Ren Ningxin, Chen Hongxia, Huang Ying, Jin Jing, Zhang Shaosen, Yan Ruoqing, Li Mengjie, Zheng Linlin, Zou Shuangmei, Li Yexiong, Tan Wen, Lin Dongxin
State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China.
Cancer Biol Med. 2025 Apr 8;22(3):266-83. doi: 10.20892/j.issn.2095-3941.2024.0540.
Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment. We previously reported that high murine double minute 1 () expression in patients with rectal cancer is linked to a favorable chemoradiation response. In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer (CRC) patients was evaluated.
Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation. RNA sequencing revealed that MDM1 regulates tumor protein 53 () expression and apoptosis. A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression. The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated.
Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker. The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression. MDM1 affected p53 expression, thereby regulating apoptosis. MDM1 overexpression limited YBX1 binding to promoter, regulated expression, and rendered CRC cells more sensitive to chemoradiation. In CRC cells with low MDM1 expression, a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy.
The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways, which is the basis for the underlying molecular mechanism, and serves as a possible predictive marker for chemoradiotherapy prognosis.
识别可预测放化疗疗效和预后的生物标志物对于个体化临床治疗至关重要。我们之前报道过，直肠癌患者中高表达的鼠双微体1（MDM1）与良好的放化疗反应相关。在本研究中，评估了MDM1在结直肠癌（CRC）患者放化疗反应中的作用。
采用集落形成和细胞增殖试验以及异种移植模型来确定MDM1表达是否影响CRC细胞对放化疗的敏感性。RNA测序显示MDM1调节肿瘤蛋白53（p53）的表达和细胞凋亡。进行了一系列分子生物学实验以确定MDM1如何影响p53表达。评估了靶向细胞凋亡的抑制剂对MDM1基因敲除细胞的作用。
基因表达谱分析显示MDM1是一种潜在的放化疗敏感性标志物。MDM1基因敲除后CRC细胞对放化疗的敏感性降低，而MDM1过表达后敏感性增加。MDM1影响p53表达，从而调节细胞凋亡。MDM1过表达限制了YBX1与p53启动子的结合，调节p53表达，并使CRC细胞对放化疗更敏感。在MDM1表达低的CRC细胞中，诱导细胞凋亡的抑制剂与放化疗联合使用可恢复对癌症治疗的敏感性。
当前研究表明，MDM1表达通过影响p53和细胞凋亡途径来影响CRC细胞对放化疗的敏感性，这是潜在分子机制的基础，并且可作为放化疗预后的一种可能的预测标志物。
