DBF4锌指(DBF4)是参与DNA复制和细胞增殖的关键成分。它充当细胞分裂周期7激酶的正调节剂。在这项研究中,我们的研究包括DBF4对肝细胞癌(HCC)进展的影响,并探讨了潜在的机制.我们利用TCGA和GEO等开放访问数据库来分析DBF4与33种不同肿瘤类型之间的关联。我们还进行了免疫组织化学实验以验证DBF4在HCC中的表达。STAD,COAD,READ,PAAD,LGG。此外,我们采用慢病毒转导在HLF和SMMC细胞中敲低DBF4,以及在Huh7细胞中过表达DBF4。随后,我们评估了DBF4对增殖的影响,迁移,和肝癌细胞的侵袭。还进行了RNA测序和KEGG途径富集分析,以确定潜在的途径,通过WB实验进一步验证。最后,途径抑制剂用于挽救实验,以确认DBF4是否通过相关途径对肿瘤细胞发挥其作用.我们的发现表明,DBF4在几乎所有检查的肿瘤中都表现出显着的表达水平,免疫组织化学分析的结果进一步证实了这一点。高DBF4表达与低总生存期(OS)相关,疾病特异性生存率(DSS),无进展间隔(PFI),无病间隔(DFI),大多数肿瘤类型的无复发间隔(RFI),特别是在HCC患者中。体外实验表明,抑制DBF4会损害增殖,迁徙,和肝癌细胞的侵袭能力,而DBF4的过表达促进了这些表型。测序结果表明,DBF4可能通过ERBB信号通路诱导这些变化。进一步的实验验证表明,DBF4激活了ERBB信号通路,导致JNK/STAT的改变,MAPK,和PI3K/AKT信号通路,从而影响增殖,迁徙,和肿瘤细胞的侵袭能力。最后,用ERBB2抑制剂达克替尼处理过表达DBF4的Huh7细胞证明了ERBB2抑制逆转DBF4过表达对增殖的促进作用的能力,迁徙,和肝癌细胞的侵袭能力。DBF4通过促进ERBB信号通路和激活其下游PI3K/AKT在HCC中发挥重要的致癌作用,JNK/STAT3和MAPK信号通路。DBF4可作为HCC患者的预后生物标志物。
DBF4 zinc finger (DBF4) is a critical component involved in DNA replication and cell proliferation. It acts as a positive regulator of the cell division cycle 7 kinase. In this study, our investigation encompassed the impact of DBF4 on hepatocellular carcinoma (HCC) progression and delved into the potential mechanisms. We utilized open-access databases like TCGA and GEO to analyze the association between DBF4 and 33 different tumor types. We also conducted immunohistochemistry experiments to validate the expression of DBF4 in HCC, STAD, COAD, READ, PAAD, and LGG. Furthermore, we employed lentiviral transduction to knockdown DBF4 in HLF and SMMC cells, as well as to overexpress DBF4 in Huh7 cells. Subsequently, we evaluated the impact of DBF4 on proliferation, migration, and invasion of hepatocellular carcinoma cells. RNA sequencing and KEGG pathway enrichment analysis were also conducted to identify potential pathways, which were further validated through WB experiments. Finally, pathway inhibitor was utilized in rescue experiments to confirm whether DBF4 exerts its effects on tumor cells via the implicated pathway. Our findings revealed that DBF4 exhibited significant expression levels in nearly all examined tumors, which were further substantiated by the results of immunohistochemistry analysis. High DBF4 expression was correlated with poor overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), disease-free interval (DFI), relapse-free interval (RFI) in majority of tumor types, particularly in patients with HCC. In vitro experiments demonstrated that inhibition of DBF4 impaired the proliferative, migratory, and invasive abilities of HCC cells, whereas overexpression of DBF4 promoted these phenotypes. Sequencing results indicated that DBF4 may induce these changes through the ERBB signaling pathway. Further experimental validation revealed that DBF4 activates the ERBB signaling pathway, leading to alterations in the JNK/STAT, MAPK, and PI3K/AKT signaling pathways, thereby impacting the proliferative, migratory, and invasive abilities of tumor cells. Lastly, treatment of Huh7 cells overexpressing DBF4 with the
ERBB2 inhibitor dacomitinib demonstrated the ability of
ERBB2 inhibition to reverse the promoting effect of DBF4 overexpression on the proliferative, migratory, and invasive abilities of HCC cells. DBF4 plays a pivotal oncogenic role in HCC by promoting the ERBB signaling pathway and activating its downstream PI3K/AKT, JNK/STAT3, and MAPK signaling pathways. DBF4 may serve as a prognostic biomarker for patients with HCC.