Upk1a, encoding uroplakin-1a, is a gene specific to the urothelium. Uroplakins are a family of membrane-spanning proteins that form urothelial plaques in the apical membrane of umbrella cells of the urothelium, providing a barrier to prevent urine passage across the urothelium in the renal pelvis, ureters, and bladder. They are also involved in nephrogenesis. The specific localization within the urothelium makes them potential immunohistochemical markers for urothelial malignancy [3].

In urothelial carcinoma of the bladder, the loss of Upk1a expression is linked to stage progression. High expression of Upk1a in muscle-invasive (pT2-4) carcinomas is associated with nodal metastasis and lymphatic vessel infiltration, but not with patient outcome. In pT4 carcinomas, absence of GATA3/Upk1a staining is significantly linked to poor patient survival [1]. In bladder transitional cell carcinoma, downregulation of Upk1a suppresses cell proliferation and enhances apoptosis, suggesting it as a potential target for treating this disease [2]. In hepatocellular carcinoma, Upk1a is highly expressed, and high expression predicts poor overall survival. Silencing Upk1a suppresses cell glycolysis and proliferation. Hypoxia-inducible factor 1α (HIF-1α) binds to the hypoxia response elements of Upk1a promoter region, up-regulating Upk1a under hypoxia, and there is a positive feedback loop between HIF-1α and Upk1a modulating glycolysis and proliferation [4].

In conclusion, Upk1a plays crucial roles in maintaining the integrity of the urothelial barrier and is involved in nephrogenesis. Its dysregulation is associated with urothelial carcinoma of the bladder, bladder transitional cell carcinoma, and hepatocellular carcinoma. Studies on Upk1a in these disease models help to understand the mechanisms of tumor progression, providing potential targets for diagnosis and treatment.

References:

1. Kaczmarek, Krystian, Plage, Henning, Furlano, Kira, Horst, David, Zecha, Henrik. 2023. Loss of Upk1a and Upk1b expression is linked to stage progression in urothelial carcinoma of the bladder. In International urology and nephrology, 56, 499-508. doi:10.1007/s11255-023-03800-0. https://pubmed.ncbi.nlm.nih.gov/37777995/

2. Zhu, Haiyan, Tang, Yuxin, Zhang, Xiangyang, Gan, Yu, Yang, Jianfu. 2015. Downregulation of UPK1A suppresses proliferation and enhances apoptosis of bladder transitional cell carcinoma cells. In Medical oncology (Northwood, London, England), 32, 84. doi:10.1007/s12032-015-0541-y. https://pubmed.ncbi.nlm.nih.gov/25701463/

3. Sivakumaar, Krithicck, Griffin, Jon, Schofield, Ella, Catto, James W F, Jubber, Ibrahim. 2024. Gene of the month: the uroplakins. In Journal of clinical pathology, 77, 291-296. doi:10.1136/jcp-2024-209388. https://pubmed.ncbi.nlm.nih.gov/38418202/

4. Song, Yang, Wang, Hui, Zou, Xue-Jing, Wu, De-Hua, Zhang, Dong-Yan. 2020. Reciprocal regulation of HIF-1α and Uroplakin 1A promotes glycolysis and proliferation in Hepatocellular Carcinoma. In Journal of Cancer, 11, 6737-6747. doi:10.7150/jca.48132. https://pubmed.ncbi.nlm.nih.gov/33046996/