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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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：蛋白酶体抑制剂（PI）是治疗多发性骨髓瘤（MM）的最重要药物之一。然而,几乎所有MM患者都出现PI抵抗，导致治疗失败。因此,MM中PI抵抗的潜在机制需要进一步研究。
方法：我们使用了几种MM细胞系来建立抗PI的MM细胞系。我们在MM细胞系中进行了RNA微阵列和EccDNA-seq，并收集了人类原代MM样品以探索基因谱。我们使用免疫共沉淀（Co-IP）评估了MUC20对PI抗性MM细胞凋亡的影响，海马生物能谱分析和体内测定。
结果：这项研究表明，粘蛋白20（MUC20）的下调可以预测MM患者的PI敏感性和预后。此外,MUC20通过抑制细胞周期蛋白依赖性激酶抑制剂2A表达（CDKN2A）诱导细胞凋亡来减弱MM细胞的PI抗性，这是通过阻碍MET原癌基因来实现的，受体酪氨酸激酶（MET）激活。此外，MUC20通过抑制PI抗性MM细胞中的胰岛素样生长因子受体-1（IGF-1R）的乳酸化抑制MET激活。本研究首次对MM进行染色体外环状DNA(eccDNA)测序,结果表明，eccDNA通过扩增驱动蛋白家族成员3C（KIF3C）来降低MM中MUC20的表达，从而诱导PI抗性。
结论：我们的发现表明，eccDNA调节的MUC20通过调节细胞凋亡来减轻MM的PI抵抗，这将为PI耐药MM的治疗提供新的策略。
方法：我们使用了几种MM细胞系来建立抗PI的MM细胞系。我们在MM细胞系中进行了RNA微阵列和EccDNA-seq，并收集了人类原代MM样品以探索基因谱。我们使用免疫共沉淀（Co-IP）评估了MUC20对PI抗性MM细胞凋亡的影响，海马生物能谱分析和体内测定。
结果：这项研究表明，粘蛋白20（MUC20）的下调可以预测MM患者的PI敏感性和预后。此外,MUC20通过抑制细胞周期蛋白依赖性激酶抑制剂2A表达（CDKN2A）诱导细胞凋亡来减弱MM细胞的PI抗性，这是通过阻碍MET原癌基因来实现的，受体酪氨酸激酶（MET）激活。此外，MUC20通过抑制PI抗性MM细胞中的胰岛素样生长因子受体-1（IGF-1R）的乳酸化抑制MET激活。本研究首次对MM进行染色体外环状DNA(eccDNA)测序,结果表明，eccDNA通过扩增驱动蛋白家族成员3C（KIF3C）来降低MM中MUC20的表达，从而诱导PI抗性。
结论：我们的发现表明，eccDNA调节的MUC20通过调节细胞凋亡来减轻MM的PI抵抗，这将为PI耐药MM的治疗提供新的策略。
