文章：

靶向MCM10破坏癌症干性并对抗肝细胞癌中的索拉非尼耐药

Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma 

原文发布日期：2025-08-01 

英文摘要：

Hepatocellular carcinoma (HCC) is the most prevalent primary malignant tumor, with sorafenib as the main treatment for advanced cases. However, the development of resistance to sorafenib, often driven by cancer stemness, significantly limits its therapeutic efficacy. Minichromosome maintenance complex component 10 (MCM10), a critical regulator of DNA replication and tumor progression, has been implicated in cancer stemness and therapeutic resistance. This study utilized datasets from TCGA and ICGC alongside in vitro and vivo experiments on clinical HCC tissues and sorafenib-resistant cell lines to evaluate MCM10’s role in HCC. The Connectivity Map (CMap) was employed to identify TW-37, a potential gene silencing agent targeting MCM10 transcription. The effects of TW-37 on MCM10 expression, cancer stemness, and sorafenib sensitivity were assessed. Elevated MCM10 expression was observed in sorafenib-resistant HCC cell lines and was associated with poor patient outcomes. MCM10 knockout diminished cancer stemness and restored sorafenib sensitivity in resistant cells. Furthermore, TW-37, identified via CMap, effectively downregulated MCM10, reduced cancer stemness, and enhanced sorafenib efficacy, offering a promising therapeutic approach. MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients. 

摘要翻译：

肝细胞癌（HCC）是最常见的原发性恶性肿瘤，晚期病例主要采用索拉非尼治疗。然而，由肿瘤干性驱动的索拉非尼耐药性显著限制了其治疗效果。微小染色体维持复合物组分10（MCM10）作为DNA复制和肿瘤进展的关键调控因子，已被证实与肿瘤干性和治疗耐药性相关。本研究利用TCGA和ICGC数据集，结合临床HCC组织和索拉非尼耐药细胞系的体外及体内实验，评估MCM10在HCC中的作用。通过连通性图谱（CMap）筛选出靶向MCM10转录的潜在基因沉默剂TW-37，并评估了TW-37对MCM10表达、肿瘤干性及索拉非尼敏感性的影响。结果显示：索拉非尼耐药HCC细胞系中MCM10表达升高，且与患者不良预后相关；敲除MCM10可降低肿瘤干性并恢复耐药细胞对索拉非尼的敏感性；经CMap鉴定的TW-37能有效下调MCM10表达、减弱肿瘤干性并增强索拉非尼疗效，为此提供了一种潜在治疗策略。MCM10在促进HCC肿瘤干性和索拉非尼耐药中起关键作用，使用TW-37靶向MCM10转录可作为克服索拉非尼耐药、改善HCC患者治疗效果的新策略。

原文链接：

Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma