Liu Pan, Xie Lisha, Wu Qiulei, Huang Lin, Liu Xiaoli, Li Wenhan, Cai Jing, Wang Zehua, Yang Ping, Cai Liqiong
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi 832003, China.
Int J Biol Sci. 2024 Apr 8;20(6):2297-2309. doi: 10.7150/ijbs.93667. eCollection 2024.
Tyrosine kinase with immunoglobulin and EGF-like domains 1 (TIE1) is known as an orphan receptor prominently expressed in endothelial cells and participates in angiogenesis by regulating TIE2 activity. Our previous study demonstrated elevated TIE1 expression in cervical cancer cells. However, the role of TIE1 in cervical cancer progression, metastasis and treatment remains elusive. Immunohistochemistry staining for TIE1 and Basigin was performed in 135 human cervical cancer tissues. Overexpressing vectors and siRNAs were used to manipulate gene expression in tumor cells. Colony formation, wound healing, and transwell assays were used to assess cervical cancer cell proliferation and migration . Subcutaneous xenograft tumor and lung metastasis mouse models were established to examine tumor growth and metastasis. Co-Immunoprecipitation and Mass Spectrometry were applied to explore the proteins binding to TIE1. Immunoprecipitation and immunofluorescence staining were used to verify the interaction between TIE1 and Basigin. Cycloheximide chase assay and MG132 treatment were conducted to analyze protein stability. High TIE1 expression was associated with poor survival in cervical cancer patients. TIE1 overexpression promoted the proliferation, migration and invasion of cervical cancer cells , as well as tumor growth and metastasis . In addition, Basigin, a transmembrane glycoprotein, was identified as a TIE1 binding protein, suggesting a pivotal role in matrix metalloproteinase regulation, angiogenesis, cell adhesion, and immune responses. Knockdown of Basigin or treatment with the Basigin inhibitor AC-73 reversed the tumor-promoting effect of TIE1 and . Furthermore, we found that TIE1 was able to interact with and stabilize the Basigin protein and stimulate the Basigin-matrix metalloproteinase axis. TIE1 expression in cervical cells exerts a tumor-promoting effect, which is at least in part dependent on its interaction with Basigin. These findings have revealed a TIE2-independent mechanism of TIE1, which may provide a new biomarker for cervical cancer progression, and a potential therapeutic target for the treatment of cervical cancer patients.
具有免疫球蛋白和表皮生长因子样结构域的酪氨酸激酶1（TIE1）是一种主要在内皮细胞中表达的孤儿受体，通过调节TIE2活性参与血管生成。我们之前的研究表明，TIE1在宫颈癌细胞中的表达升高。然而，TIE1在宫颈癌进展、转移和治疗中的作用仍不清楚。对135例人宫颈癌组织进行了TIE1和基底膜蛋白的免疫组织化学染色。使用过表达载体和小干扰RNA来调控肿瘤细胞中的基因表达。采用集落形成、伤口愈合和Transwell实验来评估宫颈癌细胞的增殖和迁移。建立皮下异种移植瘤和肺转移小鼠模型来研究肿瘤生长和转移。应用免疫共沉淀和质谱技术探索与TIE1结合的蛋白质。采用免疫沉淀和免疫荧光染色来验证TIE1与基底膜蛋白之间的相互作用。进行放线菌酮追踪实验和MG132处理以分析蛋白质稳定性。TIE1高表达与宫颈癌患者的不良生存相关。TIE1过表达促进宫颈癌细胞的增殖、迁移和侵袭，以及肿瘤生长和转移。此外，基底膜蛋白是一种跨膜糖蛋白，被鉴定为TIE1结合蛋白，提示其在基质金属蛋白酶调节、血管生成、细胞黏附和免疫反应中起关键作用。敲低基底膜蛋白或用基底膜蛋白抑制剂AC-73处理可逆转TIE1的促肿瘤作用。此外，我们发现TIE1能够与基底膜蛋白相互作用并使其稳定，刺激基底膜蛋白-基质金属蛋白酶轴。TIE1在宫颈细胞中的表达发挥促肿瘤作用，这至少部分依赖于其与基底膜蛋白的相互作用。这些发现揭示了TIE1不依赖TIE2的机制，这可能为宫颈癌进展提供一种新的生物标志物，并为治疗宫颈癌患者提供潜在的治疗靶点。
