High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer
High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer
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DOI：
10.1245/s10434-020-09383-9
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发表时间：
2021-01-03
影响因子：
3.7
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
--
作者：
Nakao, Yosuke;Nakagawa, Shigeki;Baba, Hideo
背景胰腺癌即使在根治性切除后预后也非常差。胰腺癌的治疗选择仍然有限，因此迫切需要新的治疗靶点。我们使用公共数据库搜索胰腺癌预后不良的预测基因，并在患者队列中验证所选基因对生存的影响。方法我们使用公共数据库搜索与早期胰腺癌复发相关的基因。作为验证队列，201名在我们机构接受根治性切除的患者被纳入研究。免疫组织化学(IHC)法检测目的基因的表达。我们使用小干扰RNA评估生长和侵袭性，然后使用基因集浓缩分析进行路径分析。结果从GSE21501中扩增出ARHGEF2基因，该基因具有1年内早期复发的高风险比(HR)。ARHGEF2高表达组的无复发生存期(RFS)和总生存期(OS)均明显低于ARHGEF2低表达组。多因素分析显示，ARHGEF2高表达是影响RFS(HR 1.92)和OS(HR 1.63)的独立预后不良因素。在体外，抑制ARHGEF2导致细胞生长和侵袭力下降。生物信息学分析表明，ARHGEF2的表达与MYC、G2M、E2F和CDC25A的表达有关，提示c-Myc和细胞周期基因与ARHGEF2的高表达有关。IHC显示ARHGEF2与c-Myc的表达呈正相关。结论ARHGEF2的高表达与胰腺癌的细胞周期进展有关，并预示着胰腺癌患者早期复发和预后不良。
Background Pancreatic cancer has an extremely poor prognosis, even after curative resection. Treatment options for pancreatic cancer remain limited, therefore new therapeutic targets are urgently needed. We searched for genes predictive of poor prognosis in pancreatic cancer using a public database and validated the survival impact of the selected gene in a patient cohort. Methods We used a public database to search for genes associated with early pancreatic cancer recurrence. As a validation cohort, 201 patients who underwent radical resection in our institution were enrolled. Expression of the target gene was evaluated using immunohistochemistry (IHC). We evaluated growth and invasiveness using small interfering RNAs, then performed pathway analysis using gene set enrichment analysis. Results We extracted ARHGEF2 from GSE21501 as a gene with a high hazard ratio (HR) for early recurrence within 1 year. The high ARHGEF2 expression group had significantly poorer recurrence-free survival (RFS) and poorer overall survival (OS) than the low ARHGEF2 expression group. Multivariate analysis demonstrated that high ARHGEF2 expression was an independent poor prognostic factor for RFS (HR 1.92) and OS (HR 1.63). In vitro, ARHGEF2 suppression resulted in reduced cell growth and invasiveness. Bioinformatic analysis revealed that ARHGEF2 expression was associated with MYC, G2M, E2F, and CDC25A expression, suggesting that c-Myc and cell cycle genes are associated with high ARHGEF2 expression. IHC revealed a positive correlation between ARHGEF2 and c-Myc expression. Conclusions High ARHGEF2 expression is associated with cell cycle progression, and predicts early recurrence and poor survival in patients with pancreatic cancer.