多数据库分析ARHGAP44在结直肠癌中的表达及临床意义

Multi-database analysis of the expression and clinical significance of ARHGAP44 in colorectal cancer

摘要:

目的：探讨多个数据集中结直肠组织的Rho GTP酶活化蛋白44（Rho GTPase activating protein 44，ARHGAP44）表达情况及其与结直肠癌临床病理特征和预后的关系。方法：利用基因表达汇编（the gene expression omnibus，GEO）及癌症和肿瘤基因表达图谱（the cancer genome atlas，TCGA）数据集汇总结直肠癌相关数据，分析ARHGAP44表达及其与结直肠癌临床病理学的关系，用Kaplan-Meier分析和Cox回归模型评价其预后价值。采用RT-qPCR方法检测临床样本中ARHGAP44基因表达情况，之后使用基因集富集分析（gene set enrichment analysis，GSEA）预测通路，并使用单样本基因集富集分析（single-sample gene-set enrichment analysis，ssGSEA）算法，计算ARHGAP44与免疫细胞浸润之间的关联。结果：在TCGA、GEO数据集及临床样本中，ARHGAP44表达在肿瘤中降低（P＜0.001），且与T分期及TNM分期有关（P＜0.05）。ARHGAP44的低表达是结直肠癌患者总体生存（overall survival，OS）的独立危险因素（HR=0.44，P=0.02）。GSEA结果显示，ARHGAP44高表达样本中富集了结直肠癌通路、Notch通路、T细胞受体、B细胞受体等基因集。ARHGAP44的表达与macrophages、T helper cells、肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes，TIL）和typeⅠIFNresponse等免疫信号成负相关（cor=-0.35、-0.37、-0.33、-0.35、-0.23、-0.32，P=0.008、0.006、0.027、0.021、0.041、0.021）。结论：ARHGAP44的表达在结直肠癌中被下调，可作为独立的预后生物标记物，且在肿瘤免疫学中具有潜在作用。

Abstract:

Objective：To investigate the expression of Rho GTPase activating protein 44（ARHGAP44） in colorectal tissue and its relationship with the clinicopathological characteristics and prognosis of colorectal cancer in multiple data sets. Methods：With the use of the gene expression omnibus（GEO） and the cancer genome atlas（TCGA） cohorts，we summarized the expression of ARHGAP44 and its relationship with clinicopathological characteristics of colorectal cancer，evaluated the prognostic value by the Cox regression model and Kaplan-Meier curve. The mRNA expression of ARHGAP44 was validated in clinical samples by RT-qPCR. And gene set enrichment analysis（GSEA） was used to predict the pathway. Using the ssGSEA（single-sample gene-set enrichment analysis） algo－rithm，the association between ARHGAP44 and immune cell infiltration was calculated. Results：In TCGA，GEO datasets and clinical samples，the ARHGAP44 expressions were reduced in tumor tissues（P<0.001），and related to T stage and TNM stage（P<0.05）. The low expression of ARHGAP44 showed an independent risk factor for OS（overall survival）of colorectal cancer patients（HR=0.44，P=0.02）. GSEA results showed that the high expression samples of ARHGAP44 were rich in colorectal cancer pathway，Notch pathway，T cell receptor pathway，B cell receptor pathway and other gene sets. The expression of ARHGAP44 was negatively correlated with the infiltration levels of macrophages，T helper cells，TIL（tumor-infiltrating lymphocytes） and typeⅠIFNresponse（cor=-0.35，-0.37，-0.33，-0.35，-0.23 and -0.32，P=0.008，0.006，0.027，0.021，0.041 and 0.021）. Conclusion：The expression of ARHGAP44 is down-regulated in colorectal cancer，which can be used as an independent prognostic biomarker for survival，and has a potential role in tumor immunology.