胃癌（GC）的特点是分化障碍，其确切机制仍不清楚。我们之前的研究表明，PHF10 在 GC 中表现出致癌特性，其组织学表现表明 PHF10 在调节 GC 分化障碍中具有潜在作用。这项研究揭示了GC组织中PHF10的显着上调，与分化水平呈负相关。研究发现 PHF10 会阻碍 GC 细胞的分化，同时促进其干性特性。这归因于 PHF10 和 E2F1 之间形成正反馈环，导致 GC 中表达水平失调。此外，发现 PHF10 通过 SWI/SNF 复合物的组装介导 GC 细胞中靶基因 DUSP5 的转录抑制，导致 pERK1/2 水平升高。在GC组织中，E2F1或PHF10的表达与DUSP5之间呈负相关，而E2F1或PHF10的表达与pERK1/2之间呈正相关。其他拯救实验证实，PHF10 对 GC 细胞分化的抑制作用依赖于 DUSP5-pERK1/2 轴。涉及 E2F1-PHF10-DUSP5-pERK1/2 的信号级联被确定为调节 GC 细胞分化和干细胞性的重要参与者。 PHF10 成为 GC 分化诱导治疗的一个有前景的靶标。© 2024。作者。

Gastric cancer (GC) is characterized with differentiation disorders, the precise mechanisms of which remain unknown. Our previous study showed that PHF10 exhibits oncogenic properties in GC, with its histological presentation indicating a potential role in the modulation of differentiation disorders in GC. This study reveals a significant upregulation of PHF10 in GC tissues, showing a negative correlation with differentiation level. PHF10 was found to impede the differentiation of GC cells while promoting their stemness properties. This was attributed to the formation of a positive feedback loop between PHF10 and E2F1, resulting in dysregulated expression levels in GC. Additionally, PHF10 was found to mediate the transcriptional repression of the target gene DUSP5 in GC cells through the assembly of the SWI/SNF complex, leading to an elevation in pERK1/2 levels. In GC tissues, a negative association was noted between the expression of E2F1 or PHF10 and DUSP5, whereas a positive correlation was observed between the expression of E2F1 or PHF10 and pERK1/2. Additional rescue experiments confirmed that the inhibitory effect on differentiation of GC cells by PHF10 is dependent on the DUSP5-pERK1/2 axis. The signaling cascade involving E2F1-PHF10-DUSP5-pERK1/2 was identified as an important player in regulating differentiation and stemness in GC cells. PHF10 emerges as a promising target for differentiation induction therapy in GC.© 2024. The Author(s).