MiRNA-363-3p/DUSP10/JNK axis mediates chemoresistance by enhancing DNA damage repair in diffuse large B-cell lymphoma.
MiRNA-363-3p/DUSP10/JNK axis mediates chemoresistance by enhancing DNA damage repair in diffuse large B-cell lymphoma.
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miRNA-363-3p/dusp10/jnk轴通过增强弥漫性大型B细胞淋巴瘤中的DNA损伤修复来介导化学抗性。
DOI：
10.1038/s41375-022-01565-6
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发表时间：
2022-07
期刊：
影响因子：
11.4
通讯作者：
Liu, Yanyan
中科院分区：
文献类型：
--
作者：
Zhou, Wenping;Xu, Yuanlin;Zhang, Jiuyang;Zhang, Peipei;Yao, Zhihua;Yan, Zheng;Wang, Haiying;Chu, Junfeng;Yao, Shuna;Zhao, Shuang;Yang, Shujun;Guo, Yongjun;Miao, Jinxin;Liu, Kangdong;Chan, Wing C.;Xia, Qingxin;Liu, Yanyan
基于蒽环类药物的化疗耐药性是弥漫性大B细胞淋巴瘤（DLBCL）的主要挑战。确定miRNA和基因表达谱（n = 47）以揭示潜在的化学抗性机制和治疗方法。miRNA-363- 3 p的高表达与化疗耐药性之间的独立相关性在更大的队列（n = 106）中被观察和验证。在体外和体内实验中，通过DLBCL细胞系中的异位表达和CRISPR/Cas9介导的敲除，miRNA-363- 3 p显示出减少阿霉素诱导的细胞凋亡和肿瘤缩小。发现DNA甲基化参与miRNA-363- 3 p的转录调控。进一步的研究表明，双特异性磷酸酶10（DUSP 10）是miRNA-363- 3 p的靶点，其抑制促进c-Jun N-末端激酶（JNK）的磷酸化。miRNA-363- 3 p/DUSP 10/JNK轴主要与同源重组（HR）和DNA修复途径的负调控相关。miRNA-363- 3 p的异位表达更有效地修复了阿霉素诱导的双链断裂（DSB），同时增强了非同源末端连接修复并减少了HR修复。靶向JNK和聚（ADP-核糖）聚合酶1显著抑制阿霉素诱导的DSB修复，增加阿霉素诱导的细胞凋亡和肿瘤缩小，并改善荷瘤小鼠的生存。总之，miRNA-363- 3 p/DUSP 10/JNK轴是DLBCL的一种新的化疗耐药机制，可以通过靶向治疗逆转。
Anthracycline-based chemotherapy resistance represents a major challenge in diffuse large B-cell lymphoma (DLBCL). MiRNA and gene expression profiles (n = 47) were determined to uncover potential chemoresistance mechanisms and therapeutic approaches. An independent correlation between high expression of miRNA-363-3p and chemoresistance was observed and validated in a larger cohort (n = 106). MiRNA-363-3p was shown to reduce doxorubicin-induced apoptosis and tumor shrinkage in in vitro and in vivo experiments by ectopic expression and CRISPR/Cas9-mediated knockout in DLBCL cell lines. DNA methylation was found to participate in transcriptional regulation of miRNA-363-3p. Further investigation revealed that dual specificity phosphatase 10 (DUSP10) is a target of miRNA-363-3p and its suppression promotes the phosphorylation of c-Jun N-terminal kinase (JNK). The miRNA-363-3p/DUSP10/JNK axis was predominantly associated with negative regulation of homologous recombination (HR) and DNA repair pathways. Ectopic expression of miRNA-363-3p more effectively repaired doxorubicin-induced double-strand break (DSB) while enhancing non-homologous end joining repair and reducing HR repair. Targeting JNK and poly (ADP-ribose) polymerase 1 significantly inhibited doxorubicin-induced DSB repair, increased doxorubicin-induced cell apoptosis and tumor shrinkage, and improved the survival of tumor-bearing mice. In conclusion, the miRNA-363-3p/DUSP10/JNK axis is a novel chemoresistance mechanism in DLBCL that may be reversed by targeted therapy.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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