FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression
FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression
复制标题
FOXM1通过调节KIF4A表达促进肝细胞癌进展
DOI：
10.1186/s13046-019-1202-3
复制
发表时间：
2019-05-09
影响因子：
11.3
通讯作者：
Luo, Shiwen
中科院分区：
文献类型：
--
作者：
Hu, Guohui;Yan, Zhengwei;Luo, Shiwen
Forkhead box M1(FOXM1)是叉头盒蛋白超家族中的一个与增殖相关的转录因子，包括FOXM1a、b、c和d四种异构体。FOXM1与肝细胞癌的进展有关，但其潜在的分子机制尚不清楚。本研究旨在阐明FOXM1介导的肝细胞癌进展的分子基础。方法利用生物信息学分析方法寻找预测肝癌增殖的差异表达基因。Western blotting和免疫组织化学证实FOXM1和KIF家族成员(KIF)4A在肝癌组织中表达。Kaplan-Meier生存分析分析FOXM1和KIF4A对肝癌的临床影响。通过细胞生物学实验研究了FOXM1对KIF4A表达的调节作用。通过染色质免疫沉淀和荧光素酶实验分析KIF4A与FOXM1的相互作用。通过一系列实验探讨FOXM1/KIF4A在肝细胞癌发展过程中的作用，如细胞增殖、细胞生长、细胞活力和细胞周期等。结果FOXM1和KIF4A在人原发性肝癌组织中高表达，与配对的癌旁正常肝组织相比，是肝癌复发和生存期缩短的重要危险因素。我们发现在四种异构体中，KIF4A主要受FOXM1c的调控，进一步确定KIF4A是FOXM1c的直接下游靶点。抑制FOXM1使KIF4A在肝癌细胞中的表达降低，而其过表达则相反。FOXM1诱导的肝癌细胞增殖依赖于KIF4A表达的增加，因为KIF4A基因敲除了FOXM1诱导的肝癌细胞在体内外的增殖。结论FOXM1-KIF4A轴介导了人肝癌的进展，是一种潜在的肝癌治疗靶点。
BackgroundForkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression.MethodsBioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth.ResultsFOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo.ConclusionThe FOXM1–KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.