Clinical Significance of Acyl-CoA Dehydrogenase Short Chain and Its Anti-tumor Role in Hepatocellular Carcinoma by Inhibiting Canonical Wnt/β-Catenin Pathway

Jiawei Gu; Zhipeng Cao; Gengming Niu; Jianghui Ying; Hui Wang; Hua Jiang; Chongwei Ke

doi:10.1007/s10620-024-08813-y

Clinical Significance of Acyl-CoA Dehydrogenase Short Chain and Its Anti-tumor Role in Hepatocellular Carcinoma by Inhibiting Canonical Wnt/β-Catenin Pathway

Dig Dis Sci. 2025 Jan 2. doi: 10.1007/s10620-024-08813-y. Online ahead of print.

Authors

Jiawei Gu^#^{1

2}, Zhipeng Cao^#², Gengming Niu², Jianghui Ying¹, Hui Wang¹, Hua Jiang¹, Chongwei Ke³

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
² Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Minhang District, Shanghai, 200240, China.
³ Department of General Surgery, The Fifth People's Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Minhang District, Shanghai, 200240, China. kechongwei@5thhospital.com.

^# Contributed equally.

PMID: 39746891
DOI: 10.1007/s10620-024-08813-y

Abstract

Background: The pathogenesis of hepatocellular carcinoma (HCC) emphasizes metabolic disorders. HCC patients showed abnormally low expression of Acyl-CoA dehydrogenase short chain (ACADS).

Objectives: This study aimed to elucidate the clinical significance and mechanistic role of ACADS in HCC.

Methods: We investigated the expression patterns and significance of ACADS in HCC by analyzing multiple public databases and clinical samples (Chip data). Immunohistochemistry was employed to observe the expression levels of ACADS in HCC tissues. In vitro experiments involved silencing or overexpressing ACADS in HCC cell lines, with protein expression levels determined by Western blotting. Functional validation included CCK-8, Transwell, and scratch wound healing assays. TOPFlash and FOPFlash reporter gene assays, co-immunoprecipitation, and immunofluorescence were used to explore the interaction between ACADS and β-catenin.

Results: ACADS was low expressed in HCC and was clinically associated with vascular invasion, TNM stage, and AFP levels. The low ACADS expression in HCC patients was negatively correlated with their survival. Overexpression of ACADS significantly suppressed the viability, migration, and invasive capacity of HCC cells, whereas silencing ACADS had the opposite effect. Mechanistically, co-immunoprecipitation experiments indicated that there was an interaction between ACADS and β-catenin. Overexpression of ACADS inhibited β-catenin activity and resulted in decreased nuclear β-catenin translocation and increased its cytoplasmic level. Immunofluorescence results also showed a decrease in β-catenin nuclear import following ACADS overexpression, whereas silencing ACADS led to an enhancement of its nuclear translocation.

Conclusion: ACADS emerges as a potentially valuable biomarker for HCC prognosis, exhibiting tumor-suppressive functions in HCC by participating in the regulation of β-catenin activity.

Keywords: Acyl-CoA dehydrogenase short chain; Hepatocellular carcinoma; Migration and invasion; Nuclear translocation; Prognosis; Wnt/β-catenin.

Abstract

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