Abstract
Background
Liver cancer stem cells (LCSCs) significantly impact chemo-resistance and recurrence in liver cancer. Dopamine receptor D4 (DRD4) is known to enhance the cancer stem cell (CSC) phenotype in glioblastoma and correlates with poor prognosis in some non-central nervous system tumors; however, its influence on LCSCs remains uncertain.
Methods
To investigate the gene and protein expression profiles of DRD4 in LCSCs and non-LCSCs, we utilized transcriptome sequencing and Western blotting analysis. Bioinformatics analysis and immunohistochemistry were employed to assess the correlation between DRD4 expression levels and the pathological characteristics of liver cancer patients. The impact of DRD4 on LCSC phenotypes and signaling pathways were explored using pharmacological or gene-editing techniques. Additionally, the effect of DRD4 on the protein expression and intracellular localization of β-catenin were examined using Western blotting and immunofluorescence.
Results
DRD4 expression is significantly elevated in LCSCs and correlates with short survival in liver cancer. The expression and activity of DRD4 are positive to resistance, self renewal and tumorigenicity in HCC. Mechanistically, DRD4 stabilizes β-catenin and promotes its entry into the nucleus via activating the PI3K/Akt/GSK-3β pathway, thereby enhancing LCSC phenotypes.
Conclusions
Inhibiting DRD4 expression and activation offers a promising targeted therapy for eradicating LCSCs and relieve chemo-resistance.
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Data availability
Almost all data generated or analysed during this study are included in this manuscript and additional files, while others are available from the corresponding author on reasonable request, except for the information related to patient privacy. RNA-Seq data generated in this study are available on Gene Expression Omnibus (GEO) with accession number GSE272591 at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE272591.
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Acknowledgements
We sincerely appreciate the contributions from the TCGA, GEO, GSEA, and HPA databases.
Funding
This work was supported by the Youth Fund of National Natural Science Foundation of China (Nos. 81803575 and 31902287), Key R&D and Promotion Projects of Henan Province (No.242102310467), Key Specialized Research and Promotion Project of Henan Province in 2023 (No. 232102311205), Henan Medical Science and Technology Research Program Project (No. LHGJ20210801), Program for Innovative Talents of Science and Technology in Henan Province (No. 23HASTIT043), College Students Innovation and Entrepreneurship Training Program of Henan University (No. 20231022007).
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ZY, PZ, YZ, RG, JH, QW, and HL participated in the experimental data collection; ZZ provided technical assistance; ZR designed experiments and drafted the manuscript; SL, YH, and DC helped revise the manuscript. All authors contributed to the article and approved the submitted version.
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The experiments involving animal studies and patient specimens were reviewed and approved by the Ethics Committee of the Medical School of Henan University (HUSOM2023-221 and HUSOM2023-222). Informed consent was obtained from all participants involved in the study. All authors agree with the content of the manuscript.
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Yang, Z., Zhang, P., Zhao, Y. et al. DRD4 promotes chemo-resistance and cancer stem cell-like phenotypes by mediating the activation of the Akt/β-catenin signaling axis in liver cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02811-7
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DOI: https://doi.org/10.1038/s41416-024-02811-7