致癌 LINC00857 募集 TFAP2C 以提高胃癌中的 FAT1 表达,Cancer Science

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致癌 LINC00857 募集 TFAP2C 以提高胃癌中的 FAT1 表达
Cancer Science ( IF 4.5 ) Pub Date : 2022-05-07 , DOI: 10.1111/cas.15394
Wenqing Zhang ₁ , Kaiyue Ji ₁ , Congcong Min ₂ , Cuiping Zhang ₁ , Lin Yang ₁ , Qi Zhang ₁ , Zibin Tian ₁ , Mengyuan Zhang ₁ , Xinyu Wang ₁ , Xiaoyu Li ₁

Affiliation

FAT 非典型钙粘蛋白 1 (FAT1) 是一种常见于人类癌症的突变基因，主要聚集在癌细胞的质膜上。新出现的证据表明 FAT1 与胃癌 (GC) 的进展有关。本研究旨在确定 GC 开发中与 FAT1 相关的监管网络。在 GC 组织中证实了 FAT1 的上调表达，并且观察到沉默 FAT1 导致 GC 细胞致癌表型的抑制。机制研究结果表明，FAT1 通过磷酸化 c-JUN 和 c-FOS 上调 AP-1 表达，而 LINC00857 通过募集转录因子 TFAP2C 上调 FAT1 的表达。功能实验进一步表明，LINC00857 通过 TFAP2C 介导的促进 FAT1 增强 GC 细胞的恶性生物学特性。更重要的是，LINC00857 沉默延迟了荷瘤小鼠的肿瘤生长并阻断了上皮-间质转化，这与 TFAP2C/FAT1 的表达下调有关。总之，LINC00857 通过调节 TFAP2C/FAT1/AP-1 轴在 GC 中发挥致癌作用。因此，本研究有助于加深对胃癌发生的理解，LINC00857 可作为 GC 的治疗靶点。

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Oncogenic LINC00857 recruits TFAP2C to elevate FAT1 expression in gastric cancer

FAT atypical cadherin 1 (FAT1) is a mutant gene frequently found in human cancers and mainly accumulates at the plasma membrane of cancer cells. Emerging evidence has implicated FAT1 in the progression of gastric cancer (GC). This study intended to identify a regulatory network related to FAT1 in GC development. Upregulated expression of FAT1 was confirmed in GC tissues, and silencing FAT1 was observed to result in suppression of GC cell oncogenic phenotypes. Mechanistic investigation results demonstrated that FAT1 upregulated AP-1 expression by phosphorylating c-JUN and c-FOS, whereas LINC00857 elevated the expression of FAT1 by recruiting a transcription factor TFAP2C. Functional experiments further suggested that LINC00857 enhanced the malignant biological characteristics of GC cells through TFAP2C-mediated promotion of FAT1. More importantly, LINC00857 silencing delayed the tumor growth and blocked epithelial–mesenchymal transition in tumor-bearing mice, which was associated with downregulated expression of TFAP2C/FAT1. To conclude, LINC00857 plays an oncogenic role in GC through regulating the TFAP2C/FAT1/AP-1 axis. Therefore, this study contributes to extended the understanding of gastric carcinogenesis and LINC00857 may serve as a therapeutic target for GC.

更新日期：2022-05-07

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