E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer
E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer
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DOI：
10.1158/0008-5472.can-19-2988
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发表时间：
2021-01-15
期刊：
影响因子：
11.2
通讯作者：
Yachida, Shinichi
中科院分区：
文献类型：
--
作者：
Suzuki, Masami;Saito-Adachi, Mihoko;Yachida, Shinichi
转录因子E74样因子3（ELF 3）在一系列癌症中失活，包括胆道癌（BTC）。在这里，我们研究了胆管细胞中的肿瘤抑制作用的ELF 3，通过确定几个以前未知的直接靶基因的ELF 3，似乎是牵连在胆管癌的发生。ELF 3直接抑制上皮-间质转化的关键调节因子2 EB 2，并上调管腔形成中不可或缺的因子CGN的表达。ELF 3的缺失导致细胞间连接减少和细胞运动性增强。ALOX 5和CXCL 16也被鉴定为ELF 3的额外直接靶点;它们相应的蛋白质5-脂氧合酶和CXCL 16在免疫应答中发挥作用。来自过表达ELF 3的细胞的条件培养基显著增强了自然杀伤细胞和CD 8（+）T细胞向条件培养基的迁移。表达高水平ELF 3的Bit的基因表达谱显示ELF 3相关基因的显著富集。在BTC异种移植模型中，ELF 3的激活增加了ELF 3相关基因的表达，增强了肿瘤的管状结构，并导致波形蛋白的丢失。总之，我们的研究结果表明，ELF 3是一个关键的调节上皮完整性和免疫反应在BTC.Significance：Thease发现表明，ELF 3调节上皮完整性和宿主免疫反应，并作为一个肿瘤抑制剂在胆道癌的功能。[图形]。
The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed 2 EB2, a key regulator of epithelial-mesenchymal transition, and upregulated the expression of CGN, an integral dement in lumen formation. Loss of ELF3 led to decreased cell-cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipoxygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8(+) T cells toward the conditioned medium. Gene expression profiling for Bit expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC.Significance: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer.[GRAPHICS].