Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Abstract

Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.

Large-Scale Proteomic Analysis of Follicular Lymphoma Reveals Extensive Remodeling of Cell Adhesion Pathway and Identifies Hub Proteins Related to the Lymphomagenesis

“…In line with our reports, the high-throughput sequencing and bioinformatics analyses of several tumors have revealed that CAMs are frequently identified as hub genes based on a PPIN analysis [62][63][64]. These recent studies underline the particular importance of CAMs in tumor development and progression.…”

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

“…These results suggest a reason for the lack of active ACTH secretion from these tumors. Moreover, the extracellular matrix (ECM) protein cluster is downregulated in SCAs compared to functioning ACTHomas, suggesting that this is associated with their invasive behavior (84). TREATMENT Surgery is the first-line treatment to control tumor volume for refractory corticotroph tumors, even though the postoperative recurrence rate remains high (8,85).…”

“…These results suggest a reason for the lack of active ACTH secretion from these tumors. Moreover, the extracellular matrix (ECM) protein cluster is downregulated in SCAs compared to functioning ACTHomas, suggesting that this is associated with their invasive behavior ( 84 ).…”

Genetic Basis of ACTH-Secreting Adenomas

“…Mouse models of SCAs and in vitro studies showed a reduced expression of tumor suppressor genes RB1 and KLK10 , and altered expression of other genes related to tumor progression and metastasis [ 68 ]. Moreover, transcriptome and proteome analysis comparing gene expression between SCAs and functioning corticotrope adenomas identified alterations in endoplasmic reticulum protein processing and in ACTH synthesis such as the overexpression of PCSK1N, an indirect inhibitor of ACTH maturation [ 69 ]. These differences may explain the altered ACTH secretion in SCAs [ 68 , 69 , 70 , 71 ].…”