Zhuang HuiE, Chen Yizhen, Huang Sifu
Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Fujian Medical University, Fuzhou, Fujian, China.
Front Immunol. 2025 Apr 3;16:1560322. doi: 10.3389/fimmu.2025.1560322. eCollection 2025.
Distant metastasis of colorectal cancer (CRC) significantly impacts patient prognosis. Cuproptosis is a new form of copper ion-dependent cell death. However, whether cuproptosis-related genes (CRGs) play a role in the metastatic potential of CRC remains unclear. This study focuses on CRGs-ACAD8 to explore its role and mechanism in metastatic CRC (mCRC).
Clinical sample data from TCGA, GEO, and Fujian Provincial Hospital patients were integrated to analyze ACAD8 expression and its association with the diagnosis and prognosis of CRC. Small interfering RNA, immunohistochemistry, colony formation, wound-healing assays and so on were used to evaluate the biological functions of ACAD8. Bioinformatics was applied to investigate its relationships with immune infiltration, chemotherapy sensitivity, and signaling pathways.
ACAD8 expression was significantly reduced in mCRC and demonstrated excellent diagnostic performance. Patients with high ACAD8 expression had significantly better survival. ACAD8 was closely associated with immune cell infiltration, and enhanced chemotherapy sensitivity. Pathway enrichment analysis suggested that ACAD8 might inhibit the metastasis of CRC by regulating pathways such as response to metal ions and tight junction organization. Finally, experiments confirmed a positive correlation between copper levels and ACAD8 mRNA expression, with CuCl upregulating ACAD8 expression. Knockdown of ACAD8 induced cuproptosis. CuCl inhibited the proliferation, stemness, and migratory abilities of CRC cells, while si ACAD8 attenuated these effects. Moreover, CuCl enhanced the sensitivity of CRC cells to oxaliplatin and 5-fluorouracil, whereas si ACAD8 diminished this chemosensitizing effect.
As a novel tumor suppressor, low expression of CRGs-ACAD8 is associated with the metastasis of CRC. ACAD8 holds potential diagnostic and prognostic value and may contribute to the precise treatment of CRC by regulating immune infiltration and chemotherapy sensitivity.
结直肠癌（CRC）的远处转移显著影响患者预后。铜死亡是一种新的铜离子依赖性细胞死亡形式。然而，铜死亡相关基因（CRGs）是否在CRC的转移潜能中发挥作用仍不清楚。本研究聚焦于CRGs-ACAD8，以探讨其在转移性结直肠癌（mCRC）中的作用及机制。
整合来自TCGA、GEO和福建省立医院患者的临床样本数据，分析ACAD8表达及其与CRC诊断和预后的关系。使用小干扰RNA、免疫组织化学、集落形成、伤口愈合试验等评估ACAD8的生物学功能。应用生物信息学研究其与免疫浸润、化疗敏感性和信号通路的关系。
ACAD8表达在mCRC中显著降低，并具有出色的诊断性能。ACAD8高表达的患者生存情况明显更好。ACAD8与免疫细胞浸润密切相关，并增强了化疗敏感性。通路富集分析表明，ACAD8可能通过调节对金属离子的反应和紧密连接组织等通路来抑制CRC的转移。最后，实验证实铜水平与ACAD8 mRNA表达呈正相关，CuCl上调ACAD8表达。敲低ACAD8诱导铜死亡。CuCl抑制CRC细胞的增殖、干性和迁移能力，而si ACAD8减弱了这些作用。此外，CuCl增强了CRC细胞对奥沙利铂和5-氟尿嘧啶的敏感性，而si ACAD8削弱了这种化学增敏作用。
作为一种新型肿瘤抑制因子，CRGs-ACAD8的低表达与CRC的转移有关。ACAD8具有潜在的诊断和预后价值，并可能通过调节免疫浸润和化疗敏感性为CRC的精准治疗做出贡献。
