与地塞米松、硼替佐米和沙利度胺糖皮质激素依赖方案治疗的多发性骨髓瘤反应相关的糖皮质激素受体亚型的mRNA表达及调控

The mRNA Expression and Regulation of Glucocorticoid Receptor Isoforms Associated with Response of Multiple Myeloma Treated with a Glucocorticoids-Dependent Regimen of Dexamethasone, Bortezomib and Thalidomide.

作者信息

Guan Yanchun, Si Yang, Cai Wei, Ma Liangliang, Fang Meiyun

机构信息

Department of Rheumatology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

出版信息

Ann Clin Lab Sci. 2021 Nov;51(6):805-817.

DOI:

PMID:34921034

Abstract

OBJECTIVE

Glucocorticoids (GCs) are the effective first-line drugs and indispensable in chemotherapy regimens to treat patients with multiple myeloma (MM). Previous studies in a variety of hematologic malignancies have shown that the biological action of GC is mediated through the expression and activation and of glucocorticoids receptor (GR) isoforms . GR and its regulation are crucial determinants of the efficacy of GC independent therapy. There is currently lack of research on patients with MM.

METHODS

132 patients with MM were divided into responders (78 cases) and nonresponders (54 cases) according to the efficacy evaluated after four cycles of GC-dependent regimen. 66 patients with iron-deficiency anemia were served as controls. Preparation of mononuclear bone marrow cells (MBMCs) was purified by Ficoll-Hypaque gradient centrifugation. The mRNA expression of GR α, β, γ, P, SRp30, SRp40, HSP90, NF-κB and AP-1 were detected by real time RT-PCR.

TRIAL REGISTRATION

CHiCTR-RCH-12002872.

RESULTS

The expression of four GR isoforms exhibited the following trend in MM patients and controls: GRα>GR-P>GRγ>GRβ. GRα and HSP90 expression in responders was significantly higher than that of the nonresponders (<0.050). HSP90/GRα expression in MM patients exhibited significantly higher than that in controls (<0.001). SRp30c and SRp40 mRNA expression both showed significant positive correlation with GRα transcript (<0.001). Compared with controls, NF-kB and AP -1 expression in MM patients was higher. NF-kB and AP-1 expression of nonresponders were significantly higher than that of responders. The difference was not obvious statistically (>0.050).

CONCLUSION

Our findings raise the possibility that low expression of GRα and HSP90 plays important roles in nonresponders. Lack of HSP90 might affect GR structure and further take part in nonresponse. SRp30c and SRp40 mRNA expression both showed significant positive correlation with GRα. That might become new targets for treatment of nonresponders in MM patients, although further studies are needed for clarification.

摘要

目的

糖皮质激素（GCs）是治疗多发性骨髓瘤（MM）患者的有效一线药物，在化疗方案中不可或缺。先前在多种血液系统恶性肿瘤中的研究表明，GC的生物学作用是通过糖皮质激素受体（GR）亚型的表达、激活介导的。GR及其调控是GC独立治疗疗效的关键决定因素。目前缺乏对MM患者的相关研究。

方法

根据GC依赖方案四个周期后评估的疗效，将132例MM患者分为反应者（78例）和无反应者（54例）。66例缺铁性贫血患者作为对照。通过Ficoll-Hypaque梯度离心法纯化制备单核骨髓细胞（MBMCs）。采用实时RT-PCR检测GRα、β、γ、P、SRp30、SRp40、HSP90、NF-κB和AP-1的mRNA表达。

试验注册

CHiCTR-RCH-12002872。

结果

MM患者和对照组中四种GR亚型的表达呈现以下趋势：GRα>GR-P>GRγ>GRβ。反应者中GRα和HSP90的表达显著高于无反应者（<0.050）。MM患者中HSP90/GRα的表达显著高于对照组（<0.001）。SRp30c和SRp40 mRNA表达均与GRα转录本呈显著正相关（<0.001）。与对照组相比，MM患者中NF-κB和AP-1的表达更高。无反应者中NF-κB和AP-1的表达显著高于反应者。差异无统计学意义（>0.050）。