ACTN4 is associated with the malignant potential of thymic epithelial tumors through the β-catenin/Slug pathway

Sep 22, 2026

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Thymic epithelial tumors (TETs) are uncommon mediastinal malignancies in which thymoma type B2/B3 and thymic carcinoma show high malignancy, invasion, and dissemination. Their underlying mechanisms remain unclear. The study evaluates whether α-Actinin 4 (ACTN4) influences malignant behaviors of TETs. Ty-82 thymic carcinoma cells show increased proliferation and invasiveness after ACTN4 overexpression and decreased activity after ACTN4 knockdown. ACTN4 activates signaling regulating the β-catenin/Slug pathway, supported by spheroid and in vivo dissemination suppression, with higher ACTN4, β-catenin, and Slug in disseminated lesions.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Keywords

Abbreviations

Introduction

Overview of thymic epithelial tumors

Current treatment and need for new options

Rationale for studying ACTN4 and β-catenin/Slug

Role of Slug and β-catenin/Slug pathway

DOI: 10. 1111/cas.16313 OR I G I NAL ART I C L E ACTN4 is associated with the malignant potential of thymic epithelial tumors through the β-catenin/Slug pathway Hideki Nagata1 | Soichiro Funaki1 | Kenji Kimura1 | Eriko Fukui1 | Toru Kimura1 | Takashi Kanou1 | Naoko Ose1 | Eiichi Morii2 | Yasushi Shintani1 1Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Japan 2Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan Correspondence Soichiro Funaki, Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan. Email: [so-funaki@hyo-med.ac.jp](so-funaki@hyo-med.ac.jp) Abstract 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. K E Y WO R D S ACTN4, dissemination, Slug, thymic carcinoma, thymoma Abbreviations: ACTN4, α-Actinin 4; CTOS, cancer tissue–origin spheroid; EMT, epithelial–mesenchymal transition; IHC, immunohistochemistry; KD, knockdown; OE, overexpression; TETs, thymic epithelial tumors; WB, western blotting. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Author(s) . Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 1 | INTRODUCTION Thymic epithelial tumors are the most common malignancy arising in the mediastinum.1 TETs are rare, accounting for only 0. 2%– 1. 5% of malignant tumors.2 TETs include thymoma and thymic carcinoma. The majority of TETs are thymomas, whereas thymic carcinoma accounts for 10%–20% of TETs.3 Thymoma is further divided into types A, AB, B1, B2, and B3 according to the World Health Organization classification.4 TETs are broadly classified into two categories according to malignancy: low grade and high grade. Low-grade TETs include types A, AB, and B1 thymoma, and high-grade TETs include types B2 and B3 thymoma, as well as thymic carcinoma.1,5 Surgery, chemotherapy, and radiation therapy are the standard treatments for TETs.6 The complete surgical resection is a favorable prognostic factor for TETs.7,8 Eve

FAQs

What is the main focus of the study regarding ACTN4 and TETs?

The study investigates how ACTN4 relates to the malignant potential of thymic epithelial tumors, particularly invasion and dissemination, through the β-catenin/Slug pathway.

How do ACTN4 overexpression and knockdown affect Ty-82 thymic carcinoma cells?

Overexpression of ACTN4 enhances the proliferative and invasive abilities of Ty-82 cells, while knockdown of ACTN4 attenuates these malignant properties.

What evidence supports the role of the β-catenin/Slug pathway?

Western blotting shows ACTN4 induces phosphorylation events that regulate the β-catenin/Slug pathway, and analyses of patient-derived cancer tissue–origin spheroids and disseminated lesions show consistent related protein changes.

Sep 22, 2026

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