Differential expression of miRNA199b-5p as a novel biomarker for sporadic and hereditary parathyroid tumors

Abstract

MicroRNAs (miRNAs) are dysregulated in many tumors; however, miRNA regulation in parathyroid tumors remains poorly understood. To identify differentially expressed miRNAs between sporadic and hereditary parathyroid tumors and to analyze their correlation with clinicopathological features, a microarray containing 887 miRNAs was performed; then, the differentially expressed miRNAs were validated by qRT-PCR using 25 sporadic and 12 hereditary parathyroid tumors and 24 normal parathyroid tissue samples. A receiver operating characteristic curve (ROC) analysis was applied to evaluate the utility of the miRNAs for distinguishing parathyroid tumor types. Compared to the miRNAs in the normal parathyroid tissues, 10 miRNAs were differentially expressed between the sporadic and hereditary parathyroid tumors. Seven of these miRNAs (let-7i, miR-365, miR-125a-3p, miR-125a-5p, miR-142-3p, miR-193b, and miR-199b-5p) were validated in the parathyroid tumor samples. Among these miRNAs, only miR-199b-5p was differentially expressed (P < 0.001); miR-199b-5p was significantly downregulated and negatively associated with PTH levels (γ = -0.579, P = 0.002) in the sporadic tumors but was upregulated in the hereditary tumors. This miRNA showed 67% sensitivity and 100% specificity for distinguishing sporadic and hereditary parathyroid tumors. These results reveal altered expression of a miRNA between sporadic and hereditary parathyroid tumors and the potential role of miR-199b-5p as a novel biomarker for distinguishing these two types of parathyroid tumors.

Figure 1

Supervised cluster analysis of miRNA levels in parathyroid tumors. N, normal parathyroid tissue; S, sporadic parathyroid tumor; H, hereditary parathyroid tumor. The data normalized to RNU6 were hierarchically clustered. Red indicates an increase relative to all data in this set, and green indicates a decrease relative to all data in this set.

Figure 2

Validation of most relevant miRNAs by qRT-PCR in parathyroid tumors. Scatterplots show relative expression levels of let-7i, miR-365, miR-125a-3p, miR-125a-5p, miR-142-3p, miR-193b, and miR-199b-5p in 24 normal parathyroid tissues, 25 sporadic, and 12 MEN1 parathyroid tumor samples. Horizontal bars represent the median and interquartile range. P values were calculated using the Mann-Whitney U-test.

Figure 3

Receiver operator characteristic (ROC) curves of miR-199b-5p showing the discrimination between sporadic and hereditary parathyroid tumors.

Figure 4

Different correlations between the relative expression of miR-199b-5p and serum PTH levels in parathyroid tumors. A negative association of miR-199b-5p and PTH levels was found in sporadic parathyroid tumors (γ = −0.579, P = 0.002), but there was no significant correlation for the hereditary parathyroid tumors.

Figure 5

A network predicted to be regulated by miRNA-199b-5p and the MEN1 gene. One predicted network regulated by miRNA-199b-5p and the MEN1 gene was “Gene expression, cellular development, cellular growth and proliferation”.