ARID3A Promotes Tumor Progression by Activating TNF-α/NF-κB Signaling in Dual-Phenotype Hepatocellular Carcinoma

Minjun Li,1,2,* Taixin Yang,1,* Juntao Huang,1 Xinyuan Wu,1 Jingyu Chen,1 Jindu Li,1 Binglin Shi,3 Jie Zhang,1 Bangde Xiang1,2 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi, People’s Republic of China; 3Department of General Surgery, Fangchenggang First People’s Hospital, Fangchenggang, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bangde Xiang, Email [email protected] Jie Zhang, Email [email protected]: Dual-phenotype hepatocellular carcinoma (DPHCC) is a unique subtype of hepatocellular carcinoma (HCC) characterized by strong tumor stemness and invasive capabilities. ARID3A is identified as a potential regulator of tumor stemness in DPHCC by applying transcriptomic analysis. The precise mechanisms of ARID3A on the aggressive behavior of DPHCC remain to be further explored.Materials and Methods: In vitro functional experiments and in vivo tumorigenesis assays were used to validate the malignant behaviors of ARID3A. RNA sequencing was performed on ARID3A-transfected cells to identify ARID3A-mediated regulatory mechanisms. Finally, the impact of ARID3A–TNF-α/NF-κB axis on HCC malignant behavior was analyzed through in vitro blocking or stimulation experiments.Results: The expression of ARID3A was upregulated in DPHCC and was associated with poor prognosis among these patients (p = 0.006, HR = 3.77, 95% CI:1.762– 8.069). In vitro and in vivo experiments indicated that ARID3A facilitated stemness features and tumor progression. Findings from RNA-seq suggested that ARID3A enhanced tumor stemness and activated epithelial-mesenchymal transition through the activation of TNF-α-mediated NF-κB signaling. In vitro stimulation of ARID3A-transfected cells lines with recombinant TNF-α protein or inhibition of TNF-α-mediated NF-κB signaling regulated the ARID3A-mediated invasiveness.Conclusion: Our study reveals that ARID3A acts as an oncogene and promotes aggressive features of stem-like cells in DPHCC via the ARID3A–TNF-α/NF-κB axis. Thus, it may facilitate the development therapeutic strategy for DPHCC.Keywords: dual-phenotype HCC, ARID3A oncogene, inflammatory signaling