胸腺上皮肿瘤（TET）是起源于纵隔的罕见肿瘤。 TET中，B2型、B3型胸腺瘤和胸腺癌恶性程度较高，常表现为侵袭和播散。然而，TETs的生物学特性尚未得到深入研究，其侵袭和传播机制尚不清楚。 α-肌动蛋白 4 (ACTN4) 是肌动蛋白结合蛋白的成员，据报道在多种癌症的进展中发挥重要作用。在本研究中，我们研究了ACTN4与TETs恶性潜能特征（例如侵袭和传播）之间的关系。使用Ty-82胸腺癌细胞的体外实验表明，ACTN4的过表达增强了Ty-82细胞的增殖和侵袭能力；相反，ACTN4 的敲除减弱了 Ty-82 细胞的增殖和侵袭潜力。在蛋白质印迹 (WB) 实验中，ACTN4 诱导细胞外信号调节激酶和糖原合酶激酶 3β 的磷酸化，以调节 β-catenin/Slug 通路。此外，对 TET 患者的癌症组织来源的球体进行的 WB 分析显示出与 Ty-82 细胞相似的结果。体内实验表明，ACTN4 的敲除显着抑制了 Ty-82 细胞的传播。使用手术标本对 TET 的原发性和播散性病变进行 WB 和免疫组织化学染色比较，结果显示播散性病变中 ACTN4、β-catenin 和 Slug 蛋白的表达上调。总之，我们的研究表明 ACTN4 与恶性潜在特征相关，例如通过 β-catenin/Slug 途径侵入和传播 TET。© 2024 作者。约翰·威利出版的《癌症科学》

Thymic epithelial tumors (TETs) are rare tumors arising from the mediastinum. Among TETs, thymoma type B2, B3 and thymic carcinoma are highly malignant and often present invasion and dissemination. However, the biological characteristics of TETs have not been thoroughly studied, and their mechanisms of invasion and dissemination are largely unknown. α-Actinin 4 (ACTN4) is a member of actin-binding proteins and reportedly plays important roles in the progression of several cancers. In this study, we investigated the relationship between ACTN4 and characteristics of the malignant potential of TETs, such as invasion and dissemination. In vitro experiments using Ty-82 thymic carcinoma cells revealed that overexpression of ACTN4 enhanced the proliferative and invasive ability of Ty-82 cells; conversely, knockdown of ACTN4 attenuated the proliferative and invasive potential of Ty-82 cells. In western blotting (WB) experiments, ACTN4 induced the phosphorylation of extracellular signal-regulated kinase and glycogen synthase kinase 3β to regulate the β-catenin/Slug pathway. Furthermore, WB analysis of cancer tissue-origin spheroids from patients with TETs showed results similar to those for Ty-82 cells. In vivo experiments showed that the knockdown of ACTN4 significantly suppressed the dissemination of Ty-82 cells. A WB and immunohistochemistry staining comparison of primary and disseminated lesions of TETs using surgical specimens showed upregulated expression of ACTN4, β-catenin, and Slug proteins in disseminated lesions. In summary, our study suggests ACTN4 is associated with malignant potential characteristics such as invasion and dissemination in TETs via the β-catenin/Slug pathway.© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.