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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Multiple Myeloma | Research

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis

Authors: Xiaobin Wang, Yingqing Shi, Hua Shi, Xiaoyu Liu, Aijun Liao, Zhuogang Liu, Robert Z. Orlowski, Rui Zhang, Huihan Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation.

Methods

We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay.

Results

This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM.

Conclusion

Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

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Title: MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis
Authors: Xiaobin Wang
Yingqing Shi
Hua Shi
Xiaoyu Liu
Aijun Liao
Zhuogang Liu
Robert Z. Orlowski
Rui Zhang
Huihan Wang
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Multiple Myeloma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-02972-6

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Abstract

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