RAD21: A Key Transcriptional Regulator in the Development of Residual Liver Cancer

Abstract

Objective

Thermal ablation is a commonly used therapy for hepatocellular carcinoma (HCC). Nevertheless, inadequate ablation can lead to the survival of residual HCC, potentially causing rapid progression. The underlying mechanisms for this remain unclear. This study explores the molecular mechanism responsible for the rapid progression of residual HCC.

Methods

We established an animal model of inadequate ablation in BALB/c nude mice and identified a key transcriptional regulator through high-throughput sequencing. Subsequently, we conducted further investigations on RAD21. We evaluated the expression and clinical significance of RAD21 in HCC and studied its impact on HCC cell function through various assays, including CCK-8, wound healing, Transwell migration and invasion. In vitro experiments established an incomplete ablation model verifying RAD21 expression and function. Using ChIP-seq, we determined potential molecules regulated by RAD21 and investigated how RAD21 influences residual tumor development.

Results

High RAD21 expression in HCC was confirmed and correlated with low tumor cell differentiation, tumor growth, and portal vein thrombosis. Silencing RAD21 inhibited the migration, invasion, and proliferation significantly in liver cancer cells. Patients with high RAD21 levels showed elevated multiple inhibitory immune checkpoint levels and a lower response rate to immune drugs. Heat treatment intensified the malignant behavior of liver cancer cells, resulting in increased migration, invasion, and proliferation. After subjecting it to heat treatment, the results indicated elevated RAD21 levels in HCC. Differentially expressed molecules regulated by RAD21 following incomplete ablation were primarily associated with the VEGF signaling pathway, focal adhesion, angiogenesis, and hepatocyte growth factor receptor signaling pathway etc.

Conclusion

The upregulation of RAD21 expression after incomplete ablation may play a crucial role in the rapid development of residual tumors and could serve as a novel therapeutic target.

Keywords:

• residual hepatocellular carcinoma
• incomplete ablation
• RAD21
• overexpression
• progression

Ethical Declarations

The research including animal experiment and clinical samples followed the Guide for the Care and Use of Laboratory Animals by the National Research Council committee of the USA and received ethical approval for from the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University.

Acknowledgments

We thank the Laboratory of Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Key Laboratory of Ultrasonic Molecular Imaging and Artificial Intelligence, Guangxi Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor/Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), and Ministry of Education for their support of this study, as well as thank the language editing of Home for Researchers editorial team (www.home-for-researchers.com).

Disclosure

The authors declare no conflicts of interest regarding the publication of this paper.

Additional information

Funding

This study was funded by the National Natural Science Foundation of China (81960329, 82160350, and 82160336), the Natural Science Foundation of Guangxi (2023GXNSFDA026013 and 2020GXNSFDA238005).