Wan Meixuan, Meng Hongxue, Li Huining
Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Precision Medicine Center, Harbin Medical University Cancer Hospital, Harbin, China.
Transl Cancer Res. 2024 Nov 30;13(11):6070-6086. doi: 10.21037/tcr-24-1029. Epub 2024 Nov 21.
Bladder urothelial carcinoma (BLCA), like other cancers, is strongly associated with genetic and epigenetic changes. TWIST1 is an epithelial-mesenchymal transition (EMT) promoter that has been linked to the development of many malignancies. It is still unclear, however, what role TWIST1 plays in BLCA, and the relationship between TWIST1 transcript levels and its promoter methylation and immune infiltration has been reported even less. This study aimed to reveal the potential role of TWIST1 promoter methylation-related changes in BLCA.
Transcriptional expression data of TWIST1 in BLCA were acquired from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and University of Alabama at Birmingham (UALCAN) databases. TWIST1 methylation levels and prognosis were sourced from Gene Expression Profiling Interactive Analysis 2 (GEPIA2), LinkedOmics, cBio Cancer Genomics Portal (c-BioPortal), MethSurv, and DNA Methylation Information Visualization Database (DNMIVD) databases. The methylation status of the BLCA-associated TWIST1 in preoperative and postoperative urinary exfoliated cells was subsequently analyzed using methylation-specific real-time fluorescence polymerase chain reaction, with validation of accuracy through pyrophosphate sequencing. Finally, from the Gene Set Cancer Analysis (GSCA) and Tumor-Immune System Interaction Database (TISIDB) databases, we obtained the association between TWIST1 transcript expression and DNA methylation and cancer immune infiltration and immunolabelling.
Our study demonstrated that TWIST1 expression was down-regulated in BLCA, which was negatively correlated with DNA methylation. The association between TWIST1 promoter hypermethylation and the progression, staging, grading, and recurrence of BLCA is highly significant. Furthermore, we revealed that hypermethylation of both the preoperative and postoperative TWIST1 promoters is useful as a biomarker for monitoring BLCA recurrence, particularly when considering the methylation status of specific CpG sites. Additionally, we observed that TWIST1 expression, promoter methylation, and immune infiltration immunoreactive markers correlated significantly in BLCA.
We propose that TWIST1 holds great promise as a diagnostic and therapeutic target for BLCA, with the potential to influence tumor progression and patient prognosis through the regulation of immune cell infiltration. We hope these findings contribute valuable insights to the field of BLCA research.
膀胱尿路上皮癌（BLCA）与其他癌症一样，与基因和表观遗传变化密切相关。TWIST1是一种上皮-间质转化（EMT）促进因子，与多种恶性肿瘤的发生发展有关。然而，TWIST1在BLCA中发挥何种作用仍不清楚，关于TWIST1转录水平与其启动子甲基化及免疫浸润之间的关系报道更少。本研究旨在揭示TWIST1启动子甲基化相关变化在BLCA中的潜在作用。
从癌症基因组图谱（TCGA）、基因表达综合数据库（GEO）和阿拉巴马大学伯明翰分校（UALCAN）数据库获取BLCA中TWIST1的转录表达数据。TWIST1甲基化水平和预后数据来自基因表达谱交互分析2（GEPIA2）、LinkedOmics、cbioportal癌症基因组学门户（c-BioPortal）、MethSurv和DNA甲基化信息可视化数据库（DNMIVD）。随后采用甲基化特异性实时荧光聚合酶链反应分析术前和术后尿液脱落细胞中与BLCA相关的TWIST1的甲基化状态，并通过焦磷酸测序验证准确性。最后，从基因集癌症分析（GSCA）和肿瘤-免疫系统相互作用数据库（TISIDB）获取TWIST1转录表达与DNA甲基化及癌症免疫浸润和免疫标记之间的关联。
我们的研究表明，BLCA中TWIST1表达下调，且与DNA甲基化呈负相关。TWIST1启动子高甲基化与BLCA的进展、分期、分级和复发之间的关联非常显著。此外，我们发现术前和术后TWIST1启动子的高甲基化均可用作监测BLCA复发的生物标志物，尤其是考虑特定CpG位点的甲基化状态时。此外，我们观察到BLCA中TWIST1表达、启动子甲基化和免疫浸润免疫反应标志物之间存在显著相关性。
我们认为TWIST1有望成为BLCA的诊断和治疗靶点，有可能通过调节免疫细胞浸润影响肿瘤进展和患者预后。我们希望这些发现为BLCA研究领域提供有价值的见解。
