CDK4 as a Prognostic Marker of Hepatocellular Carcinoma and CDK4 Inhibitors as Potential Therapeutics
Fobao Lai1, Yingbing Fang2, Cong Cheng3
1Department of Oncology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
Background:
The proteins CDK4 and CDK6, which are extremely homologous, control cell cycle entry. For the treatment of breast tumors that include hormone receptors, CDK4 and CDK6 inhibitors have been authorized. The link between CDK4 and liver hepatocellular carcinoma (LIHC), however, has not yet been established.
Objective:
The study aimed to explore the link between CDK4 and LIHC and the effect of CDK4 inhibitors on LIHC.
Methods:
In this study, we have evaluated CDK4's prognostic relevance in LIHC using data from The Cancer Genome Atlas (TCGA). The relationship between clinical-pathologic features and CDK4 expression has been evaluated using the Kruskal-Wallis test, the Wilcoxon signed-rank test, and logistic regression. We have analyzed CDK4 and factors related to the prognosis of HCC using the Kaplan-Meier technique and multivariate Cox regression. Gene set enrichment analysis (GSEA) identified CDK4-related critical pathways. To investigate the connections between CDK4 and cancer immune infiltrates, TCGA data were employed in single-sample gene set enrichment analysis (ssGSEA). For functional validation, CDK4 was chosen since it can be inhibited by recognized CDK4/ 6-inhibitors (e.g., abemaciclib).
Results:
Poorer overall and disease-specific outcomes were linked to high CDK4 expression in HCC patients. GSEA suggested that CDK4 and immune response are closely connected. The amount of Th2 cells infiltrating was positively correlated with CDK4 expression, while the amount of cytotoxic cells infiltrating was negatively correlated, according to ssGSEA. Both in vitro and in vivo, the anti-tumor efficacy of CDK4 inhibitor has been found to be superior to that of sorafenib.
Conclusion:
This study suggests a relationship between CDK4 and immune infiltration and prognosis in HCC. Additionally, a CDK4 inhibitor may have anti-tumor properties against hepatocellular cancer.
Insights
High CDK4 expression correlates with poor liver cancer prognosis and altered immune cell infiltration. CDK4 inhibitors show superior anti-tumor effects compared to sorafenib in hepatocellular carcinoma (HCC).
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle entry and are targets for hormone receptor-positive breast cancer treatment.
- The prognostic and therapeutic role of CDK4 in liver hepatocellular carcinoma (LIHC) remains unestablished.
Purpose of the Study:
- To investigate the prognostic significance of CDK4 in LIHC.
- To explore the association between CDK4 expression and immune infiltration in LIHC.
- To evaluate the potential of CDK4 inhibitors as a therapeutic strategy for LIHC.
Main Methods:
- Prognostic relevance of CDK4 in LIHC was assessed using The Cancer Genome Atlas (TCGA) data.
- Statistical analyses included Kruskal-Wallis, Wilcoxon signed-rank, logistic regression, Kaplan-Meier, and multivariate Cox regression.
- Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were employed to identify CDK4-related pathways and immune infiltrates.
Main Results:
- High CDK4 expression was associated with poorer overall and disease-specific survival in HCC patients.
- CDK4 expression correlated with immune cell infiltration, including increased Th2 cells and decreased cytotoxic cells.
- CDK4 inhibitors demonstrated superior anti-tumor efficacy compared to sorafenib in both in vitro and in vivo models.
Conclusions:
- CDK4 plays a significant role in LIHC prognosis and is linked to immune infiltration patterns.
- CDK4 inhibitors represent a promising therapeutic approach for hepatocellular carcinoma.
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