膜联蛋白A5在胰腺癌中的预后意义及机制的生物信息学分析

doi:10.7659/j.issn.1005-6947.2022.09.008

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膜联蛋白A5在胰腺癌中的预后意义及机制的生物信息学分析
DOI:
                        10.7659/j.issn.1005-6947.2022.09.008
                    
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作者单位:1.徐州医科大学附属连云港医院，肝胆外科，江苏 连云港 222001;2.徐州医科大学附属连云港医院，病理科，江苏 连云港 222001
作者简介:仲成成，徐州医科大学附属连云港医院硕士研究生，主要从事肝胆外科方面的研究。
通信作者:王仲，Email: 18961326366@189.cn
基金项目:国家自然科学基金资助项目（81900772）；江苏省连云港市卫生计生科技计划基金资助项目（201906，202102）；江苏省连云港市科技计划基金资助项目（SF2119）；南京医科大学康达学院第一附属医院博士科研启动基金资助项目（BS202003、KD2021KYJJZD024）。

Bioinformatics analysis of prognostic significance and mechanism of annexin A5 in pancreatic cancer

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1.Department of Hepatobiliary Surgery, the Affiliated Lianyungang Hospital of Xuzhou Medical University. Lianyungang, Jiangsu 222001, China;2.Department of Pathology, the Affiliated Lianyungang Hospital of Xuzhou Medical University. Lianyungang, Jiangsu 222001, China

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摘要:

背景与目的 胰腺癌是一种诊断较晚、预后差的侵袭性疾病，对于胰腺癌的分子机制研究对改善胰腺癌患者的预后具有重要意义。膜联蛋白A5（ANXA5）与人类肿瘤的发生与发展关系密切，但ANXA5与胰腺癌患者预后的关系及具体机制尚不十分清楚。本研究通过生物信息学分析结合实验验证探讨ANXA5的表达与胰腺癌预后的关系及其作用机制。方法从TCGA和GEO数据库（GSE15471、GSE16515、GSE21501）下载胰腺癌转录组及临床数据，利用R包分析GEO数据库中ANXA5基因在胰腺癌组织与癌旁正常组织的表达情况，并利用GEPIA在线网站分析TCGA数据库中胰腺癌患者组织与GTEx数据库中正常组织ANXA5基因表达情况。采用Kaplan-Meier的方法分析ANXA5的表达水平对胰腺癌患者总生存时间的影响，然后单因素及多因素Cox分析判断胰腺癌相关危险因素，并利用GSEA分析ANXA5在胰腺癌中可能的信号通路并分析其相关性。最后采用免疫组织化学法检测49例胰腺癌组织和癌旁组织中ANXA5的表达，并分析其与预后及胰腺癌临床病理特征的关系。结果数据库分析显示，在GSE15471与GSE16515数据集，以及TCGA数据库中ANXA5在胰腺癌组织中的均表达明显升高（均P<0.05）；在GSE21501数据集与TCGA数据库中ANXA5高表达的患者总体生存期明显短于低表达患者（均P<0.05）；TCGA中ANXA5表达是胰腺癌患者预后的独立危险因素（HR=1.819，95% CI=1.058~3.126，P=0.03）；ANXA5基因与胰腺癌TGF-β通路及肿瘤上皮-间质转化（EMT）高度相关。胰腺癌组织样本分析结果显示，ANXA5的表达明显高于癌旁组织（P<0.001），且此基因高表达预示着较差的预后（P=0.008 2）；ANXA5表达是胰腺癌患者预后的独立危险因素（HR=3.06，95% CI=1.046~8.952，P=0.041）；ANXA5的表达与肿瘤临床分期（P=0.000 94）及淋巴结转移（P<0.001）明显相关。结论 ANXA5在胰腺癌中表达升高，其高表达是胰腺癌患者预后的危险因素，其机制可能是通过TGF-β通路及EMT进程促进胰腺癌发展有关。

Abstract:

Background and Aims Pancreatic cancer is an invasive disease with a late diagnosis and poor prognosis. The studies on the molecular mechanism of pancreatic cancer are of great significance in improving the prognosis of patients with pancreatic cancer. Annexin A5 (ANXA5) is closely related to the occurrence and development of human tumors, but the association of ANXA5 with the prognosis and its mechanism are not very clear. Therefore, this study was conducted to investigate the relationship between the expression of ANXA5 and the prognosis of pancreatic cancer and its action mechanism by bioinformatics analysis combined experimental verification.Methods The transcriptome and clinical data of pancreatic cancer were downloaded from TCGA and GEO databases (GSE15471, GSE16515, GSE21501). The expression of ANXA5 gene in pancreatic cancer tissue and adjacent normal tissue in GEO database was analyzed by R packet, and the expression of ANXA5 gene in pancreatic cancer tissue in TCGA database and normal tissue in GTEx database was analyzed by GEPIA online website. The effect of ANXA5 expression on the overall survival time of patients with pancreatic cancer was analyzed by Kaplan-Meier method, and the risk factors of pancreatic cancer were determined by univariate and multivariate Cox analysis. The possible signal pathway of ANXA5 in pancreatic cancer and its correlation were analyzed using GSEA. Finally, immunohistochemical method was used to detect the expression of ANXA5 in 49 cases of pancreatic cancer and adjacent tissues, and its relationship with prognosis and clinicopathologic features of pancreatic cancer was analyzed.Results The results of database analysis showed that ANXA5 expressions were significantly increased in pancreatic cancer tissues in GSE15471 and GSE16515 data sets as well as in TCGA database (all P<0.05); the overall survival time of patients with high expression of ANXA5 was significantly shorter than that of patients with its low expression in either GSE21501 data set or TCGA database (both P<0.05); the expression of ANXA5 was an independent risk factor for the prognosis of pancreatic cancer patients in TCGA (HR=1.819, 95% CI=1.058-3.126, P=0.03); ANXA5 gene was highly correlated with both TGF-β pathway and epithelial-mesenchymal transition (EMT) in pancreatic cancer. The results of analysis of the pancreatic cancer tissue samples showed that the expression of ANXA5 in pancreatic cancer was significantly higher than that in adjacent tissue (P<0.001), and the high expression of this gene predicted a poor prognosis (P=0.008 2); the expression of ANXA5 was an independent risk factor for the prognosis of pancreatic cancer patients in TCGA (HR=3.06, 95% CI=1.046-8.952, P=0.041); the expression of ANXA5 was significantly associated with clinical stage (P=0.000 94) and lymph node metastasis (P<0.001).Conclusion The expression of ANXA5 is increased in pancreatic cancer, and its high expression is a risk factor for the prognosis of patients with pancreatic cancer. The mechanism may be associated with its promoting the development of pancreatic cancer through TGF-β pathway and EMT process.

表 1 ANXA5表达与胰腺癌患者临床特征的关系[n（%）]Table 1 Relationship between ANXA5 expression and clinical characteristics of patients with pancreatic cancer [n (%)]

图1 ANXA5在胰腺癌组织与正常组织的表达情况 A：GSE15471；B：GSE16515；C：TCGA；D：49例样本表达情况；E-F：免疫组化检测ANXA5的表达Fig.1 Expressions of ANXA5 in pancreatic cancer tissues and normal tissues in GSE database and TCGA database A: GSE15471; B: GSE16515; C: TCGA; D: Expression of ANXA5 in the 49 samples; E-F: Immunohistochemical staining for ANXA5 expression

图2 ANXA5表达与预后的关系 A：GSE21501中Kaplan-Meier生存率曲线；B：TCGA中Kaplan-Meier生存率曲线；C：49例样本的Kaplan-Meier生存率曲线Fig.2 Relationship between ANXA5 expression and prognosis A: Kaplan-Meier survival curve in GSE21501; B: Kaplan-Meier survival curve in TCGA; C: Kaplan-Meier survival curve of the 49 samples

图3 GSE21501与TCGA中单多因素Cox回归分析及49例样本中ANXA5表达与临床病理参数的关系 A：GSE21501中单多因素Cox回归分析；B：TCGA中单多因素Cox回归分析；C：49例样本中单多因素Cox回归分析；D-I：49例样本中ANXA5表达与临床病理参数的关系Fig.3 Univariate and multivariate Cox regression analysis of TCGA and GSE21501 and the relationship between ANXA5 expression and clinicopathological parameters in 49 samples A: Univariate and multivariate Cox regression analysis in GSE21501; B: Univariate and multivariate Cox regression analysis in TCGA; C: Univariate and multivariate Cox regression analysis in the 49 samples; D-I: The relationship between ANXA5 expression and clinicopathologic parameters in the 49 samples

图4 GSEA富集分析中TGF-β通路情况 A：GSE21501；B：TCGAFig.4 Enrichment analysis of the TGF-β pathway in GSEA A: GSE21501; B: TCGA

图5 ANXA5基因与TGF-β通路及EMT相关基因的相关性热图 A：GSE21501；B：TCGAFig.5 Heat map of the relationship of the ANXA5 gene with the TGF-β pathway and EMT related genes A: GSE21501; B: TCGA