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Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis

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Abstract

Purpose

The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy.

Methods

Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl4).

Results

Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment.

Conclusion

Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AFP:

Alpha-fetoprotein

ALT:

Alanine aminotransferase

ALB:

Albumin

APS:

Ammonium persulfate

AST:

Aspartate aminotransferase

AUC:

Area under curve

BCLC:

Barcelona Clinic Liver Cancer

BS:

Binding site

CF:

Core-fucosylation

ChIP:

Chromatin immunoprecipitation

CCl4 :

Carbon tetrachloride

DDA:

Data dependent acquisition

DMSO:

Dimethylsulfoxide

EMT:

Epithelial-mesenchymal transition

FOXO3:

Forkhead Box O3

HCC:

Hepatocellular carcinoma

IC50:

Half maximal inhibitory concentration

IHC:

Immunohistochemistry

MVI:

Microvascular invasion

PBS:

Phosphate buffer saline

PCR:

Polymerase chain reaction

PRM:

Parallel Reaction Monitoring

PVTT:

Portal vein tumor thrombosis

ROC:

Receiver operating characteristic curve

shRNA:

Short hairpin RNA

siRNA:

Small interfering RNA

SLRP:

Small leucine-rich proteoglycan

STAT3:

Signal transducer and activator of transcription 3

TBL:

Total bilirubin

TCGA:

The Cancer Genome Atlas

TF:

Transcription Factor

WD:

Western diet

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Acknowledgements

We acknowledge Guang Yang and Guangneng Liao for their help with the mice management. We also acknowledge the support provided by LC-Bio company (Hangzhou, China) with the RNA sequencing and related analysis experiments. We also acknowledge the support provided by Fangfang Wang (Institute of hematology, West China Hospital) with flow cytometry assay and related analysis.

Funding

This work was supported by grants from the Natural Science Foundation of China (NO. 82173255, 82270691 and 82273330), the Key R&D projects of Sichuan Provincial Department of Science and Technology (NO. 2022YFS0253, 2023YFS0026).

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Author notes

  1. Yifei Tan, Yongjie Zhou and Wei Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China

    Yifei Tan, Yongjie Zhou, Qiong Wu, Jian Yang, Tao Lv, Lvnan Yan, Yujun Shi & Jiayin Yang

  2. Department of Ultrasonography, West China Second University Hospital, Sichuan University, Chengdu, China

    Yifei Tan & Hong Luo

  3. Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Wei Zhang

  4. Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China

    Zhenru Wu, Qing Xu, Yujun Shi & Jiayin Yang

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  1. Yifei Tan
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Contributions

Conception and design: Y. T., Y. Z., and Y. S.; Development of methodology: Y. T., Y. Z., W. Z., Z. W., Q. X.; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Y. T., Y. Z., W. Z., Q. W., Jian Y. and T. L.; Analysis and interpretation of data: Y. T., Y. Z., L. Y. and Y. S.; Writing, review, and/or revision of the manuscript: Y. T., Y. Z., Jia. Y and H. L.; Administrative, technical, or material support: Y. Z., Q. W. and Y. S.; Study supervision: Jia. Y., Y. S. and H. L.

Corresponding authors

Correspondence to Hong Luo, Yujun Shi or Jiayin Yang.

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This study was approved by the ethics committee of the West China Hospital, Sichuan University. The protocols applied in the current study conformed to the ethical guidelines of 1975 Declaration of Helsinki, and written informed consent were provided by all patients.

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Tan, Y., Zhou, Y., Zhang, W. et al. Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00919-9

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