Inhibitors of DNA binding and cell differentiation (ID) proteins regulate cellular differentiation and tumor progression. Whether ID family proteins serve as a linkage between pathological differentiation and cancer stemness in colorectal cancer is largely unknown. Here, the expression of ID4, but not other ID family proteins, was enriched in LGR5-high colon cancer stem cells. Its high expression was associated with poor pathological differentiation of colorectal tumors and shorter survival in patients. Knockdown of ID4 inhibited the growth and dissemination of colon cancer cells, while enhancing chemosensitivity. Through gene expression profiling analysis, brain-derived neurotrophic factor (BDNF) was identified as a downstream target of ID4 expression in colorectal cancer. BDNF knockdown decreased the growth and migration of colon cancer cells, and its expression enhanced dissemination, anoikis resistance and chemoresistance. ID4 silencing attenuated the epithelial-to-mesenchymal transition pattern in colon cancer cells. Gene cluster analysis revealed that ID4 and BDNF expression was clustered with mesenchymal markers and distant from epithelial genes. BDNF silencing decreased the expression of mesenchymal markers Vimentin, CDH2 and SNAI1. These findings demonstrated that ID4-BDNF signaling regulates colorectal cancer survival, with the potential to serve as a prognostic marker in colorectal cancer.

中文翻译：

---

ID4 可预测不良预后并促进 BDNF 介导的结直肠癌发生。

DNA 结合和细胞分化 (ID) 蛋白的抑制剂调节细胞分化和肿瘤进展。ID 家族蛋白是否作为结直肠癌病理分化和癌症干性之间的联系在很大程度上是未知的。在这里，ID4 的表达，而不是其他 ID 家族蛋白的表达，在 LGR5 高的结肠癌干细胞中得到了丰富。其高表达与结直肠肿瘤病理分化差和患者生存期较短有关。ID4 的敲低抑制了结肠癌细胞的生长和传播，同时增强了化学敏感性。通过基因表达谱分析，脑源性神经营养因子（BDNF）被确定为结直肠癌中 ID4 表达的下游靶点。BDNF 敲低降低了结肠癌细胞的生长和迁移，及其表达增强了传播、抗失巢凋亡和化学抗性。ID4 沉默减弱了结肠癌细胞中的上皮-间充质转化模式。基因聚类分析显示，ID4 和 BDNF 表达与间充质标记物聚类并远离上皮基因。BDNF 沉默降低了间充质标志物波形蛋白、CDH2 和 SNAI1 的表达。这些发现表明，ID4-BDNF 信号调节结直肠癌的存活率，有可能作为结直肠癌的预后标志物。基因聚类分析显示，ID4 和 BDNF 表达与间充质标记物聚类并远离上皮基因。BDNF 沉默降低了间充质标志物波形蛋白、CDH2 和 SNAI1 的表达。这些发现表明，ID4-BDNF 信号调节结直肠癌的存活率，有可能作为结直肠癌的预后标志物。基因聚类分析显示，ID4 和 BDNF 表达与间充质标记物聚类并远离上皮基因。BDNF 沉默降低了间充质标志物波形蛋白、CDH2 和 SNAI1 的表达。这些发现表明，ID4-BDNF 信号调节结直肠癌的存活率，有可能作为结直肠癌的预后标志物。