背景:上尿路尿路上皮癌(UTUC)是一种罕见的疾病,与膀胱癌(BC)属于同一类尿路上皮癌。尽管有类似的非手术治疗方式,UTUC显示出比BC更高的转移倾向。此外,尽管两种癌症都表现出相似的分子疾病出现机制,测序数据揭示了一些差异。我们的研究调查了UTUC和BC之间的转录组差异,探讨了UTUC转移趋势加剧背后的原因,构建UTUC转移和预后模型,并提出UTUC的个性化治疗策略。
方法:在我们的研究中,我们利用差异基因表达分析,互动网络,和Cox回归探讨UTUC转移倾向的增强。我们使用多种技术制定并验证了预后风险模型,包括细胞共培养,逆转录定量聚合酶链反应(rt-qPCR),西方印迹,和Transwell实验。我们的方法还涉及生存分析,风险模型构建,利用CTRPv2、PRISM和CMap数据库进行药物筛选。我们使用Masson染色技术进行组织学评估。使用R软件和GraphPadPrism9进行所有统计评估,加强了我们研究方法的严格和全面性质。
结果:通过炎性纤维化筛查显示,与BC相比,UTUC中蛋白聚糖调节的细胞外基质和细胞粘附分子减少,使UTUC更容易转移。我们证明了SDC1,LUM,VEGFA,WNT7B,和TIMP3在促进UTUC转移中至关重要。基于这五个分子的风险模型可以有效预测UTUC转移风险和无病生存时间。鉴于UTUC与BC不同的独特分子机制,我们发现,UTUC患者通过酪氨酸激酶抑制剂(TKIs)以及常规吉西他滨和顺铂化疗方案,可以更好地缓解与UTUC易转移相关的不良预后问题.
结论:由于UTUC的高转移倾向,其预后不良与活性氧积累引起的炎性纤维化密切相关。利用5种分子SDC1、LUM、VEGFA,WNT7B,TIMP3能有效预测患者预后。UTUC患者除了常规治疗方案外还需要专门治疗,TKIs表现出巨大的潜力。
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.
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.
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.
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.