPK2 as a prognostic marker for a high-risk, molecularly distinct cancer subtype.