Transcriptomic insights into UTUC: role of inflammatory fibrosis and potential for personalized treatment

Abstract

Abstract Background Upper tract urothelial carcinoma (UTUC) is a rare disease, belonging to the same category of urothelial cancers as bladder cancer (BC). Despite sharing similar non-surgical treatment modalities, UTUC demonstrates a higher metastasis propensity than BC. Furthermore, although both cancers exhibit similar molecular disease emergence mechanisms, sequencing data reveals some differences. Our study investigates the transcriptomic distinctions between UTUC and BC, explores the causes behind UTUC's heightened metastatic tendency, constructs a model for UTUC metastasis and prognosis, and propose personalized treatment strategies for UTUC. Methods In our research, we utilized differential gene expression analysis, interaction networks, and Cox regression to explore the enhanced metastatic propensity of UTUC. We formulated and validated a prognostic risk model using diverse techniques, including cell co-culture, reverse transcription quantitative polymerase chain reaction (rt-qPCR), western blotting, and transwell experiments. Our methodological approach also involved survival analysis, risk model construction, and drug screening leveraging the databases of CTRPv2, PRISM and CMap. We used the Masson staining technique for histological assessments. All statistical evaluations were conducted using R software and GraphPad Prism 9, reinforcing the rigorous and comprehensive nature of our research approach. Results Screening through inflammatory fibrosis revealed a reduction of extracellular matrix and cell adhesion molecules regulated by proteoglycans in UTUC compared with BC, making UTUC more metastasis-prone. We demonstrated that SDC1, LUM, VEGFA, WNT7B, and TIMP3, are critical in promoting UTUC metastasis. A risk model based on these five molecules can effectively predict the risk of UTUC metastasis and disease-free survival time. Given UTUC's unique molecular mechanisms distinct from BC, we discovered that UTUC patients could better mitigate the issue of poor prognosis associated with UTUC's easy metastasis through tyrosine kinase inhibitors (TKIs) alongside the conventional gemcitabine and cisplatin chemotherapy regimen. Conclusions The poor prognosis of UTUC because of its high metastatic propensity is intimately tied to inflammatory fibrosis induced by the accumulation of reactive oxygen species. The biological model constructed using the five molecules SDC1, LUM, VEGFA, WNT7B, and TIMP3 can effectively predict patient prognosis. UTUC patients require specialized treatments in addition to conventional regimens, with TKIs exhibiting significant potential.

Keywords

• UTUC
• Bladder Cancer
• Aristolochic acid
• Fibrosis
• TKIs