Department of General Surgery, Chongqing University Central Hospital (Chongqing Emergency Medical Center), Chongqing, China.
Cell Biochem Biophys. 2024 Dec;82(4):3437-3452. doi: 10.1007/s12013-024-01430-6. Epub 2024 Jul 17.
Colorectal cancer is one of the most common malignant tumors worldwide, with high incidence and mortality rates making it a focus of research. Chemotherapy is a primary treatment modality for colon cancer, but chemotherapy resistance severely impacts treatment efficacy. MIF has been found to promote tumor progression and resistance in various cancers. This study aims to investigate the role of MIF in chemotherapy resistance in colon cancer and its potential mechanisms, particularly through the upregulation of CXCR7 expression, affecting the metabolism and drug sensitivity of colon cancer cells. The expression levels of MIF in colon cancer tissues and its association with patient prognosis were evaluated by analyzing TCGA and HPA data. Subsequently, the expression levels of MIF in colon cancer cell lines and resistant cell lines were detected by qRT-PCR and immunohistochemistry, and the effect of MIF on oxaliplatin sensitivity was assessed. The impact of MIF on the metabolic activity of colon cancer cells was measured using a cellular energy metabolism analyzer. Further experiments explored the mechanism by which MIF affects the metabolic activity of colon cancer cells through the upregulation of CXCR7 expression, and the role of CTCF in regulating CXCR7 transcription was validated by silencing CTCF. Finally, the effect of MIF on drug sensitivity of colon cancer cells was verified in a mouse xenograft tumor model. In this study, we found that the expression of MIF in colon cancer tissues was significantly higher than in normal tissues, and high MIF expression was associated with poor prognosis in patients. The expression levels of MIF in resistant colon cancer cell lines were significantly higher than in parental cell lines, and MIF overexpression significantly increased the resistance of colon cancer cells to oxaliplatin. Conversely, silencing MIF significantly reduced the IC50 value of resistant cells and increased apoptosis. MIF overexpression significantly increased the ECAR and OCR levels of colon cancer cells, while MIF knockdown significantly reduced these metabolic indicators. Further studies indicated that MIF affects the metabolic activity of colon cancer cells by upregulating CXCR7 expression. CTCF binding peaks at the CXCR7 promoter region and luciferase activity assays indicated that CTCF regulates CXCR7 transcription, and silencing CTCF significantly enhanced the sensitivity of colon cancer cells to oxaliplatin. In vivo experiments in mice showed that MIF silencing combined with oxaliplatin treatment significantly inhibited tumor growth and increased the necrotic area of tumor tissues. In conclusion, this study reveals the crucial role of MIF in chemotherapy resistance in colon cancer through the upregulation of CXCR7 expression, with CTCF playing an important regulatory role in this process. Our findings provide new theoretical insights and potential therapeutic targets for overcoming chemotherapy resistance in colon cancer. Future research should further explore the roles of MIF and CXCR7 in other types of cancers and the potential of MIF and CXCR7 as therapeutic targets.
结直肠癌是全球最常见的恶性肿瘤之一，其发病率和死亡率均较高，因此成为研究的重点。化疗是结肠癌的主要治疗方式，但化疗耐药严重影响治疗效果。MIF 已被发现可促进多种癌症的肿瘤进展和耐药性。本研究旨在探讨 MIF 在结肠癌化疗耐药中的作用及其潜在机制，特别是通过上调 CXCR7 表达，影响结肠癌细胞的代谢和药物敏感性。通过分析 TCGA 和 HPA 数据评估 MIF 在结肠癌组织中的表达水平及其与患者预后的关系。随后，通过 qRT-PCR 和免疫组化检测 MIF 在结肠癌细胞系和耐药细胞系中的表达水平，并评估 MIF 对奥沙利铂敏感性的影响。使用细胞能量代谢分析仪测量 MIF 对结肠癌细胞代谢活性的影响。进一步的实验通过上调 CXCR7 表达探讨了 MIF 影响结肠癌细胞代谢活性的机制，并通过沉默 CTCF 验证了 CTCF 在调节 CXCR7 转录中的作用。最后，在小鼠异种移植肿瘤模型中验证了 MIF 对结肠癌细胞药物敏感性的影响。在本研究中，我们发现 MIF 在结肠癌组织中的表达明显高于正常组织，高 MIF 表达与患者预后不良相关。耐药结肠癌细胞系中 MIF 的表达水平明显高于亲本细胞系，MIF 过表达显著增加了结肠癌细胞对奥沙利铂的耐药性。相反，沉默 MIF 显著降低了耐药细胞的 IC50 值并增加了细胞凋亡。MIF 过表达显著增加了结肠癌细胞的 ECAR 和 OCR 水平，而 MIF 敲低显著降低了这些代谢指标。进一步的研究表明，MIF 通过上调 CXCR7 表达影响结肠癌细胞的代谢活性。CTCF 在 CXCR7 启动子区域的结合峰和荧光素酶活性测定表明，CTCF 调节 CXCR7 转录，沉默 CTCF 显著增强了结肠癌细胞对奥沙利铂的敏感性。体内实验结果表明，MIF 沉默联合奥沙利铂治疗显著抑制肿瘤生长并增加肿瘤组织的坏死面积。总之，本研究通过上调 CXCR7 表达揭示了 MIF 在结肠癌化疗耐药中的关键作用，其中 CTCF 在这一过程中发挥了重要的调节作用。我们的研究结果为克服结肠癌化疗耐药提供了新的理论见解和潜在的治疗靶点。未来的研究应进一步探讨 MIF 和 CXCR7 在其他类型癌症中的作用以及 MIF 和 CXCR7 作为治疗靶点的潜力。
