背景：在结直肠癌（CRC）中，包括KRAS、BRAF和p53在内的多基因突变使得CRC具有高转移能力和对EGFR靶向治疗的抵抗能力。了解调节抗EGFR耐药性CRC转移的分子机制可以提高CRC治疗效果。本研究旨在调查IL-8和KRAS激活对高脂血症相关的KRAS和p53突变CRC产生的反应性氧化物（ROS）产生和转移的影响。方法：细胞因子蛋白芯片分析确定了包括IL-8在内的分泌因子的上调表达。分别从国立成功大学医院和TCGA数据集中检查IL-8和血管生成素样4（ANGPTL4）之间的临床相关性。确定了游离脂肪酸（FFAs）处理的KRAS/p53突变CRC细胞中IL-8、ANGPTL4、NADPH氧化酶4（NOX4）和上皮间质转化（EMT）标志物的表达情况。通过体外和体内评估抗氧化剂、他汀类药物和cetuximab治疗或抑制IL-8、KRAS和EGFR对高脂血症诱导的CRC细胞的转移能力的影响。此外，还阐明了抗氧化剂和IL-8、KRAS消耗对ROS产生和高脂血症促进的CRC转移之间相关性的影响。结果：在本研究中，我们发现游离脂肪酸促进了KRAS/p53突变而非单一突变或非突变CRC细胞的转移能力。在KRAS/p53突变细胞中，IL-8是最丰富的分泌因子，并且与油酸（OA）处理条件下NOX4表达和ROS产生的上调相关。此外，KRAS/p53突变CRC的转移依赖于ANGPTL4/IL-8/NOX4轴和KRAS的激活。抗氧化剂和KRAS的失活也抑制了OA诱导的EMT和转移。虽然KRAS介导EGF和OA促进的CRC细胞侵袭，但EGFR的抑制并不影响OA诱导的ANGPTL4/IL-8/NOX4轴和CRC转移。使用维生素E和他汀类药物饲喂高脂饮食小鼠或使用IL-8消耗细胞明显抑制了CRC的肿瘤越床和转移性肺生长。结论：抗氧化剂、他汀类药物和IL-8靶向治疗可能为治疗多基因突变和抗EGFR耐药性的转移性CRC提供更好的效果。©作者。

Background: Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. Methods: The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. Results: In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. Conclusion: The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.© The author(s).