Paclitaxel-induced Immune Dysfunction and Activation of Transcription Factor AP-1 Facilitate Hepatitis B Virus Replication

作者全名："Chen, Shi; Li, Benhua; Luo, Wei; Rehman, Adeel Ur; He, Miao; Yang, Qian; Wang, Shunyao; Guo, Jinjun; Chen, Ling; Li, Xiaosong"

作者地址："[Chen, Shi; Li, Benhua; Rehman, Adeel Ur; Yang, Qian; Wang, Shunyao; Li, Xiaosong] Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing, Peoples R China; [Luo, Wei] Southwest Med Univ, Affiliated Tradit Chinese Med Hosp, Luzhou, Sichuan, Peoples R China; [He, Miao] Chongqing Med Univ, Lab Anim Ctr, Chongqing, Peoples R China; [Guo, Jinjun] Chongqing Med Univ, Bishan Hosp, Bishan Hosp Chongqing, Chongqing, Peoples R China; [Chen, Ling] Chongqing Med Univ, Ctr Expt Teaching Management, Chongqing, Peoples R China"

通信作者："Li, XS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing, Peoples R China.; Chen, L (通讯作者)，Chongqing Med Univ, Ctr Expt Teaching Management, Chongqing, Peoples R China."

来源：JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY

ESI学科分类：　

WOS号：WOS:001181539700001

JCR分区：Q2

影响因子：3.1

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Paclitaxel; HBV reactivation; Transcription factor; AP-1; Immune system; Gut microbiota

摘要："Background and Aims: Hepatitis B virus (HBV) reactivation is commonly observed in individuals with chronic HBV infection undergoing antineoplastic drug therapy. Paclitaxel (PTX) treatment has been identified as a potential trigger for HBV reactivation. This study aimed to uncover the mechanisms of PTX-induced HBV reactivation in vitro and in vivo, which may inform new strategies for HBV antiviral treatment. Methods: The impact of PTX on HBV replication was assessed through various methods including enzyme-linked immunosorbent assay, dual-luciferase reporter assay, quantitative real-time PCR, chromatin immunoprecipitation, and immunohistochemical staining. Transcriptome sequencing and 16S rRNA sequencing were employed to assess alterations in the transcriptome and microbial diversity in PTX-treated HBV transgenic mice. Results: PTX enhanced the levels of HBV 3.5 -kb mRNA, HBV DNA, HBeAg, and HBsAg both in vitro and in vivo. PTX also promoted the activity of the HBV core promoter and transcription factor AP -1. Inhibition of AP -1 gene expression markedly suppressed PTX-induced HBV reactivation. Transcriptome sequencing revealed that PTX activated the immune-related signaling networks such as IL-17, NF kappa B, and MAPK signaling pathways, with the pivotal common key molecule being AP -1. The 16S rRNA sequencing revealed that PTX induced dysbiosis of gut microbiota. Conclusions: PTX-induced HBV reactivation was likely a synergistic outcome of immune suppression and direct stimulation of HBV replication through the enhancement of HBV core promoter activity mediated by the transcription factor AP -1. These findings propose a novel molecular mechanism, underscoring the critical role of AP -1 in PTX-induced HBV reactivation."

基金机构：Innovation and Development Joint Fund of Chongqing Natural Science Foundation [CST-B2023NSCQ-LZX0099]; Chongqing Science and Health Joint Medical High-end Talent Project [2022GDRC012]; Chongqing Biomedical R&D Major Special Project [CSTB2022TIAD-STX0013]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K202100402]; CQMU Program for Youth Innovation in Future Medicine [W0073]; Southwest Medical University and Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University Joint Project; [2020XYLH-021]

基金资助正文："This received financial support from various sources including the Innovation and Development Joint Fund of Chongqing Natural Science Foundation (Grant number CST-B2023NSCQ-LZX0099) , Chongqing Science and Health Joint Medical High-end Talent Project (Grant No. 2022GDRC012) , Chongqing Biomedical R&D Major Special Project (Grant No. CSTB2022TIAD-STX0013) , Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202100402) , CQMU Program for Youth Innovation in Future Medicine (Grant No. W0073) , and the Southwest Medical University and Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University Joint Project (Grant No. 2020XYLH-021) ."