ATF5 inhibits autophagy and the Wnt/β-catenin pathway by upregulating mTOR to suppress the stemness of liver cancer stem cells

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-08-18 DOI:10.1016/j.tice.2025.103094

Jie Jiang , Xiangfang Li , Huangyan Zhang , Wei Liu , Chunhai Hu , Zongqiang Hu

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引用次数: 0

Abstract

Background

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, and cancer stem cells (CSCs) are considered risk factors for HCC progression. Research has indicated a link between reduced ATF5 expression and the aggressive growth of HCC, yet the effect of ATF5 on the stemness of HCC is still ambiguous. Therefore, the aim of this study is to explore the role and potential mechanism of ATF5 in the stemness of HCC.

Methods

HCC clinical specimens were used to identify ATF5 expression and assess its correlation with HCC stemness. The expression of key genes and proteins was detected using RTqPCR, western blotting and immunofluorescence. The cell phenotypes were detected by flow cytometry. The effects of ATF5 overexpression on the stemness of HCC cells were explored by tumor sphere formation and colony formation assays.

Results

Our research revealed that ATF5 levels were downregulated in HCC, whereas the level of the CSC marker CD133 was upregulated. In addition, ATF5 expression was negatively correlated with that of CD133. After ATF5 overexpression in Huh7 and Hep3B cells, the expression levels of the stemness-related markers CD133, EpCAM, NANOG, OCT4 and SOX2 in HCC cells decreased, and the sphere-forming and colony formation abilities also decreased, indicating that ATF5 is a negative regulatory factor of HCC stemness. In vivo animal experiments further demonstrated that ATF5 inhibits tumor growth and the stemness of cancer stem cells in vivo. From a mechanistic standpoint, ATF5 suppresses autophagy by increasing mTOR expression and suppressing Wnt/β-catenin pathway activation, thereby suppressing the stemness of HCC cells.

Conclusion

Our research revealed that ATF5 can inhibit the stemness of HCC cells, laying the foundation for the development of new therapies for HCC.

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ATF5通过上调mTOR抑制肝癌干细胞的干性，从而抑制自噬和Wnt/β-catenin通路

背景：肝细胞癌（HCC）是全球癌症相关死亡的第三大常见原因，而癌症干细胞（CSCs）被认为是HCC进展的危险因素。研究表明，ATF5表达降低与HCC侵袭性生长之间存在联系，但ATF5对HCC干性的影响仍不明确。因此，本研究的目的是探讨ATF5在HCC发生中的作用及其潜在机制。方法应用肝细胞癌临床标本检测ATF5表达，并评估其与肝细胞癌干细胞的相关性。采用RTqPCR、western blotting和免疫荧光检测关键基因和蛋白的表达。流式细胞术检测细胞表型。通过肿瘤球形成和集落形成实验探讨ATF5过表达对HCC细胞干性的影响。结果HCC中ATF5水平下调，而CSC标志物CD133水平上调。此外，ATF5的表达与CD133呈负相关。在Huh7和Hep3B细胞中过表达ATF5后，HCC细胞中干细胞相关标志物CD133、EpCAM、NANOG、OCT4和SOX2的表达水平下降，成球和集落形成能力也下降，提示ATF5是HCC干细胞的负调控因子。体内动物实验进一步证明了ATF5在体内抑制肿瘤生长和肿瘤干细胞的干性。从机制角度来看，ATF5通过增加mTOR表达和抑制Wnt/β-catenin通路激活来抑制自噬，从而抑制HCC细胞的干性。结论我们的研究发现ATF5可以抑制HCC细胞的干性，为肝癌新疗法的开发奠定基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.