Topoisomerase I Inhibition Radiosensitizing Hepatocellular Carcinoma by RNF144A-mediated DNA-PKcs Ubiquitination and Natural Killer Cell Cytotoxicity  

作　　者：Chiao-Ling Tsai Po-Sheng Yang Feng-Ming Hsu Ann-Lii Cheng Wan-Ni Yu Jason Chia-Hsien Cheng 

机构地区：[1]Graduate Institute of Clinical Medicine,National Taiwan University College of Medicine,China Taipei [2]Division of Radiation Oncology,Department of Oncology,National Taiwan University Hospital,China Taipei [3]Department of General Surgery,Mackay Memorial Hospital,China Taipei [4]Graduate Institute of Oncology,National Taiwan University College of Medicine,China Taipei [5]Cancer Center,National Taiwan University,China Taipei [6]Taiwan Liposome Company,China Taipei

出　　处：《Journal of Clinical and Translational Hepatology》2023年第3期614-625,共12页临床与转化肝病杂志（英文版）

基　　金：National Taiwan University Hospi-tal(NTUH 106-M3649,107-M4030,108-M4213,109-M4767 and 110-M5149);the Ministry of Science and Technology of Taiwan(MOST 106-2314-B-002-063-,107-2314-B-002-097-and 108-2314-B-002-046-).

摘　　要：Background and Aims: Topoisomerase I (TOP1) partici-pates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A. Methods: In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular car-cinoma (HCC) cell lines (Huh7/PLC5) by clonogenic surviv-als. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy. Results: Lipotecan/RT had a superior synergis-tic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility com-plex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear transloca-tion with the cumulated DNA-PKcs and radio-resistance of PLC5 cells. Conclusions: TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

关 键 词：Hepatocellular carcinoma RADIOTHERAPY DNA topoisomerase I Li-potecan RNF144A. 

分 类 号：R73[医药卫生—肿瘤]