MiRNA-363-3p/DUSP10/JNK axis mediates chemoresistance by enhancing DNA damage repair in diffuse large B-cell lymphoma
Wenping Zhou, Yuanlin Xu, Jiuyang Zhang, Peipei Zhang, Zhihua Yao, Zheng Yan, Haiying Wang, Junfeng Chu, Shuna Yao, Shuang Zhao, Shujun Yang, Yongjun Guo, Jinxin Miao, Kangdong Liu, Wing C. Chan, Qingxin Xia, Yanyan Liu
Abstract
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.