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

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 in vitro. 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 (P<0.050). HSP90/GRα expression in MM patients exhibited significantly higher than that in controls (P<0.001). SRp30c and SRp40 mRNA expression both showed significant positive correlation with GRα transcript (P<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 (P>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.

Keywords: activating protein-1; glucocorticoid receptor isoform; heat shock protein 90; multiple myeloma; nonresponse; nuclear factor-kappa B; serine/arginine-rich protein.