Abstract
PurposeMCM7 (minichromosome maintenance complex component 7), a DNA replication licensing factor, is a host gene for the oncogenic miR-106b~25 cluster. It has been recently revealed as a relevant prognostic biomarker in a variety of cancers, including pituitary adenomas. The purpose of this study was to assess whether miR-106b~25 and MCM7 levels correlate with tumor invasiveness in a cohort of ACTH-immunopositive adenomas.MethodsTissue samples were obtained intraoperatively from 25 patients with pituitary adenoma. Tumor invasiveness was assessed according to the Knosp grading scale. MCM7, Ki-67 and TP53 levels were assessed by immunohistochemical staining, while the expression of miR-106b-5p, miR-93-5p, miR-93-3p and miR-25-3p were measured using quantitative real-time PCR performed on RNA isolated from FFPE tissues.ResultsWe have found a significant increase in MCM7 and Ki-67 labeling indices in invasive ACTHomas. Moreover, MCM7 was ubiquitously overexpressed in Crooke’s cell adenomas. The expression of miR-93-5p was significantly elevated in invasive compared to noninvasive tumors. In addition, all four microRNAs from the miR-106b~25 cluster displayed marked upregulation in Crooke’s cell adenomas. Remarkably, MCM7 and miR-106b-5p both strongly correlated with Knosp grade. A combination of MCM7 LI and miR-106b~25 cluster expression was able to accurately differentiate invasive from noninvasive tumors and had a significant discriminatory ability to predict postoperative tumor recurrence/progression.ConclusionsmiR-106b~25 and its host gene MCM7 are potential novel biomarkers for invasive ACTH-immunopositive pituitary adenomas. Additionally, they are both significantly upregulated in rare Crooke’s cell adenomas and might therefore contribute to their aggressive phenotype.
Highlights
Corticotroph adenomas represent approximately 5–10% of all pituitary adenomas (PAs) [1, 2]
We have found a significant increase in maintenance complex component 7 (MCM7) and Ki-67 labeling indices in invasive ACTHomas
We evaluated the expression of Ki-67, MCM7, TP53 and MGMT and sought associations with the clinicopathological characteristics of PA patients: age, tumor size, tumor invasiveness and the histological variant of the tumor (Table 2)
Summary
Corticotroph adenomas represent approximately 5–10% of all pituitary adenomas (PAs) [1, 2] Their most common clinical manifestation is Cushing’s disease that is caused by hormonally active, adrenocorticotropin (ACTH) secreting tumors. When compared to other types of silent adenomas (mainly null cell and gonadotroph adenomas), silent corticotroph adenomas (SCAs) are considered to recur earlier and more frequently [7,8,9] Based on their morphology observed using electron microscopy and low molecular weight keratin (LMWK)-CAM5.2 immunohistochemical staining, corticotroph adenomas are divided into densely (DG-ACTH) and sparsely (SG-ACTH) granulated that correspond to subtype I and subtype II silent corticotroph adenomas, respectively [10] (Fig. 1a, b). Crooke’s cells are corticotrophs that, in the setting of glucocorticoid excess (regardless of its etiology), undergo massive accumulation of perinuclear cytokeratin filaments, giving their cytoplasm a distinct hyalinized appearance on hematoxylin and eosin stain (Fig. 1c, d)
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