鉴定 EMT 相关的 TMC7 可变剪接事件促进胰腺癌的侵袭和迁移。
Identification of EMT-related alternative splicing event of TMC7 to promote invasion and migration of pancreatic cancer.
机构信息
Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Research Institute of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Front Immunol. 2023 Jan 12;13:1089008. doi: 10.3389/fimmu.2022.1089008. eCollection 2022.
OBJECTIVE
Epithelial-to-mesenchymal transition (EMT) is tightly associated with the invasion and metastasis of pancreatic cancer with rapid progression and poor prognosis. Notably, gene alternative splicing (AS) event plays a critical role in regulating the progression of pancreatic cancer. Therefore, this study aims to identify the EMT-related AS event in pancreatic cancer.
METHODS
The EMT-related gene sets, transcriptomes, and matched clinical data were obtained from the MSigDB, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Key gene AS events associated with liver metastasis were identified by prognostic analysis, gene set variation analysis (GSVA), and correlation analysis in pancreatic cancer. The cell line and organoid model was constructed to evaluate these key gene AS events in regulating pancreatic cancer . Furthermore, we established an EMT-related gene set consisting of 13 genes by prognostic analysis, the role of which was validated in two other databases. Finally, the human pancreatic cancer tissue and organoid model was used to evaluate the correlation between the enrichment of this gene set and liver metastasis.
RESULTS
Prognostic analysis and correlation analysis revealed that eight AS events were closely associated with the prognosis of pancreatic cancer. Furthermore, the expression of TMC7 and CHECK1 AS events was increased in the metastatic lesions of the human tissue and organoid model. Additionally, the knockdown of exon 17 of TMC7 significantly inhibited the proliferation, invasion, and migration of pancreatic cancer cells in 2D and 3D cell experiments. Finally, the expression of exon 17 of TMC17 exhibited a significant correlation with the poor prognosis in pancreatic ductal adenocarcinoma (PDAC).
CONCLUSION
The AS events of TMC7 and CHECK1 were associated with liver metastasis in pancreatic cancer. Moreover, exon 17 of TMC7 could be a potential therapeutic target in pancreatic cancer.
目的
上皮间质转化（EMT）与胰腺癌的侵袭和转移密切相关，其进展迅速，预后不良。值得注意的是，基因选择性剪接（AS）事件在调控胰腺癌的进展中起着关键作用。因此，本研究旨在鉴定胰腺癌中的 EMT 相关 AS 事件。
方法
从 MSigDB、癌症基因组图谱（TCGA）、国际癌症基因组联合会（ICGC）和基因表达综合数据库（GEO）中获取 EMT 相关基因集、转录组和匹配的临床数据。通过预后分析、基因集变异分析（GSVA）和相关性分析，在胰腺癌中鉴定与肝转移相关的关键基因 AS 事件。构建细胞系和类器官模型，评估这些关键基因 AS 事件对调控胰腺癌的作用。此外，我们通过预后分析建立了一个由 13 个基因组成的 EMT 相关基因集，在另外两个数据库中验证了其作用。最后，用人胰腺癌细胞和类器官模型评估该基因集的富集与肝转移的相关性。
结果
预后分析和相关性分析表明，有 8 个 AS 事件与胰腺癌的预后密切相关。此外，TMC7 和 CHECK1 的 AS 事件在人组织和类器官模型的转移病灶中表达增加。此外，TMC7 外显子 17 的敲低显著抑制了 2D 和 3D 细胞实验中胰腺癌细胞的增殖、侵袭和迁移。最后，TMC17 外显子 17 的表达与胰腺导管腺癌（PDAC）的不良预后显著相关。
结论
TMC7 和 CHECK1 的 AS 事件与胰腺癌的肝转移有关。此外，TMC7 的外显子 17 可能是胰腺癌的潜在治疗靶点。
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