miR-26a Plays an Important Role in Cell Cycle Regulation in ACTH-Secreting Pituitary Adenomas by Modulating Protein Kinase Cδ

Abstract The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cδ (PRKCD) is a direct target of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing's disease.

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The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Endocrine Related Cancer ◽

10.1530/erc-15-0109 ◽

2015 ◽

Vol 22 (5) ◽

pp. 793-803 ◽

Cited By ~ 9

Author(s):

Katharina Lampichler ◽

Patricio Ferrer ◽

Greisa Vila ◽

Mirjam I Lutz ◽

Florian Wolf ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Pituitary Adenoma ◽

Cell Survival ◽

Pituitary Adenomas ◽

Target Gene ◽

Human Pituitary ◽

Hh Signaling

The Hedgehog (Hh) pathway is an important regulator of early tissue patterning and stem cell propagation. It was found to be aberrantly activated in numerous types of human cancer and might be relevant in cancer stem cells. The identification of adult stem cells in the pituitary raised the question if tumor-initiating cells and Hh signaling are involved in pituitary adenoma formation. The present study aimed at the evaluation of Hh signaling in relation to stem cell and cell cycle markers in 30 human pituitary adenomas and in cultured murine adenoma cells. Therefore, expression levels of components of the Hh pathway, stem cell marker SOX2, cell cycle regulator tumor-protein 53 (TP53), proliferation marker Ki67 (MKI67) and superoxide dismutase 1 (SOD1) were evaluated in 30 human pituitary adenomas in comparison to control tissue. Modulation of cell function and target gene expression by the inhibition and activation of the Hh pathway were studied in murine adenoma cells. We show that transcription factor glioma-associated oncogene 1 (GLI1) is overexpressed in 87% of all pituitary adenomas. The expression of GLI1 significantly correlated with that of SOX2, TP53, MKI67 and SOD1. Inhibition of GLI1 resulted in the downregulation of the above genes and severe cell death in mouse adenoma cells. On the other hand, activation of the Hh pathway increased cell viability and target gene expression. In conclusion, our findings point toward an alternative, ligand-independent Hh pathway activation with GLI1 playing a major role in the cell survival of pituitary adenoma cells.

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Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

Yearbook of Endocrinology ◽

10.1016/s0084-3741(08)79040-1 ◽

2008 ◽

Vol 2008 ◽

pp. 343-344

Author(s):

W. Ludlam

Keyword(s):

Pituitary Adenoma ◽

Matrix Metalloproteinase ◽

Cell Line ◽

Pituitary Adenomas ◽

Matrix Metalloproteinase 9 ◽

Differentially Expressed ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Adenoma Cell ◽

Metalloproteinase 9

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Pituitary adenoma in aged rats. A case report

Journal of the Hellenic Veterinary Medical Society ◽

10.12681/jhvms.14948 ◽

2018 ◽

Vol 59 (1) ◽

pp. 58

Author(s):

M KATSIMPOULAS ◽

M FOTEINOU ◽

E PARONIS ◽

P ALEXAKOS ◽

N KOSTOMITSOPOULOS

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Large Scale ◽

Laboratory Animals ◽

Neoplastic Disease ◽

Aged Rats ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Neoplastic Lesion ◽

Toxicological Studies

The prevalence of neoplastic disease in the rat is well defined, because this species has been routinely used for decades in large-scale carcinogenic, aging and toxicological studies. Stock and strain-specific differences in the prevalence of some types of tumors are well documented. Pituitary adenoma is a neoplastic lesion which can be observed in older or aged rats of both sexes. In addition to sex, strain, diet, genetic factor, breeding history and accommodation may also play a role. Pituitary adenoma can also affect hamster, guinea pig and mice. The aim of this article is to report an incidence of pituitary adenomas, which was observed in a rat breeding colony of the Center for Experimental Surgery of the Biomedical Research Foundation of the Academy of Athens. During the clinical examination five female Wistar rats, at the age of 18 to 24 months old, expressed anorexia, weight loss, ataxia and bilateral blindness. At necropsy, the pituitary gland was enlarged with lobulations, often dark red to brown and hemorrhagic in appearance. In some cases there was a marked compression of the overlying mesencephalon. Histological examination with haematoxylin-eosin were observed cords and nests of glandular cells bound by strands of connective tissue, with an abundant capillary network. On immunohistochemical examination were observed strong positive reaction of synaptophysin. Findings were similar to pituitary adenoma. Pituitary adenoma is a serious non-reversible disease leading to the death of the animal. Laboratory animals with pituitary adenomas can be used as models in research of human pituitary adenoma.

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Magmas, a Gene Newly Identified as Overexpressed in Human and Mouse ACTH-Secreting Pituitary Adenomas, Protects Pituitary Cells from Apoptotic Stimuli

Endocrinology ◽

10.1210/en.2010-0441 ◽

2010 ◽

Vol 151 (10) ◽

pp. 4635-4642 ◽

Cited By ~ 23

Author(s):

Federico Tagliati ◽

Erica Gentilin ◽

Mattia Buratto ◽

Daniela Molè ◽

Ettore Ciro degli Uberti ◽

...

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Mitochondrial Protein ◽

Pituitary Tumors ◽

Pituitary Cells ◽

Subcellular Compartment ◽

Adenoma Cell ◽

Macrophage Colony ◽

Reduced Rate ◽

Acth Secreting

Pituitary tumors are mostly benign, being locally invasive in 5–35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH-secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation.

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Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

American Journal Of Pathology ◽

10.2353/ajpath.2007.060736 ◽

2007 ◽

Vol 170 (1) ◽

pp. 356-365 ◽

Cited By ~ 68

Author(s):

Isa M. Hussaini ◽

Christy Trotter ◽

Yunge Zhao ◽

Rana Abdel-Fattah ◽

Samson Amos ◽

...

Keyword(s):

Pituitary Adenoma ◽

Matrix Metalloproteinase ◽

Cell Line ◽

Pituitary Adenomas ◽

Matrix Metalloproteinase 9 ◽

Differentially Expressed ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Adenoma Cell ◽

Metalloproteinase 9

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IL-18 expression in clinical human pituitary adenoma

Technology and Health Care ◽

10.3233/thc-191967 ◽

2021 ◽

pp. 1-6

Author(s):

Qi Shao ◽

Ning Liu ◽

Guo-Fu Li ◽

Qian-Cheng Meng ◽

Jia-Hao Yao ◽

...

Keyword(s):

Pituitary Adenoma ◽

Mrna Expression ◽

Pituitary Adenomas ◽

Adrenocorticotropic Hormone ◽

Pituitary Tumors ◽

Thyroid Stimulating Hormone ◽

Mrna Levels ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Real Time Quantitative Pcr

BACKGROUND: IL-18 is known as an interferon-inducing factor that belongs to the IL-1 family, and is synthesized as an inactive precursor protein. OBJECTIVE: The present study aims to investigate the expression of IL-18, IL-18R, R and IL-18 binding protein (BP) mRNA in various types of human pituitary tumors, such as adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH)-producing adenomas and non-function adenomas. METHODS: Pituitary adenoma tissues were obtained during the surgery of 41 patients: nine patients had ACTH-producing pituitary adenomas, nine patients had GH-producing pituitary adenomas, five patients had TSH-producing pituitary adenomas, seven patients had PRL-producing pituitary adenomas, and 11 patients had non-functioning adenomas. The mRNA expression levels of IL-18, IL-18BP, IL-18R and IL-18R were quantified using real-time quantitative PCR. RESULTS: The mRNA expression of IL-18 was significantly higher in ACTH-, GH- and PRL-producing adenomas, when compared to non-function tumors. Similarly, a significantly higher mRNA expression of IL-18BP and IL-18R was observed in ACTH-, GH- and PRL-producing adenomas, when compared with non-functional adenomas. In contrast, no upregulation of IL-18R mRNA was observed in any of the pituitary adenomas. CONCLUSIONS: The mRNA levels of IL-18, IL-18BP and IL-18R are significantly elevated in clinical pituitary tumors, such as ACTH-, GH- and PRL-producing adenomas, when compared to non-functional adenomas. These present results suggest the possibility that IL-18 may be involved in the pathogenesis of pituitary adenoma.

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Characterization of SNARE Proteins in Human Pituitary Adenomas: Targeted Secretion Inhibitors as a New Strategy for the Treatment of Acromegaly?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2602 ◽

2013 ◽

Vol 98 (12) ◽

pp. E1918-E1926 ◽

Cited By ~ 6

Author(s):

Edwin A. Garcia ◽

Giampaolo Trivellin ◽

Elena D. Aflorei ◽

Michael Powell ◽

Joana Grieve ◽

...

Keyword(s):

Catalytic Activity ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Hormone Secretion ◽

Snare Proteins ◽

University Hospitals ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Gh Secretion ◽

Ghrh Receptor

Context: Targeted secretion inhibitors (TSIs), a new class of recombinant biotherapeutic proteins engineered from botulinum toxin, represent a novel approach for treating diseases with excess secretion. They inhibit hormone secretion from targeted cell types through cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) proteins. qGHRH-LHN/D is a TSI targeting pituitary somatotroph through binding to the GHRH-receptor and cleavage of the vesicle-associated membrane protein (VAMP) family of SNARE proteins. Objective: Our objective was to study SNARE protein expression in pituitary adenomas and to inhibit GH secretion from somatotropinomas using qGHRH-LHN/D. Design: We analyzed human pituitary adenoma analysis for SNARE expression and response to qGHRH-LHN/D treatment. Setting: The study was conducted in University Hospitals. Patients: We used pituitary adenoma samples from 25 acromegaly and 47 nonfunctioning pituitary adenoma patients. Outcome: Vesicle-SNARE (VAMP1–3), target-SNARE (syntaxin1, SNAP-23, and SNAP-25), and GHRH-receptor detection with RT-qPCR, immunocytochemistry, and immunoblotting. Assessment of TSI catalytic activity on VAMPs and release of GH from adenoma cells. Results: SNARE proteins were variably expressed in pituitary samples. In vitro evidence using recombinant GFP-VAMP2&3 or pituitary adenoma lysates suggested sufficient catalytic activity of qGHRH-LHN/D to degrade VAMPs, but was unable to inhibit GH secretion in somatotropinoma cell cultures. Conclusions: SNARE proteins are present in human pituitary somatotroph adenomas that can be targeted by TSIs to inhibit GH secretion. qGHRH-LHN/D was unable to inhibit GH secretion from human somatotroph adenoma cells. Further studies are required to understand how the SNARE proteins drive GH secretion in human somatotrophs to allow the development of novel TSIs with a potential therapeutic benefit.

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PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

Protein and Peptide Letters ◽

10.2174/0929866526666190722145449 ◽

2019 ◽

Vol 26 (11) ◽

pp. 800-818

Author(s):

Zujian Xiong ◽

Xuejun Li ◽

Qi Yang

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Cell Cycle Progression ◽

Key Factors ◽

Cycle Progression ◽

Sister Chromatids ◽

Regulation Of Cell Cycle ◽

Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

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