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Published on: January 7, 2019
Integrative multi-omics profiling reveals DRG1 promotes hepatocellular carcinoma via c-Myc phosphorylation and
Peng Wang1, Junying Xu2, Hao Huang2
1Shihezi University School of Medicine, Shihezi 832000, China; The First Affiliated Hospital of Shihezi University, Shihezi 832000, China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832000, China; The Clinical Research Center for Infectious Diseases of Xinjiang Production and Construction Corps, Shihezi 832000, China.
Background & Aims:
Developmentally regulated GTP-binding protein 1 (DRG1), a member of the GTPase family, has been implicated in cancer progression; however, its biological function and therapeutic relevance in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to define the role of DRG1 in HCC progression and uncover its underlying regulatory mechanisms.
Methods:
Multi-omics analyses, clinical tissue validation, in vitro functional assays, and in vivo xenograft models were integrated to investigate the biological function, regulatory mechanism, and therapeutic relevance of DRG1 in HCC.
Results:
DRG1 was significantly upregulated in HCC tissues and associated with aggressive clinicopathological characteristics and poor patient survival. Integrated single-cell and spatial transcriptomic analyses revealed preferential DRG1 expression in malignant regions and its association with an immunosuppressive tumor microenvironment. Mechanistically, DRG1 promoted HCC cell proliferation through regulation of c-Myc activation, while HDAC2 was identified as an upstream regulator of DRG1 expression. Furthermore, DRG1 depletion enhanced sensitivity to lenvatinib treatment in HCC models.
Conclusions:
Our findings identify DRG1 as a potential prognostic biomarker and therapeutic target in HCC. The HDAC2-DRG1-c-Myc regulatory network contributes to malignant progression, while DRG1 inhibition represents a potential strategy to improve lenvatinib response.
Insights
Developmentally regulated GTP-binding protein 1 (DRG1) is upregulated in hepatocellular carcinoma (HCC), promoting cancer progression. Inhibiting DRG1 may improve lenvatinib treatment efficacy in HCC patients.
Area of Science:
- Hepatocellular Carcinoma Research
- Cancer Biology
- Molecular Oncology
Background:
- Developmentally regulated GTP-binding protein 1 (DRG1) is a GTPase implicated in cancer, but its role in hepatocellular carcinoma (HCC) is unclear.
- Understanding DRG1's function and therapeutic potential in HCC is crucial for advancing treatment strategies.
Purpose of the Study:
- To define the role of DRG1 in HCC progression.
- To uncover the regulatory mechanisms of DRG1 in HCC.
- To evaluate DRG1's therapeutic relevance in HCC.
Main Methods:
- Integrated multi-omics analyses, including single-cell and spatial transcriptomics.
- Clinical tissue validation and in vitro/in vivo functional assays.
- Investigation of DRG1's role in HCC cell proliferation and response to lenvatinib.
Main Results:
- DRG1 is upregulated in HCC, correlating with aggressive features and poor survival.
- DRG1 expression is linked to an immunosuppressive tumor microenvironment.
- DRG1 promotes HCC proliferation via c-Myc activation, regulated by HDAC2.
- DRG1 depletion sensitizes HCC models to lenvatinib.
Conclusions:
- DRG1 serves as a prognostic biomarker and potential therapeutic target in HCC.
- The HDAC2-DRG1-c-Myc axis drives HCC malignancy.
- DRG1 inhibition is a promising strategy to enhance lenvatinib efficacy.
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