High Expression of Integrin α3 Predicts Poor Prognosis and Promotes Tumor Metastasis and Angiogenesis by Activating the c-Src/Extracellular Signal-Regulated Protein Kinase/Focal Adhesion Kinase Signaling Pathway in Cervical Cancer
High Expression of Integrin α3 Predicts Poor Prognosis and Promotes Tumor Metastasis and Angiogenesis by Activating the c-Src/Extracellular Signal-Regulated Protein Kinase/Focal Adhesion Kinase Signaling Pathway in Cervical Cancer
复制标题
整合素α3的高表达通过激活宫颈癌中的c-Src/细胞外信号调节蛋白激酶/粘着斑激酶信号通路来预测不良预后并促进肿瘤转移和血管生成
DOI：
10.3389/fonc.2020.00036
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发表时间：
2020-02-14
影响因子：
4.7
通讯作者：
Yao, Shuzhong
中科院分区：
文献类型：
--
作者：
Du, Qiqiao;Wang, Wei;Yao, Shuzhong
背景：宫颈癌仍然是女性死亡的主要原因，因为它会转移到远处的组织和器官。整合素参与癌症转移。但整合素α 3是否参与宫颈癌转移尚在研究中。在这项研究中，我们探讨的效果和详细的机制，通过整合素α 3调节宫颈细胞的迁移，侵袭，和angiogenesis.Methods：首先，我们探讨了整合素α 3的mRNA和蛋白质表达水平在宫颈癌细胞系和组织样本从患者。在使用shRNA敲低整合素α 3的表达后，在体外研究宫颈癌细胞的增殖、迁移和侵袭，以及可能涉及的信号通路。此外，测试人脐静脉内皮细胞的管形成、增殖和迁移，以确定其对血管生成的影响。斑马鱼肿瘤迁移和裸鼠肺转移模型用于体内分析。结果：我们检测了142例宫颈癌患者和20例正常宫颈的样本。整合素α 3在患者中高度表达，并预测不良的总生存率和无病生存率。在SiHa细胞中，用整合素α 3 shRNA处理诱导蛋白质粘着斑激酶磷酸化并增强粘着斑。这些事件介导的c-Src和细胞外信号调节蛋白激酶级联的激活。因此，整合素α 3增加SiHa细胞的迁移能力。此外，敲低整合素α 3降低了人脐静脉内皮细胞的管形成、增殖和迁移，以及基质金属蛋白酶9的水平，表明其对血管生成的影响。稳定转染整合素α 3的shRNA降低了SiHa细胞在斑马鱼模型中的迁移能力，并减少了异种移植小鼠模型中的肺转移。结论：整合素α 3招募c-Src/细胞外信号调节蛋白激酶级联反应，导致黏着斑激酶磷酸化。此外，它还调节粘着斑，赋予宫颈癌细胞增强的迁移和侵袭能力，并通过基质金属蛋白酶-9促进血管生成。我们的研究结果可能揭示了宫颈癌转移的机制，并强调整合素α 3作为宫颈癌患者的候选预后生物标志物和治疗靶点。
Background: Cervical cancer remains a leading cause of death in women due to metastasis to distant tissues and organs. Integrins are involved in cancer metastasis. However, whether integrin alpha 3 participates in cervical cancer metastasis is under investigation. In this study, we explored the effect and detailed mechanism through which integrin alpha 3 regulates cervical cell migration, invasion, and angiogenesis.Methods: First, we explored the mRNA and protein expression levels of integrin alpha 3 in cervical cancer cell lines and tissue samples obtained from patients. After knocking down the expression of integrin alpha 3 using shRNA, the proliferation, migration, and invasion of cervical cancer cells, as well as the possible signaling pathways involved, were investigated in vitro. In addition, tube formation, proliferation, and migration of human umbilical vein endothelial cells were tested to identify their effect on angiogenesis. Zebrafish tumor migration and nude mouse lung metastasis models were utilized for the in vivo analysis.Results: We examined samples from 142 patients with cervical cancer and 20 normal cervixes. Integrin alpha 3 was highly expressed in patients and predicted poor overall survival and disease-free survival. In SiHa cells, treatment with integrin alpha 3 shRNA induced the phosphorylation of protein focal adhesion kinase and enhanced focal adhesion. These events were mediated by the activation of c-Src and extracellular signal-regulated protein kinase cascades. Consequently, integrin alpha 3 increased the migratory ability of SiHa cells. In addition, knockdown of integrin alpha 3 decreased the tube formation, proliferation, and migration of human umbilical vein endothelial cells, as well as the levels of matrix metalloproteinase-9, indicating its effect on angiogenesis. Stable transfection with integrin alpha 3 shRNA reduced the migratory ability of SiHa cells in the zebrafish model and diminished lung metastasis in the xenograft mouse model.Conclusion: Integrin alpha 3 recruits the c-Src/extracellular signal-regulated protein kinase cascade, leading to phosphorylation of focal adhesion kinase. Moreover, it regulates focal adhesion, endowing cervical cancer cells with potentiated migratory and invasive ability, and promotes angiogenesis via matrix metalloproteinase-9. Our findings may shed light on the mechanism involved in cervical cancer metastasis and highlight integrin alpha 3 as a candidate prognostic biomarker and therapeutic target in patients with cervical cancer.