Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

Falch, Camilla Maria; Sundaram, Arvind; Øystese, Kristin Astrid Berland; Normann, Kjersti Ringvoll; Lekva, Tove; Silamiķelis, Ivars; Eieland, Alexander Kirkeby; Andersen, Marianne; Bollerslev, Jens; Olarescu, Nicoleta Cristina

doi:10.1530/eje-17-0702

Cited by 23 publications

(13 citation statements)

References 43 publications

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“…The ECM plays a critical role in tumorigenesis and invasiveness/aggressiveness in several cancers, being a bridge between cell differentiation and proliferation, angiogenesis, and cell motility. The epithelial–mesenchymal transition process (EMT) has previously been studied in several subtypes of pituitary tumors and found to be of importance for both hormone production and aggressiveness [ 38 , 39 , 40 , 41 ]. Interestingly, in a recent multi-omics study, the silent corticotroph tumors presented low EMT, whereas USP8-wild-type functioning tumors showed and increased EMT, somehow challenging the classical imagistic phenotype of SCA as an aggressive tumor [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

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

Eieland

Normann

Sundaram

et al. 2020

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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

Eieland

Normann

Sundaram

et al. 2020

Cancers

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“…PAs containing side population cells that are depleted from endothelial and immune cells, express the properties of tumor stem cell, including EMT-linked factors (22). Gonadotroph adenomas of different growth rates present different gene expression profiles: the higher expression levels of genes are related to EMT resting in the fast-growing tumors (23). Our research is the first study to investigate genome-wide mRNA expression based on Five-Tiered prognostic classification of PitNETs.…”

Section: Discussionmentioning

confidence: 94%

JAG1, Regulated by microRNA-424-3p, Involved in Tumorigenesis and Epithelial–Mesenchymal Transition of High Proliferative Potential-Pituitary Adenomas

Chen

Feng

et al. 2020

Front. Oncol.

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Pituitary adenomas (PAs) are a neoplastic proliferation of anterior pituitary. Signature of Notch pathway relies upon the histopathological type of PAs. The details of Notch pathway that are involved in the migration and invasion of Pas are still unclear. This paper filters and testifies the relation between Notch signaling pathway and the migration/invasion in subtypes of PAs. The diversity of genes and pathways is investigated based on transcriptome data of 60 patients by KEGG pathway analysis and GSEA. A series of functional experiments demonstrate the role of candidate genes by overexpression and antibody blocking in GH3 cell line. Volcano map and GSEA results exhibit the differential and the priority of Jagged1 canonical Notch Ligand (JAG1) in the Notch pathway combined with clinical features. JAG1 is involved in epithelial–mesenchymal transition (EMT) in PAs by correlation analysis of RNA-seq data. Progression-free survival (PFS) of patients with high JAG1 was shorter than patients with low JAG1 according to follow-up data (P = 0.006). Furthermore, overexpression and antibody blocking experiments in GH3 cell line indicate that JAG1 could promote cell proliferation, migration, and G1/S transition. Double luciferase reporter assay gives manifests that JAG1 is the target gene of miR-424-3p, and mimics or inhibitor of miR-424-3p can regulate the level of JAG1 which, in turn, affects cell proliferation and the levels of MMP2 and VIM in GH3 cell line, respectively. Our study delves into the relation between the Notch signaling pathway and cell proliferation and EMT in PAs, providing a potential treatment through targeting JAG1.

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“…Falch et al . compared the transcriptome of fast‐growing GT with slow growing GT (51). The only gene differentially expressed in both studies was LGALS3BP .…”

Section: Discussionmentioning

confidence: 99%

Gonadotroph tumours with a low SF‐1 labelling index are more likely to recur and are associated with enrichment of the PI3K‐AKT pathway

Hickman

Bruce

Otten

et al. 2020

Neuropathology Appl Neurobio

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Aims: The gonadotroph tumour (GT) is the most frequently resected pituitary neuroendocrine tumour. Although many symptomatic GT are successfully resected, some recur. We sought to identify histological biomarkers that may predict recurrence and explore biological mechanisms that explain this difference in behaviour. Methods: SF-1 immunohistochemistry of 51 GT, a subset belonging to a longitudinal prospective cohort study (n = 25), was reviewed. Four groups were defined: Group 1recently diagnosed GT (n = 20), Group 2-non-recurrent GT with long-term follow up (n = 11), Group 3-initial resections of GT that recur (n = 7) and Group 4-recurrent GT (n = 13). The percentage of SF-1 immunolabelling in the lowest staining fields (SF-1 labelling index (SLI)) was assessed and RNA sequencing was performed on 5 GT with SLI <80% and 5 GT with SLI >80%. Results: Diffuse, strong SF-1 immunolabelling was the most frequent pattern in Groups 1/2, whereas patchy SF-1 staining predominated in Groups 3/4. There was a lower median SLI in Groups 3/4 than 1/2. Overall, GT with SLI <80% recurred earlier than GT with SLI >80%. Differential expression analysis identified 89 statistically significant differentially expressed genes (FDR <0.05) including over-expression of pituitary stem cell genes (SOX2, GFRA3) and various oncogenes (e.g. BCL2, ERRB4) in patchy SF-1 GT. Gene set enrichment analysis identified significant enrichment of genes involved in the PI3K-AKT pathway. Conclusions: We speculate that patchy SF-1 labelling in GT reflects intratumoural heterogeneity and are less differentiated tumours than diffusely staining GT. SF-1 immunolabelling patterns may have prognostic significance in GT, but confirmatory studies are needed for further validation.

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Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

Cited by 23 publications

References 43 publications

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

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

JAG1, Regulated by microRNA-424-3p, Involved in Tumorigenesis and Epithelial–Mesenchymal Transition of High Proliferative Potential-Pituitary Adenomas

Gonadotroph tumours with a low SF‐1 labelling index are more likely to recur and are associated with enrichment of the PI3K‐AKT pathway

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