BATF2 inhibits the stem cell-like properties and chemoresistance of gastric cancer cells through PTEN/AKT/β-catenin pathway

Sep 21, 2026

Gastric cancer is a major cause of cancer mortality, and cancer stem cells drive progression and resistance to chemotherapy, limiting the effectiveness of conventional treatment. This study evaluates how the tumor suppressor BATF2 modulates cancer stem cell-like phenotypes and drug response. Single-cell RNA sequencing and cellular, spheroid, organoid, and in vivo tumor assays measure BATF2 expression, 5-Fu sensitivity, transporter activity, and signaling pathway regulation. BATF2 enhances 5-Fu responsiveness by suppressing ABCG2 and stabilizing PTEN to inhibit AKT, reducing nuclear β-catenin and stem marker expression. The findings link BATF2/PTEN/AKT/β-catenin signaling to diminished chemoresistance and suggest a therapeutic strategy targeting BATF2 to improve gastric cancer outcomes.

LanguageEnglish

CategoryResearch & Report

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Pages16

Reading Time40 min

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Abstract

Background

Methods

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Introduction

Ivyspring International Publisher Theranostics 2024; 14(18): 7007-7022. doi: 10.7150/thno.98389 Research Paper BATF2 inhibits the stem cell-like properties and chemoresistance of gastric cancer cells through PTEN/AKT/β-catenin pathway Longlong Cao1,2,3†􀀍, Kai Weng1,2,3†, Lujie Li1,2,3†, Guangtan Lin1,2,3†, Yuxuan Zhao1,2,3†, Youxin Gao1,2,3, Xiaobo Huang1,2,3, Qiyue Chen1,2,3, Jiabin Wang1,2,3, Chaohui Zheng1,2,3, Changming Huang1,2,3, Jianwei Xie1,2,3􀀍, Ping Li1,2,3􀀍 1. Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P. R. China. 2. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, Fujian 350001, P. R. China. 3. Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian 350001, P. R. China. †These authors contributed equally to this work. 􀀍 Corresponding authors: Ping Li, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001 Fujian Province, [China. E-mail: pingli811002@163.com](China. E-mail: pingli811002@163.com); Longlong Cao, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001 Fujian Province, China. E-mail: [1291821982@qq.com](1291821982@qq.com); Jianwei Xie, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001 Fujian Province, [China. E-mail: xjwhw2019@163.com. Telephone:](China. E-mail: xjwhw2019@163.com. Telephone:) +86-591-83363366, Fax: +86-591-83320319. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions. Received: 2024.05.13; Accepted: 2024.09.23; Published: 2024.10.21 Abstract Background: Gastric cancer (GC) ranks as the fifth leading cause of cancer mortality, with cancer stem cells (CSCs) playing a critical role in tumor progression and resistance to chemotherapy. Conventional chemotherapy often fails to effectively target these stem cells. BATF2, a tumor suppressor, is known for its role in gastric cancer, but its influence on cancer stem cell-like properties and chemotherapy response remains unclear. Methods: Single-cell RNA sequencing (scRNA-seq) analysis was performed on 9 gastric cancer samples to evaluate the expression and regulatory function of BATF2. In vitro experiments involving cell cultures, tumor cell spheroids, and organoids were conducted to assess BATF2's impact on 5-Fu sensitivity and its interaction with drug transporters and signaling pathways. In vivo studies, including subcutaneous tumor formation assays, immunohistochemistry, and immunoblotting, were used to validate findings. Results: BATF2 was confirmed as a tumor suppressor in gastric cancer through scRNA-seq analysis. Elevated BATF2 expression correlated with improved outcomes from postoperative chemotherapy in GC patients and increased sensitivity to 5-Fu. BATF2 enhanced 5-Fu responsiveness by inhibiting the ABCG2 drug transporter and promoting PTEN stability, which suppressed AKT phosphorylation. This led to reduced nuclear β-catenin levels and decreased expression of stem cell markers CD44, SOX2, and NANOG, ultimately reducing chemoresistance and stem-like properties in GC cells. Conclusions: BATF2 plays a pivotal role in regulating stem-like characteristics and chemoresistance in gastric cancer through the BATF2/PTEN/AKT/ABCG2 pathway. These findings suggest a novel therapeutic strategy targeting BATF2 to enhance chemotherapy effectiveness in gastric cancer treatment. Introduction Gastric cancer ranks as one of the top malignant tumors globally, with new cases reaching approximately 0.968 million annually and being the fifth leading cause of cancer-related

FAQs

What problem does the study address in gastric cancer treatment?

The study targets chemotherapy failure caused by cancer stem cells that promote tumor progression and chemoresistance.

How do the authors investigate BATF2’s role?

They use single-cell RNA sequencing plus in vitro cell culture, spheroids, organoids, and in vivo tumor formation assays with validation by immunohistochemistry and immunoblotting.

What mechanism links BATF2 to improved 5-Fu response?

BATF2 enhances 5-Fu responsiveness by inhibiting the ABCG2 drug transporter and promoting PTEN stability, which suppresses AKT phosphorylation and reduces nuclear β-catenin and stem marker expression.

Sep 21, 2026

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