Li Meng, Jiang Xia, Wang Guiqi, Zhai Congjie, Liu Ying, Li Hongyan, Zhang Yan, Yu Weifang, Zhao Zengren
Department of General Surgery, The First Hospital of Hebei Medical University, No. 89 Donggang Road, Shijiazhuang, Hebei, China.
The First Department of Colorectal Surgery, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, China.
J Cancer. 2019 Aug 28;10(21):5223-5233. doi: 10.7150/jca.29269. eCollection 2019.
Integrin β4 (ITGB4) has been reported to be involved in carcinomas. Currently, ITGB4 has been characterized in colon cancer, however, its clinical significance is not very clear. In the present study, we utilized the large public datasets from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and collected clinical samples in our center to investigate the transcriptional expressions of ITGB4 in colon cancer, and then explored the associations of ITGB4 with clinicopathological features and overall survival. The statistical analyses suggested that ITGB4 mRNA expressions were up-regulated significantly in colon cancer. High ITGB4 expression was observed to be associated with elder onset age, proximal tumor location, and high microsatellite instability (MSH) status. Further, Kaplan-Meier curves and univariate analysis demonstrated high ITGB4 expression was significantly associated with unfavorable overall survival in colon cancer (HR=1.292, 95%CI=1.084-1.540, P=0.004). And significant association was also found after adjusting the confounding factors including age, gender, and stage (adjusted HR=1.254, 95%CI=1.050-1.497, P=0.012). The annotation of ITGB4 co-expressed genes suggested the pathways including cell growth, positive regulation of cell migration, and apoptotic signaling might be involved in the potential mechanisms of ITGB4 in colon cancer development. The molecular regulation mechanism of ITGB4 ectopic expression in colon cancer was also explored and the results indicated that ITGB4 might be up-regulated by the transcription factor FOSL1 (FOS like 1, AP-1 Transcription Factor Subunit) and its promoter hypomethylation. Our results revealed that ITGB4 might be a therapeutic target and prognosis marker for individual therapy of colon cancer.
整合素β4（ITGB4）已被报道与癌症有关。目前，ITGB4已在结肠癌中得到表征，然而，其临床意义尚不完全清楚。在本研究中，我们利用来自NCBI基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）数据库的大型公共数据集，并在我们中心收集临床样本，以研究ITGB4在结肠癌中的转录表达，然后探讨ITGB4与临床病理特征和总生存期的关联。统计分析表明，ITGB4 mRNA表达在结肠癌中显著上调。观察到高ITGB4表达与发病年龄较大、肿瘤近端位置以及高微卫星不稳定性（MSH）状态相关。此外，Kaplan-Meier曲线和单因素分析表明，高ITGB4表达与结肠癌患者不良的总生存期显著相关（HR=1.292，95%CI=1.084-1.540，P=0.004）。在调整包括年龄、性别和分期等混杂因素后，也发现了显著关联（调整后HR=1.254，95%CI=1.050-1.497，P=0.012）。ITGB4共表达基因的注释表明，包括细胞生长、细胞迁移的正调控和凋亡信号传导等途径可能参与了ITGB4在结肠癌发生发展中的潜在机制。我们还探讨了ITGB4在结肠癌中异位表达的分子调控机制，结果表明ITGB4可能受转录因子FOSL1（FOS样蛋白1，AP-1转录因子亚基）及其启动子低甲基化上调。我们的研究结果表明，ITGB4可能是结肠癌个体化治疗的治疗靶点和预后标志物。
