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TONSL promotes hepatocellular carcinoma progression and radioresistance by orchestrating DNA damage repair and cell cycle dynamics

gastroenterology-and-hepatology
internal-medicine
oncology
pathology
radiology-and-medical-imaging

Abstract

Tonsoku-like, DNA repair protein (TONSL) plays a critical role in DNA replication in normal cells. However, its function in hepatocellular carcinoma (HCC) remains largely unknown. This study demonstrated the higher expression level of TONSL in HCC tissues compared to non-tumor tissues using RNA expression profile from the TCGA, GEO, and ICGC-LIRI-JP datasets. High expression of TONSL predicted poor overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) in patients with HCC. Bioinformatics analysis showed TONSL was positively correlated with the infiltration of exhausted T cells and regulatory T cells in HCC, and negatively correlated with the infiltration of effector CD8 T cells. TONSL expression was higher in radiotherapy-resistant HCC cells in comparison with its parental HCC cell line. Downregulation of TONSL re-sensitized the radioresistant HCC cells to radiotherapy. Furthermore, knockdown of TONSL alleviated sorafenib resistance in HCC cells. Finally, pan-cancer analysis showed that TONSL was highly expressed in various cancer types and was associated with poor prognosis in various cancer types. Our finding highlights the critical role of TONSL in HCC progression and its contribution to radiotherapy and sorafenib resistance by orchestrating DNA damage repair and cell cycle dynamics, suggesting its potential as a therapeutic target and prognostic biomarker.
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