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

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

  • Tissue Cell. 2025 Aug 18:97:103094. doi: 10.1016/j.tice.2025.103094.
Jie Jiang 1,  Xiangfang Li 2,  Huangyan Zhang 2,  Wei Liu 3,  Chunhai Hu 3,  Zongqiang Hu 4
Affiliations

Affiliations

  • 1 Kunming Medical University, Kunming, Yunnan 650500, China.
  • 2 Scientific Research Management Department, The People's Hospital of Chuxiong Yi Autonomous Prefecture, The Fourth Affiliated Hospital of Dali University, Teaching Hospital of Kunming Medical University, Chuxiong, Yunnan 675000, China.
  • 3 Department II of Hepatobiliary Surgery, The People's Hospital of Chuxiong Yi Autonomous Prefecture, The Fourth Affiliated Hospital of Dali University, Teaching Hospital of Kunming Medical University, Chuxiong, Yunnan 675000, China.
  • 4 Kunming Medical University, Kunming, Yunnan 650500, China; Scientific Research Management Department, The People's Hospital of Chuxiong Yi Autonomous Prefecture, The Fourth Affiliated Hospital of Dali University, Teaching Hospital of Kunming Medical University, Chuxiong, Yunnan 675000, China; Department II of Hepatobiliary Surgery, The People's Hospital of Chuxiong Yi Autonomous Prefecture, The Fourth Affiliated Hospital of Dali University, Teaching Hospital of Kunming Medical University, Chuxiong, Yunnan 675000, China. Electronic address: huzongqiang6@kmmu.edu.cn.
PMID: 40857870 DOI: 10.1016/j.tice.2025.103094
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.

Keywords

ATF5; Cancer stem cells; Hepatocellular carcinoma; Wnt/β-catenin pathway; mTOR.

Figures
Products
Inhibitors & Agonists
Other Products