Circulating miR‑451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma

Abstract

The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4–8 weeks before positive results were obtained via MFC, and 4–16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.

miR-139-5p and miR-451a as a Diagnostic Biomarker in LUSC

“… 21 In peripheral blood of patients with multiple myeloma, circulating miR-451a levels may be a novel biomarker and play a role in monitoring minimal residual disease and predicting recurrence in patients. 22 …”

“…21 In peripheral blood of patients with multiple myeloma, circulating miR-451a levels may be a novel biomarker and play a role in monitoring minimal residual disease and predicting recurrence in patients. 22 In adrenocortical carcinoma, a higher level of miR-139-5p has been associated with worse OS compared with a low miR-139-5p level. In patients with HCC, miR-139-5p is also a prognostic indicator, and its expression is negatively correlated with OS and relapse-free survival (RFS).…”

The microRNA-451a/chromosome segregation 1-like axis suppresses cell proliferation, migration, and invasion and induces apoptosis in nasopharyngeal carcinoma

“…For example, miR-451a suppresses disease aggressiveness in papillary thyroid cancer [ 35 ]. Moreover, its down-regulated expression in multiple myeloma promoted cancer relapse in patients [ 44 ]. Furthermore, exogenous miR-451a expression can inhibit drug resistance and restore drug sensitivity in patients with acute myeloid leukemia [ 45 ].…”