Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

Abstract

Abstract. The identification of a specific molecular marker for aggressiveness of nonfunctioning pituitary adenomas (NFPAs) is urgently required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, low expression of secreted frizzled-related protein 2 (sFRP2) in NFPAs was demonstrated by reverse transcription-quantitative polymerase chain reaction, western blot and immunohistochemical analyses. The results confirmed an abnormal accumulation of free β-catenin in the nuclei of NFPAs, which is the core step for the activation of the Wnt canonical signaling pathway. Furthermore, cyclin D1 and c-Myc, the downstream proteins of the Wnt canonical signaling pathway, were overexpressed in aggressive NFPAs. These findings demonstrated the activation of the Wnt canonical signaling pathway in aggressive NFPAs. In addition, sFRP2 expression was observed to be inversely correlated to the aggressiveness of NFPAs. Therefore, sFRP2 may act as a tumor suppressor through modulation of the cellular cytosolic pool of β-catenin in NFPAs. Furthermore, the expression of sFRP2 may serve as a biomarker for NFPAs aggressiveness and prognosis.

Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas

“…In this study, PTMScan experiment found the increased level of Bcl9 in NFPAs, and upregulations of many target genes such as c-Myc and c-Jun in canonical Wnt pathway. Moreover, some studies clearly demonstrated that β-catenin was accumulated in the nucleus of NFPAs (22), several Wnt target genes such as Cyclin D1 and c-MY were upregulated in NFPAs (21,22), and the inhibitor of Wnt pathway including Wnt inhibitory factor 1 (WIF1) and secreted frizzled related protein (sFRP) were significantly decreased in NFPAs (22,46). All these data revealed that canonical Wnt pathway was activated in NFPAs to participate in cell apoptosis, proliferation, differentiation, and motility.…”

Decreased expression of SFRP2 promotes development of the pituitary corticotroph adenoma by upregulating Wnt signaling

“…Thus, SFRP2 may be a useful marker for predicting characteristics of pituitary ACTH adenoma. In fact, researchers have already reported that SFRP2 expression is associated with the degree of tumor malignancy and invasive ability in various human cancers ( 12 , 18 ). However, this is the first description of the aberrant expression of SFRP2 in the tumorigenesis of CD.…”

“…The 5 µ m thick sections were prepared from the formalin-fixed and paraffin embedded tissues (3 NHP and 23 CD). IHC staining was performed as previously reported ( 12 ). Specific primary antibody against SFRP2 (dilution 1:200; cat.…”

“…The staining percentage was graded as follows: 0–25% staining, 1; 26–50% staining, 2; 51–75% staining, 3; and 76–100% staining, 4. The immunoreactive score was calculated as intensity of the staining multiplied by the percentage of positive cells, which was then categorized as low (0–6) and high ( 7 – 12 ) expression.…”

“…Thus, decreased expression of SFRP2 results in upregulation of Wnt/β-catenin signaling, which regulates diverse developmental processes, such as differentiation, cell migration, cell adhesion and proliferation ( 7 ). In fact, it has been reported that decreased expression of SFRP2 activates Wnt/β-catenin signaling, which promotes the development of various tumors types, including colorectal cancer ( 8 ), esophageal carcinoma ( 9 ), medulloblastoma ( 10 ), hepatocellular carcinoma ( 11 ) and aggressive nonfunctioning pituitary adenoma ( 12 ).…”