2. Academic Validation
  3. DRD4 promotes chemo-resistance and cancer stem cell-like phenotypes by mediating the activation of the Akt/β-catenin signaling axis in liver cancer

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 Oct;131(7):1212-1223. doi: 10.1038/s41416-024-02811-7.
Zhengyan Yang # 1 2,  Pai Zhang # 3 4,  Yiwei Zhao # 1 3,  Ran Guo 1,  Jinglin Hu 1,  Qi Wang 1 2,  Zhi Zhao 5,  Handi Liu 1,  Shuangyu Lv 1 2,  Zhiguang Ren 6 7 8,  Yanzhong Hu 9,  Daxiang Cui 10
Affiliations

Affiliations

  • 1 Henan International Joint Laboratory for Nuclear Protein Regulation, Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
  • 2 Medical and Industrial Interdisciplinary Research Institute, Henan University, Kaifeng, 475004, China.
  • 3 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, 475004, China.
  • 4 Genetics and Prenatal Diagnosis Department, Luoyang Maternal and Child Health Hospital, Luoyang, 471023, China.
  • 5 Henan University-affiliated Zhengzhou Yihe Hospital, Zhengzhou, 450000, China.
  • 6 Henan International Joint Laboratory for Nuclear Protein Regulation, Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China. Renzhiguang66@outlook.com.
  • 7 Medical and Industrial Interdisciplinary Research Institute, Henan University, Kaifeng, 475004, China. Renzhiguang66@outlook.com.
  • 8 Key Laboratory of Clinical Resources Translation, The First Affiliated Hospital, Henan University, Kaifeng, 475004, China. Renzhiguang66@outlook.com.
  • 9 Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, 475004, China. hyz@henu.edu.cn.
  • 10 Medical and Industrial Interdisciplinary Research Institute, Henan University, Kaifeng, 475004, China. daxiangcui@126.com.
  • # Contributed equally.
PMID: 39174739 DOI: 10.1038/s41416-024-02811-7
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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