KHDC4通过激活Notch信号通路促进肝细胞癌上皮间质转化促进肿瘤转移  

Study on KHDC4 enhancing hepatocellular carcinoma epithelial-mesenchymal transition and facilitate tumor metastasis by activating Notch signaling pathway

作　　者：潘勐 张琦 胡光龙 陈鹏 陈晓鹏 Pan Meng;Zhang Qi;Hu Guanglong;Chen Peng;Chen Xiaopeng(Department of Hepatobiliary Surgery,the Second Affiliated Hospital of Wannan Medical College,Wuhu,Anhui 241001,China;Department of Hepatobiliary Surgery,the First Affiliated Hospital of Wannan Medical College,Wuhu,Anhui 241001,China)

机构地区：[1]皖南医学院第二附属医院肝胆外科,安徽芜湖241001 [2]皖南医学院第一附属医院肝胆外科,安徽芜湖241001

出　　处：《齐齐哈尔医学院学报》2025年第8期714-722,共9页Journal of Qiqihar Medical University

基　　金：安徽省自然科学基金面上项目(2108085MH283);皖南医学院重点科研基金项目(WK2022ZF26);皖南医学院第二附属医院“登峰计划”科研项目(DFJH2022012)。

摘　　要：目的探究KHDC4在肝细胞癌(Hepatocellular carcinoma,HCC)中的表达及其对肝癌上皮间质转化(Epithelial-mesenchymal transition,EMT)和转移的促进作用,并解析其潜在机制。方法结合TCGA与GEO数据库,比较KHDC4在肝癌及邻近组织的表达,并通过60例临床HCC样本的免疫组化验证。分析TCGA中371例HCC患者数据,评估KHDC4的预后作用。采用RT-qPCR与Western blotting检测细胞系中KHDC4表达,通过基因操纵调控HCC细胞中KHDC4水平,体外实验(CCK8、迁移侵袭试验)验证其功能,同时分析EMT标志物及Notch信号通路相关分子变化。体内实验构建裸鼠移植瘤模型,评估KHDC4对肿瘤形成的影响。此外,免疫组化分析人HCC组织,探讨KHDC4与细胞标志物表达的关系。结果TCGA与GEO数据库分析均证实HCC中KHDC4表达显著高于癌旁组织(P<0.0001)。临床60例样本验证此趋势,且高表达KHDC4肝癌患者生存期缩短。RT-qPCR与Western blotting显示肝癌细胞系KHDC4表达上调。细胞实验表明,KHDC4敲低抑制肝癌增殖、迁移与侵袭,下调Notch信号并改变EMT标志物;反之,过表达则促进这些恶性特征。裸鼠模型进一步验证KHDC4对肿瘤形成的促进作用。免疫组化分析揭示KHDC4表达与间充质标记物正相关。结论本研究揭示了KHDC4通过激活Notch信号通路促进HCC发生EMT促进肿瘤转移的新机制,有望为肝癌治疗策略的创新提供有力支持。Objective To investigate the expression of KHDC4 in hepatocellular carcinoma(HCC)and its role in promoting epithelial-mesenchymal transition(EMT)and metastasis of HCC,and to analyze the underlying mechanism.Methods TCGA and GEO databases were combined to compare the expression of KHDC4 in HCC and adjacent tissues,and it was verified by immunohistochemistry in 60 clinical HCC samples.The data of 371 patients with HCC in TCGA database were analyzed to evaluate the prognostic role of KHDC4.RT-qPCR and Western blotting were used to detect the expression of KHDC4 in the cell lines,and KHDC4 level in HCC cells was regulated by gene manipulation.In vitro experiments(CCK8,migration and invasion assay)were used to verify the function of KHDC4,and the EMT markers and Notch signaling pathway related molecular changes were analyzed.A nude mouse transplanted tumor model was established in vivo to assess the effect of KHDC4 on tumor formation.In addition,human HCC tissues were analyzed by immunohistochemistry to explore the relationship between KHDC4 and cell marker expression.Results TCGA and GEO database analysis confirmed that KHDC4 expression was significantly higher in liver cancer tissues than in adjacent tissues(P<0.0001).Sixty clinical samples confirmed this trend,and HCC patients with high KHDC4 expression had shorter survival time.RT-qPCR and Western blotting results showed that the expression of KHDC4 in HCC cell line was up-regulated.Cell experiments showed that KHDC4 knockdown inhibited the proliferation,migration and invasion of HCC,down-regulated Notch signaling and changed EMT markers;conversely,overexpression promoted these malignant features.A nude mouse model further verified the effect of KHDC4 on tumor formation.Immunohistochemical analysis revealed that KHDC4 expression was positively correlated with mesenchymal markers.Conclusions This study uncovers a novel mechanism whereby KHDC4 promotes EMT and tumor metastasis in HCC through activation of the Notch signaling pathway,offering promising insights that

关 键 词：肝细胞癌 生物信息学 上皮间质转化 肿瘤转移 

分 类 号：R735.7[医药卫生—肿瘤]