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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair

Authors: Xing Guo, Donghua He, Enfan Zhang, Jing Chen, Qingxiao Chen, Yi Li, Li Yang, Yang Yang, Yi Zhao, Gang Wang, Jingsong He, Zhen Cai

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear.

Methods

Through gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance.

Results

MM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice.

Conclusions

Our research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.
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Metadata
Title
HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair
Authors
Xing Guo
Donghua He
Enfan Zhang
Jing Chen
Qingxiao Chen
Yi Li
Li Yang
Yang Yang
Yi Zhao
Gang Wang
Jingsong He
Zhen Cai
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0883-3

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