Object: A large number of studies have suggested that stemness is an essential mechanism for drug resistance, metastasis and relapse in hepatocellular carcinoma (HCC). The aim of this study was to determine the impact of MCM2 on stemness and identify potential mechanisms that complement the stemness regulatory network in HCC. Methods: MCM2 expression features and prognostic significance were analyzed in multiple cohorts, including TCGA LIHC dataset, GSE14520 dataset, Guangxi cohort, and GSE76427 dataset. Stemness-related molecules and phenotypes were examined to evaluate the impact of MCM2 on stemness. The expression levels of key molecules of the hippo signaling pathway together with downstream target genes were examined to evaluate the effect of MCM2 on hippo signaling. This was further demonstrated by rescue experiments with hippo signaling pathway inhibitors (super-TDU). Sorafenib-resistant cells were constructed to assess the effect of MCM2 on drug resistance. A xenotransplantation model of nude mice was constructed to validate the role of MCM2 in vivo. Results: MCM2, which is expressed at higher levels in HCC tissue than in normal liver tissues, is a good indicator for distinguishing tumor tissues from normal liver tissues and can help differentiate HCC patients at different BCLC stages. The annotation of the differentially expressed genes in the MCM2 high and low expression groups indicated that MCM2 may be associated with the hippo signaling pathway. In addition, the expression of MCM2 in HCC tissues was correlated with the expression of YAP1/TAZ, which are key molecules of the hippo signaling pathway. It indicated that manipulation of MCM2 expression affects hippo signaling and stemness, while the inhibition of hippo signaling significantly reversed the effect of MCM2 on stemness. Disruption of MCM2 expression significantly elevated the sensitivity of sorafenib-resistant cells to sorafenib, as evidenced by the decrease in IC50 and diminished sphere-forming capacity. The in vivo assays showed that MCM2 effectively enhanced the efficacy of sorafenib. Conclusion: MCM2 is a good prognostic marker. MCM2 enhances the stemness of HCC cells by affecting the Hippo signaling pathway, while the downregulation of MCM2 inhibits resistance towards sorafenib.

目的：大量研究表明，干细胞性是肝细胞癌（HCC）耐药、转移和复发的重要机制。本研究的目的是确定 MCM2 对干性的影响，并确定补充 HCC 中干性调节网络的潜在机制。方法：在多个队列中分析 MCM2 表达特征和预后意义，包括 TCGA LIHC 数据集、GSE14520 数据集、广西队列和 GSE76427 数据集。检查干性相关分子和表型以评估 MCM2 对干性的影响。检查河马信号通路关键分子和下游靶基因的表达水平，以评估MCM2对河马信号通路的影响。河马信号通路抑制剂 (super-TDU) 的救援实验进一步证明了这一点。构建索拉非尼耐药细胞以评估 MCM2 对耐药性的影响。构建裸鼠异种移植模型以验证MCM2在体内的作用。结果：MCM2在HCC组织中的表达水平高于正常肝组织，是区分肿瘤组织与正常肝组织的良好指标，有助于区分不同BCLC分期的HCC患者。MCM2高表达组和低表达组中差异表达基因的注释表明MCM2可能与河马信号通路有关。此外，HCC组织中MCM2的表达与河马信号通路关键分子YAP1/TAZ的表达相关。这表明操纵 MCM2 表达会影响 hippo 信号传导和干性，而抑制 hippo 信号会显着逆转 MCM2 对干性的影响。MCM2 表达的中断显着提高了索拉非尼耐药细胞对索拉非尼的敏感性，IC50 降低和球形成能力降低就证明了这一点。体内试验表明，MCM2 有效地增强了索拉非尼的疗效。结论：MCM2是一个很好的预后标志物。MCM2 通过影响 Hippo 信号通路增强 HCC 细胞的干性，而 MCM2 的下调抑制对索拉非尼的耐药性。MCM2 表达的中断显着提高了索拉非尼耐药细胞对索拉非尼的敏感性，IC50 降低和球形成能力降低就证明了这一点。体内试验表明，MCM2 有效地增强了索拉非尼的疗效。结论：MCM2是一个很好的预后标志物。MCM2 通过影响 Hippo 信号通路增强 HCC 细胞的干性，而 MCM2 的下调抑制对索拉非尼的耐药性。MCM2 表达的中断显着提高了索拉非尼耐药细胞对索拉非尼的敏感性，IC50 降低和球形成能力降低就证明了这一点。体内试验表明，MCM2 有效地增强了索拉非尼的疗效。结论：MCM2是一个很好的预后标志物。MCM2 通过影响 Hippo 信号通路增强 HCC 细胞的干性，而 MCM2 的下调抑制对索拉非尼的耐药性。