Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung City 824, Taiwan.
Life Sci. 2024 Sep 15;353:122914. doi: 10.1016/j.lfs.2024.122914. Epub 2024 Jul 14.
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.
结直肠癌（CRC）仍然是一个全球性的主要健康问题，尽管化疗和靶向治疗取得了进展，但转移性病例的预后仍然较差。伊立替康是治疗晚期 CRC 的关键药物，但由于耐药性的发展，它面临着挑战。本研究旨在了解结直肠癌中伊立替康耐药的机制。
我们使用 HT29 细胞创建了对伊立替康耐药的细胞系。这些耐药细胞被用于研究 CDK7-MDK 轴的作用。我们进行了批量 RNA 测序，在小鼠体内进行了实验，并分析了患者组织，以研究 CDK7-MDK 轴对细胞对伊立替康的反应的影响。
与亲本细胞相比，对伊立替康耐药的 HT29 细胞（一种重要的结直肠癌药物）表现出明显的表型和分子改变，包括增强的干细胞特征和细胞因子和药物抗性蛋白水平升高。值得注意的是，这些耐药细胞中的 CDK7 表达显著升高，靶向 CDK7 有效降低了它们的存活率和肿瘤生长，增强了伊立替康的敏感性。RNA-seq 分析表明，抑制伊立替康耐药 HT29 细胞中的 CDK7 显著降低了 Midkine (MDK) 的表达。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。
本研究揭示了 CDK7 和 MDK 如何影响结直肠中的伊立替康耐药，并强调了 MDK 靶向治疗的潜力。我们假设抑制 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。
