Whole exome sequencing reveals novel risk genes of pituitary neuroendocrine tumors

Pečulis, Raitis; Rovīte, Vita; Megnis, Kaspars; Balcere, Inga; Breikša, Austra; Nazarovs, Jurijs; Stukēns, Jānis; Konrāde, Ilze; Sokolovska, Jeļizaveta; Pīrāgs, Valdis; Kloviņš, Jānis

doi:10.1371/journal.pone.0265306

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…The reference genome was indexed using Hisat2 v2.0.5, and the paired-end clean reads were aligned to the reference genome. Calculate the read counts mapped to each gene using featureCounts v1.5.0-p3, and then calculate the fragments per kilobase of transcript per million mapped fragments (FPKM) of each gene based on its length and mapped read counts [40,41].…”

Section: Transcriptome Sequencingmentioning

confidence: 99%

Biomimetic composite hydrogel promotes new bone formation in rat bone defects through regulation of miR-19b-3p/WWP1 axis by loaded extracellular vesicles

Guo,

Wu,

Liu

et al. 2023

J Nanobiotechnol

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Objective This study aims to investigate the mechanism by which biomimetic composite hydrogels loaded with bone marrow mesenchymal stem cells (BMSCs) derived microRNA-19b-3p/WWP1 axis through extracellular vesicles (EVs) affect the new bone formation in rat bone defects. Methods First, synthesize the bionic composite hydrogel Gel-OCS/MBGN. Characterize it through field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and FTIR. Then, conduct performance tests such as rheology, dynamic mechanical analysis, in vitro mineralization, and degradation. Rat BMSCs were selected for in vitro cell experiments, and EVs derived from BMSCs were obtained by differential centrifugation. The EVs were loaded onto Gel-OCS/MBGN to obtain Gel-OCS/MBGN@EVs hydrogel. Cell viability and proliferation were detected by live/dead cell staining and CCK-8 assay, respectively. ALP and ARS staining was used to evaluate the osteogenic differentiation of BMSCs. Differential gene expression analysis of osteogenic differentiation was performed using high-throughput sequencing. TargetScan database predicted the binding site between miR-19b-3p and WWP1, and a dual-luciferase reporter assay was performed to confirm the targeting binding site. A rat bone defect model was established, and new bone formation was evaluated by Micro-CT, H&E staining, and Masson's trichrome staining. Immunofluorescence staining and immunohistochemistry were used to detect the expression levels of osteogenic-related factors in rat BMSCs. RT-qPCR and Western blot were used to detect the expression levels of genes and proteins in tissues and cells. Result Gel-OCS/MBGN was successfully constructed and loaded with EVs, resulting in Gel-OCS/MBGN@EVs. The in vitro drug release experiment results show that Gel-OCS/MBGN could sustainably release EVs. Further experiments have shown that Gel-OCS/MBGN@EVs could significantly promote the differentiation of BMSCs into osteoblasts. Experiments have shown that WWP1 is a key factor in osteogenic differentiation and is regulated by miR-19b-3p. EVs promote osteogenic differentiation by suppressing WWP1 expression through the transmission of miR-19b-3p. In vivo animal experiments have demonstrated that Gel-OCS/MBGN@EVs significantly promote bone repair in rats with bone defects by regulating the miR-19b-3p/WWP1 signaling axis. Conclusion Functional Gel-OCS/MBGN@EVs were obtained by constructing Gel-OCS/MBGN and loading EVs onto it. EVs could deliver miR-19b-3p to BMSCs, inhibit the expression of WWP1, and promote the osteogenic differentiation of BMSCs, ultimately promoting bone regeneration in rats with bone defects. Graphical Abstract

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Section: Transcriptome Sequencingmentioning

confidence: 99%

Biomimetic composite hydrogel promotes new bone formation in rat bone defects through regulation of miR-19b-3p/WWP1 axis by loaded extracellular vesicles

Guo,

Wu,

Liu

et al. 2023

J Nanobiotechnol

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“…Hypersecretion usually involves overproduction of growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL) and others. [2] In contrast, non-functioning PitNETs primarily consist of macroadenomas (>10 mm) due to compression of structures in the surrounding region.…”

Section: Introductionmentioning

confidence: 99%

“…Hypersecretion usually involves overproduction of growth hormone (GH), adrenocorticotropic hormone, prolactin, and others. 2 In contrast, nonfunctioning PitNETs primarily consist of macroadenomas (> 10 mm) due to compression of structures in the surrounding region. Gonadotroph tumors, although known to secrete gonadotropins, are typically classified as nonfunctioning as they usually do not cause a clinical syndrome.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-Derived Ligand-Receptor Interactome of Major PitNET Subgroups

Batchu

Diaz

Patel

et al. 2023

J Neurol Surg B Skull Base

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Introduction: ¬¬Pituitary neuroendocrine tumors (PitNETs) are rare skull base tumors that can impart significant disability owing to their locally invasive potential. To date, the gamut of PitNET subtypes remains ill-understood at the ligand-receptor (LR) interactome level, potentially limiting therapeutic options. Here we present findings from in silico analysis of LR complexes formed by PitNETs with clinical presentations of acromegaly, Cushing’s Disease, high prolactin production, and without symptoms of hormone hypersecretion. Methods: Previously published PitNET gene expression data was acquired from ArrayExpress. These data represented all secretion types. LR interactions were analyzed via a crosstalk score approach. Results: CORT ligand was significantly involved in tumor-to-tumor signaling across all PitNET subtypes but prolactinomas, which evidenced active CORT depletion. Likewise, CCL25 ligand was implicated in 20% of the top LR complex interactions along the tumor-to-stroma signaling axis, but silent PitNETs reported unique depletion of the CCL25 ligand. Along the stroma-to-tumor signaling axis, all clinical PitNET subtypes enriched stromal VIP ligand interactions with tumor SCTR. All clinical PitNET subtypes enriched stromal DEFB103B ligand interactions with stromal chemokine receptors along the stroma-to-stroma signaling axis. In PitNETs causing Cushing’s Disease, immune checkpoint ligand CD274 reported high stromal expression, and prolactinomas reported low stromal expression. Moreover, prolactinomas evidenced distinctly high stromal expression of immune-exhausted T cell response marker IL10RA compared to other clinical subtypes. Conclusion: Relative crosstalk score analysis revealed a great diversity of ligand-receptor complex interactions across clinical PitNET subtypes and between solid tumor compartments. More data is needed to exact clinical relevance.

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Whole Genome Sequencing and single-cell transcriptomics identifyKMT2Das a potential new driver for pituitary adenomas

Brunner,

Meylan-Merlini,

Muriset

et al. 2024

Preprint

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The pituitary gland is a main component of the endocrine system and a master controller of hormone production and secretion. Unlike neoplastic formation in other organs, Pituitary Neuroendocrine Tumors (PitNETs) are frequent in the population (16%) and, for unknown reasons, almost exclusively benign. So far, few genes have been identified as drivers for PitNETs, such as GNAS in somatotroph tumors and USP8 in corticotroph tumors. Using whole genome sequencing, we uncover a potential novel driver, the histone methyltransferase KMT2D, in a patient in his 50s suffering from a mixed somato-lactotroph tumor. Coverage ratio between germline and tumor revealed extensive chromosomal alterations. Single-cell RNA sequencing of the tumor shows up-regulation of known tumorigenic pathways compared to a healthy reference, as well as a different immune infiltration profile compared to other PitNETs, more closely resembling the profile of carcinomas than adenomas. Genome-wide DNA methylation analysis identified 792 differentially methylated regions, including notable hypomethylation in the promoter of SPON2, an immune-related gene. Our results show that tumors considered as quiet and non-aggressive can share drivers, features, and epigenetic alterations with metastatic forms of cancer, raising questions about the biological mechanisms controlling their homeostasis.

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Whole exome sequencing reveals novel risk genes of pituitary neuroendocrine tumors

Cited by 3 publications

References 41 publications

Biomimetic composite hydrogel promotes new bone formation in rat bone defects through regulation of miR-19b-3p/WWP1 axis by loaded extracellular vesicles

Biomimetic composite hydrogel promotes new bone formation in rat bone defects through regulation of miR-19b-3p/WWP1 axis by loaded extracellular vesicles

Transcriptome-Derived Ligand-Receptor Interactome of Major PitNET Subgroups

Whole Genome Sequencing and single-cell transcriptomics identifyKMT2Das a potential new driver for pituitary adenomas

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