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VLCAD inhibits the proliferation and invasion of hepatocellular cancer cells through regulating PI3K/AKT axis

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Abstract

Purpose

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is an essential mediator in fatty acid metabolism. The progression of human hepatocellular carcinoma (HCC) is closely associated with the disorder of energy supply. Here, we aimed to investigate the role and underlying molecule mechanism of VLCAD in pathological process of HCC.

Methods

In this study, VLCAD was induced silencing and overexpression using small hairpin RNA (shRNA) and lentiviral-mediated vector in HCC cell lines. The proliferation of HCC cells was determined using CCK-8 assay. Transwell assay and lung metastasis were performed to analysis cell metastasis in vitro and in vivo. ECAR and OCR were used to evaluate the activity of glycolysis and mitochondrial oxidative phosphorylation.

Results

Our data indicated that VLCAD was downregulated in human HCC tissues and cells. VLCAD overexpression strongly suppressed the proliferation and metastasis of HCC cells associating with the decrease of ATP accumulation and glycolysis activity. Importantly, the PI3K/AKT inhibitor LY294002 strongly abolished the role of shVLCAD in HCC cells. Our results suggested that VLCAD suppressed the growth and metastasis in HCC cells by inhibiting the activities of glycolysis and mitochondrial oxidative phosphorylation metabolism via PI3K/AKT pathway.

Conclusions

Together, present findings not only demonstrated the protective role of and molecular network of VLCAD in HCC cells but also indicated its and potential use as a target in the therapy of HCC.

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Acknowledgements

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Authors and Affiliations

  1. Department of General Surgery, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, China

    QW Zhu

  2. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China

    Yue Yu

  3. Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China

    Yu Zhang

  4. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China

    XH Wang

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  1. QW Zhu
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Contributions

QZ and XW are responsible for the conception or design of the work. QZ, YY, YZ and XW contribute the acquisition, analysis, or interpretation of data for the work. QZ and YY provide the tissue samples. YZ helps in the follow-up of the patients. XW helps in reviewing the histopathology slides. All authors finally approved the manuscript version to be published. XW is the guarantor of the article.

Corresponding author

Correspondence to XH Wang.

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The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by Ethical Committee of The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University and conducted in accordance with the ethical standards.

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Supplementary Information

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12094_2021_2733_MOESM1_ESM.jpg

Supplementary file1 Gene set enrichment analysis (GSEA) analysis of VLCAD in HCC tissues. A-B. VLCAD is enrichment in the metastasis and glycolysis of HCC tissues. C-D. VLCAD is negatively correlated with the PI3/AKT pathway in HCC tissues (JPG 274 KB)

12094_2021_2733_MOESM2_ESM.jpg

Supplementary file2 Knockdown and overexpression of VLCAD in HCC cells. A and B. stand for the relative mRNA and protein level of VLCAD in HCC cells (Hep3B, HepG2, Huh7 and SKHEP1) and normal liver cells (LO2). * p < 0.01 vs LO2, ** p < 0.01 vs LO2, *** p < 0.001 vs LO2. C and D. stand for the relative mRNA and protein levels of VLCAD were deeply suppressed in HEP3B and SKHEP1 cells transfected with shVLCAD-1, shVLCAD-2 and shVLCAD-3 respectively. *** p < 0.001 vs shNC. E and F. The level of VLCAD was overexpressed in HepG2 and Huh7 cells transfected with oeVLCAD. *** p < 0.001 vs oeNC (JPG 2728 KB)

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Zhu, Q., Yu, Y., Zhang, Y. et al. VLCAD inhibits the proliferation and invasion of hepatocellular cancer cells through regulating PI3K/AKT axis. Clin Transl Oncol 24, 864–874 (2022). https://doi.org/10.1007/s12094-021-02733-3

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  • DOI: https://doi.org/10.1007/s12094-021-02733-3

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