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Abstract：
Multiple myeloma (MM) is a hematological tumor with high mortality and recurrence rate. Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM. However, the development of drug resistance is a pervasive obstacle to treating MM. Therefore, elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies. To elucidate the mechanisms of carfilzomib resistance, we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells. Differential gene expression analyses revealed major alterations in the major histocompatibility complex (MHC) and cell adhesion molecules. The upregulation of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene was accompanied by the downregulation of MHC genes and cell adhesion molecules. Furthermore, to investigate the roles of these genes, we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules. Furthermore, TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice, indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity. Furthermore, our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules. The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity. Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.
摘要：
多发性骨髓瘤（MM）是一种高死亡率和复发率的血液肿瘤。卡非佐米是新一代蛋白酶体抑制剂，被用作MM的一线治疗。然而,耐药性的发展是治疗MM的普遍障碍。因此,阐明耐药机制有助于制定新的治疗方法。为了阐明卡非佐米耐药的机制，我们检索了GSE78069微阵列数据集,其中包含卡非佐米耐药的LP-1MM细胞和亲本MM细胞.差异基因表达分析揭示了主要组织相容性复合物（MHC）和细胞粘附分子的主要变化。肿瘤坏死因子（TNF）受体超家族成员1A（TNFRSF1A）基因的上调伴随着MHC基因和细胞粘附分子的下调。此外，为了研究这些基因的作用，我们建立了卡非佐米耐药细胞模型，观察到卡非佐米耐药诱导TNFRSF1A过表达和TNFRSF1A沉默逆转了卡非佐米耐药并重新激活了细胞粘附分子的表达。此外，TNFRSF1A沉默抑制免疫活性小鼠MM细胞的肿瘤发生，表明TNFRSF1A可能通过抑制抗肿瘤免疫而导致卡非佐米耐药。此外，我们的结果表明，TNFRSF1A过表达在MM细胞中赋予卡非佐米抗性，并抑制MHC基因和细胞粘附分子的表达。MHC基因和细胞粘附分子的抑制可能会削弱免疫细胞与癌细胞之间的相互作用，从而削弱抗肿瘤免疫力。未来的研究有必要进一步研究TNFRSF1A在MM细胞中的调控作用的信号通路。
