DDX55 promotes hepatocellular carcinoma progression by interacting with BRD4 and participating in exosome‐mediated cell‐cell communication

• Published in: Cancer science 2022-09, Vol.113 (9), p.3002-3017
• Main Authors: Yu, Bin, Zhou, Shujun, Long, Dakun, Ning, Yuxiang, Yao, Hanlin, Zhou, Encheng, Wang, Yanfeng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Antibodies; Biomarkers; BRD4; Cell adhesion & migration; Cell cycle; Cell growth; Cell interactions; Cell migration; Cell proliferation; Consortia; DDX55; DNA helicase; Endothelial cells; Epigenetics; exosome; Exosomes; Gene expression; Genomes; Hepatocellular carcinoma; Liver cancer; Mesenchyme; Metastasis; Nanoparticles; Original; Phenotypes; Polymerase chain reaction; Proteins; Survival analysis; Therapeutic targets; Transcription factors; Transmission electron microscopy; Tumorigenesis; Tumors; Variance analysis; β‐Catenin
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15393

The involvement of DEAD‐box helicase 55 (DDX55) in oncogenesis has been suggested, but its biological role in hepatocellular carcinoma (HCC) remains unknown. The present study verified the upregulation of DDX55 in HCC tissues compared with non‐tumor controls. DDX55 displayed the highest prognostic values among the DEAD‐box protein family for recurrence‐free survival and overall survival of HCC patients. In addition, the effects of DDX55 in the promotion of HCC cell proliferation, migration, and invasion were determined ex vivo and in vivo. Mechanistically, we revealed that DDX55 could interact with BRD4 to form a transcriptional regulatory complex that positively regulated PIK3CA transcription. Following that, β‐catenin signaling was activated in a PI3K/Akt/GSK‐3β dependent manner, thus inducing cell cycle progression and epithelial–mesenchymal transition. Intriguingly, both DDX55 mRNA and protein were identified in the exosomes derived from HCC cells. Exosomal DDX55 was implicated in intercellular communication between HCC cells with high or low DDX55 levels and between HCC cells and endothelial cells, thereby promoting the malignant phenotype of HCC cells and angiogenesis. In conclusion, DDX55 may be a valuable prognostic biomarker and therapeutic target in HCC. DDX55 was significantly upregulated in hepatocellular carcinoma (HCC) and served as an independent prognostic factor for HCC patients. Mechanistically, DDX55 could interact with BRD4 and activate PI3K/Akt/GSK‐3β/β‐catenin pathway in HCC. Strikingly, exosome‐mediated intercellular transfer of DDX55 was observed in HCC, thereby promoting malignant phenotype of HCC cells and angiogenesis of endothelial cells. DDX55 may be a valuable prognostic biomarker and therapeutic target in HCC.