结直肠癌（CRC）仍然是一个主要的全球健康问题，尽管化疗和靶向治疗取得了进展，但转移病例的预后较差。伊立替康是晚期结直肠癌治疗的关键药物，由于耐药性的发展而面临挑战。本研究旨在了解结直肠癌中伊立替康耐药的潜在机制。我们使用 HT29 细胞创建了对伊立替康耐药的细胞系。这些耐药细胞被用来研究 CDK7-MDK 轴的作用。我们采用批量 RNA 测序，对小鼠进行体内实验，并分析患者组织，以检查 CDK7-MDK 轴对细胞对伊立替康反应的影响。我们的研究结果表明，HT29 细胞对伊立替康（一种重要的结直肠癌药物）具有耐药性，与亲本对应物相比，它们表现出显着的表型和分子改变，包括干细胞特征的提高以及细胞因子和耐药蛋白水平的增加。值得注意的是，这些耐药细胞中的 CDK7 表达显着较高，靶向 CDK7 有效降低了它们的存活率和肿瘤生长，从而增强了伊立替康敏感性。 RNA-seq 分析表明，抑制伊立替康耐药 HT29 细胞中的 CDK7 显着降低 Midkine (MDK) 表达。通过 siRNA 和 CDK7 抑制剂 THZ1 降低 CDK7 和 MDK 水平，增强了耐药 HT29 细胞对伊立替康的敏感性。我们的研究揭示了 CDK7 和 MDK 如何影响结直肠中的伊立替康耐药性，并强调了 MDK 靶向治疗的潜力。我们假设通过抑制 MDK 可以提高伊立替康的敏感性和整体治疗效果。这一发现鼓励对 MDK 作为治疗靶点进行仔细而积极的研究，以提高结直肠癌患者的治疗效果。版权所有 © 2024。由 Elsevier Inc. 出版。

Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer.We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan.Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan.Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.Copyright © 2024. Published by Elsevier Inc.