胞嘧啶脱氨酶通过调控NFκB信号通路中的上皮-间充质转化增强肝癌侵袭性

Cytidine deaminase enhances liver cancer invasion by modulating epithelial-mesenchymal transition via NFκB signaling

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Biomedical Journal

影响因子:4.4

分区:医学3区 / 生化与分子生物学3区医学：研究与实验3区

发表日期:2024 Sep 19

作者: Chia-Jung Liao, Yang-Hsiang Lin, Huei-Tzu Chien, Yi-Wen Wang, Tzu-Kang Lin, Chau-Ting Yeh, Kwang-Huei Lin

DOI: 10.1016/j.bj.2024.100789

摘要

癌症转移是癌症相关死亡的主要原因，强调理解其潜在机制的重要性。肝细胞癌（HCC）作为一种高度恶性癌症，被选作研究模型。我们旨在通过体内外选择策略建立高转移能力的细胞株，并通过微阵列分析鉴定关键的转移相关基因，与亲本细胞进行比较。结果显示，高转移细胞的侵袭能力显著强于亲本细胞。微阵列分析发现，胞嘧啶脱氨酶（CDA）是高转移细胞中过表达的基因之一，此基因与系统性化疗抗药性相关。来自癌症基因组图谱（TCGA）的数据分析显示，虽然CDA在HCC中表达下调，但高CDA表达的患者预后较差。细胞模型证实，CDA过表达增强细胞迁移和侵袭能力，而敲除CDA则抑制这些能力。研究上皮-间充质转化（EMT）关键分子发现，CDA过表达增加Fascin、N-钙黏连蛋白、β-连环蛋白和Snail的表达，同时降低E-钙黏连蛋白的表达。相反，CDA敲低则产生相反的结果。此外，发现CDA调控NF-κB信号通路，进而控制N-钙黏连蛋白的表达，从而促进HCC细胞的侵袭能力。我们分离出高转移能力的细胞，鉴定出潜在的HCC转移相关基因。CDA通过调控NF-κB通路促进细胞侵袭，具有作为预后和治疗决策生物标志物的潜力。未来研究应探索CDA作为预后标志物和治疗靶点的潜力。

Abstract

Cancer metastasis is the leading cause of cancer-related deaths, underscoring the importance of understanding its underlying mechanisms. Hepatocellular carcinoma (HCC), a highly malignant type of cancer, was selected as our research model.We aimed to develop high-metastatic cell lines using in vitro and in vivo selection strategies and identify critical metastasis-related genes through microarray analyses by comparing them with parental cells.Our results showed that the high-metastatic cell lines exhibited significantly stronger invasion abilities than parental cells. Microarray analyses identified cytidine deaminase (CDA), a gene associated with systemic chemotherapy resistance, as one of the overexpressed genes in the high-metastatic cells. Data analysis from The Cancer Genome Atlas Program revealed that while CDA is downregulated in HCC, patients with high CDA expression tend to have poorer prognoses. Cell models confirmed that CDA overexpression enhances cell migration and invasion, whereas CDA knockdown inhibits these abilities. Investigating the key molecules involved in the epithelial-mesenchymal transition (EMT), we found that CDA overexpression increases the expression of fascin, N-cadherin, β-catenin, and snail while decreasing E-cadherin expression. Conversely, CDA knockdown produced opposite results. Additionally, we discovered that CDA regulates NF-κB signaling, which controls the expression of N-cadherin, thereby promoting the invasion capability of HCC cells.We isolated highly metastatic cells and identified potential HCC metastasis-related genes. CDA promotes cell invasion by regulating EMT through the NF-κB pathway. Future studies are warranted to explore the potential of CDA as a biomarker for prognosis and therapeutic decision-making.