Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China.
Cancer Med. 2023 May;12(10):11983-11999. doi: 10.1002/cam4.5873. Epub 2023 Mar 31.
Integrins are critical to cancer progression. Integrin alpha 5 (ITGA5) is correlated with the prognosis of cervical cancer patients. However, whether ITGA5 plays an active role in cervical cancer progression or not remains unknown.
ITGA5 protein expression was detected in 155 human cervical cancer tissues by immunohistochemistry. Data from The Cancer Genome Atlas were utilized to identify risk factors for the overall survival of cervical cancer patients and ITGA5-associated differentially expressed genes. Analyses of single-cell RNA-seq based on Gene Expression Omnibus datasets were performed to show the coexpression of ITGA5 and angiogenesis factors. Tube formation assay, 3D spheroid sprout assay, qRT-PCR, Western Blotting, ELISA, and immunofluorescence were conducted to explore the angiogenic function of ITGA5 in vitro and underlying mechanisms.
High ITGA5 level was significantly correlated with increased risk in terms of overall survival and advanced disease stage in cervical cancer patients. ITGA5-associated differentially expressed genes linked ITGA5 to angiogenesis, and immunohistochemistry showed a positive correlation between ITGA5 and microvascular density in cervical cancer tissues. Moreover, tumor cells transfected with ITGA5-targeting siRNA decreased ability to promote endothelial tube formation in vitro. ITGA5/VEGFA coexpression was observed in a tumor cell subpopulation and the decreased endothelial angiogenesis by downregulating ITGA5 could be reversed by VEGFA. Bioinformatics analysis highlighted the PI3K-Akt signaling pathway as downstream of ITGA5. Downregulation of ITGA5 in tumor cells significantly decreased p-AKT and VEGFA levels. Fibronectin (FN1) coated cells or transfected with FN1-targeting siRNA showed fibronectin may play a critical role on ITGA5-mediated angiogenesis.
ITGA5 promotes angiogenesis and possibly be a potential predictive biomarker for poor survival of patients in cervical cancer.
整合素对于癌症的进展至关重要。整合素 α5（ITGA5）与宫颈癌患者的预后相关。然而，ITGA5 是否在宫颈癌的进展中发挥积极作用仍不清楚。
通过免疫组织化学检测 155 例人宫颈癌组织中 ITGA5 蛋白的表达。利用癌症基因组图谱的数据，确定影响宫颈癌患者总生存率和 ITGA5 相关差异表达基因的风险因素。基于基因表达综合数据库的单细胞 RNA-seq 分析显示 ITGA5 与血管生成因子的共表达。进行管形成试验、3D 球体发芽试验、qRT-PCR、Western Blotting、ELISA 和免疫荧光实验，以探讨 ITGA5 在体外的血管生成功能及其潜在机制。
高 ITGA5 水平与宫颈癌患者的总生存率增加和疾病进展有关。ITGA5 相关的差异表达基因将 ITGA5 与血管生成联系起来，免疫组织化学显示 ITGA5 与宫颈癌组织中的微血管密度呈正相关。此外，转染 ITGA5 靶向 siRNA 的肿瘤细胞降低了体外促进内皮管形成的能力。在肿瘤细胞亚群中观察到 ITGA5/VEGFA 共表达，下调 ITGA5 可降低内皮血管生成，而 VEGFA 可逆转这种作用。生物信息学分析突出了 PI3K-Akt 信号通路是 ITGA5 的下游通路。肿瘤细胞中 ITGA5 的下调显著降低了 p-AKT 和 VEGFA 水平。纤连蛋白（FN1）包被细胞或转染 FN1 靶向 siRNA 表明，纤连蛋白可能在 ITGA5 介导的血管生成中发挥关键作用。
ITGA5 促进血管生成，可能是宫颈癌患者生存不良的潜在预测生物标志物。
