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

Abstract

Jin-Shu Pang,1,* Xiu-Mei Bai,1,* Wei-Jun Wan,1 Tong Kang,1 Rong Wen,1 Li-Peng Li,1 Hai-Hui Yin,1 Chun-Miao Lu,2 Dong-Yue Wen,1 Yun He,1,* Hong Yang1,* 1Department of Medical Ultrasound, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Experimental Research, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Yang; Yun He, Email [email protected]; [email protected]: 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

Keywords

• residual hepatocellular carcinoma
• incomplete ablation
• rad21
• overexpression
• progression.