Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target./n

中文翻译：

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KIF11通过ERBB2/PI3K/AKT信号通路促进胆囊癌细胞增殖

增殖是胆囊癌的重要标志之一，胆囊癌是一种相对罕见但致命的恶性肿瘤。本研究旨在探讨候选hub基因对胆囊癌增殖和肿瘤发生的生物学影响和分子机制。我们分析了差异表达的基因以及这些基因与 MKI67 之间的相关性，并表明 KIF11 是胆囊癌 (GBC) 增殖的主要上调调节因子之一。基因本体、基因集富集分析和KEGG通路分析表明，KIF11可能通过ERBB2/PI3K/AKT信号通路促进GBC细胞增殖。功能获得和功能丧失测定表明，KIF11 在体外调节 GBC 细胞周期和癌细胞增殖。GBC细胞表现出G2M期细胞周期停滞，用 KIF11 的特异性抑制剂 Monastrol 处理后细胞增殖和克隆形成能力降低。异种移植模型显示 KIF11 在体内促进 GBC 生长。拯救实验表明，KIF11 诱导的 GBC 细胞增殖依赖于 ERBB2/PI3K/AKT 通路。此外，我们发现 H3K27ac 信号在 UCSC 基因组浏览器数据库中的 KIF11 启动子区域中富集。差异表达分析表明，EP300是一种修饰H3K27ac信号的主要组蛋白乙酰转移酶，在胆囊癌中高表达，相关分析表明EP300在几乎所有癌症类型中都与KIF11呈正相关。我们进一步发现，在组蛋白乙酰化抑制剂治疗后，KIF11 以剂量依赖性和时间依赖性方式显着下调。目前的结果强调高 KIF11 表达通过 ERBB2/PI3K/AKT 信号通路促进 GBC 细胞增殖。这些发现可能有助于加深我们对 GBC 癌症发展和新诊断和治疗靶点开发的潜在机制的理解。/n