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PRMT3 介导的 IGF2BP1 精氨酸甲基化促进肝癌中奥沙利铂耐药性的产生。

PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer.

机构信息

State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.

出版信息

Nat Commun. 2023 Apr 6;14(1):1932. doi: 10.1038/s41467-023-37542-5.

DOI:10.1038/s41467-023-37542-5
PMID:37024475
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10079833/
Abstract

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.

摘要

虽然基于奥沙利铂的化疗在治疗肝细胞癌（HCC）方面已显示出疗效，但原发性或获得性奥沙利铂耐药仍是临床治疗中的主要挑战。本研究通过使用 CRISPR/Cas9 激活文库进行功能筛选、对临床样本进行转录组分析，以及在体外和体内进行功能验证，鉴定出 PRMT3 是奥沙利铂耐药的关键驱动因素。在机制上，PRMT3 介导的奥沙利铂耐药部分依赖于 IGF2BP1 在 R452 处的甲基化，这对于 IGF2BP1 稳定 PRMT3-IGF2BP1 轴的效应因子 HEG1 的 mRNA 功能至关重要。此外，PRMT3 的过表达可能是 HCC 患者奥沙利铂耐药的一个生物标志物。总之，本研究定义了 PRTM3-IGF2BP1-HEG1 轴作为奥沙利铂耐药的重要调节因子和治疗靶点，并提示可以将预处理活检中的 PRMT3 表达水平用作 HCC 患者奥沙利铂耐药的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/5346aec07d14/41467_2023_37542_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0becb2ec9a10/41467_2023_37542_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0153c928034b/41467_2023_37542_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0db295b105fe/41467_2023_37542_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/5346aec07d14/41467_2023_37542_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/47a87cf61b5b/41467_2023_37542_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0156ba673ac1/41467_2023_37542_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/9ab389b1b0ae/41467_2023_37542_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0becb2ec9a10/41467_2023_37542_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0153c928034b/41467_2023_37542_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/0db295b105fe/41467_2023_37542_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3de/10079833/5346aec07d14/41467_2023_37542_Fig7_HTML.jpg

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