Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China.
Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P.R. China.
FASEB J. 2024 Sep;38(17):e70045. doi: 10.1096/fj.202401427R.
Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor-β1 (TGF-β1) drives epithelial- mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF-β1 in ovarian cancer and its role in reversing TGF-β1-induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5-ethynyl-2-deoxyuridine, colony-forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF-β1 was investigated using qRT-PCR and enzyme-linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co-immunoprecipitation. The results revealed that TIPE2 protein was significantly down-regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF-β1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF-β1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies.
上皮性卵巢癌是致命的妇科恶性肿瘤，其特征是高转移。转化生长因子-β1（TGF-β1）驱动上皮-间质转化（EMT），这是肿瘤转移的关键过程。肿瘤坏死因子-α诱导蛋白 8（TNFAIP8）样 2（TIPE2）作为先天和适应性免疫的负调节剂，涉及多种癌症。然而，其与卵巢癌中 TGF-β1 的关系及其在逆转 TGF-β1 诱导的 EMT 中的作用尚不清楚。本研究使用定量 RT-PCR（qRT-PCR）、western blot 和免疫组织化学检测 TIPE2 mRNA 和蛋白表达。通过 5-乙炔基-2-脱氧尿苷、集落形成、Transwell 迁移和侵袭测定评估 TIPE2 过表达和敲低对上皮性卵巢癌细胞增殖、迁移和侵袭的影响。使用 qRT-PCR 和酶联免疫吸附试验研究 TIPE2 与 TGF-β1 之间的关系，通过共免疫沉淀鉴定 TIPE2 与 Smad2 之间的相互作用。结果表明，TIPE2 蛋白在上皮性卵巢癌组织中显著下调，并与肿瘤的病理类型、患者年龄、肿瘤分化程度和 FIGO 分期相关。TIPE2 和 TGF-β1 在人卵巢癌细胞的进展过程中似乎起着相反的作用。此外，TIPE2 通过与 Smad2 在体外或腹膜转移模型中结合，抑制卵巢癌细胞的转移和 EMT。因此，这些发现表明 TIPE2 通过调节 TGF-β1/Smad2/EMT 信号通路在上皮性卵巢癌转移中发挥关键抑制作用，可能成为卵巢癌的潜在靶点，为未来的诊断和治疗策略提供重要方向。
