Neuropeptide Y regulates proliferation and apoptosis in granulosa cells in a follicular stage-dependent manner

Urata, Yoko; Salehi, Reza; Lima, Patrícia; Osuga, Yutaka; Tsang, Benjamin K.

doi:10.1186/s13048-019-0608-z

Cited by 16 publications

(18 citation statements)

References 39 publications

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“…Moreover, NPY5R in granulosa cells varies among follicular stage and its response is strong at early antral (EA) stage. NPY5R regulates granulosa cell proliferation in a follicular stage-dependent manner, with an induction at EA and suppression at late antral follicles ( Urata et al, 2020 ). Conversely, NPY-induced increases in VEGF expression in 4T1 cells were attenuated only under Y5R antagonism ( Medeiros and Jackson, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking the NPY5R gene failed to prefer food odors over pheromones after fasting ( Horio and Liberles, 2021 ). Additionally, it was reported that NPY5R was involved in regulating the proliferation and apoptosis of granulosa cells ( Urata et al, 2020 ). More recently, NPY5R was found to be a molecular marker for tumorigenesis of HR (+)/HER2 (−) BC in adolescents and young adults ( Yi and Zhou, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Methylation Biomarker NPY5R Sensitizes Breast Cancer Cells to Chemotherapy

Liu

Wang

Sun

et al. 2022

Front. Cell Dev. Biol.

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Breast cancer (BC) is the most common tumor in women, and the molecular mechanism underlying its pathogenesis remains unclear. In this study, we aimed to investigate gene modules related to the phenotypes of BC, and identify representative candidate biomarkers for clinical prognosis of BC patients. Using weighted gene co-expression network analysis, we here identified NPY5R as a hub gene in BC. We further found that NPY5R was frequently downregulated in BC tissues compared with adjacent tumor-matched control tissues, due to its aberrant promoter CpG methylation which was confirmed by methylation analysis and treatment with demethylation agent. Higher expression of NPY5R was closely associated with better prognosis for BC patients. Gene set enrichment analysis showed that transcriptome signatures concerning apoptosis and cell cycle were critically enriched in specimens with elevated NPY5R. Ectopic expression of NPY5R significantly curbed breast tumor cell growth, induced cell apoptosis and G2/M arrest. Moreover, NPY5R also promoted the sensitivity of BC cells to doxorubicin. Mechanistically, we found that NPY5R restricted STAT3 signaling pathway activation through interacting with IL6, which may be responsible for the antitumor activity of NPY5R. Collectively, our findings indicate that NPY5R functions as a tumor suppressor but was frequently downregulated in BC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Novel Methylation Biomarker NPY5R Sensitizes Breast Cancer Cells to Chemotherapy

Liu

Wang

Sun

et al. 2022

Front. Cell Dev. Biol.

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“…8). Genes examined that were putatively up-regulated by FSH glycoforms included: a) Phospholipase D1 ( Pld1 ), which encodes an enzyme implicated in a number of cellular pathways, including signal transduction mediated by GPCRs and receptor tyrosine kinases, subcellular trafficking, and regulation of mitosis [57]; b) Neuropeptide Y (NPY) receptor Y1 ( Npy1R ), which encodes for a GPCR involved in Npy-regulated granulosa cell proliferation and apoptosis [58, 59]; c) Antimüllerian hormone gene ( Amh ), encoding a glycoprotein belonging to the transforming growth factor beta superfamily, which is involved in follicular development [60]; and d) Vascular endothelial growth factor B ( Vegf-B ), a gene that encodes the VEGF-B protein, a factor involved in angiogenesis [61]. The FSH down-regulated gene examined was BCL2 like 1 ( Bcl2l1 ) which acts as anti-or pro-apoptotic regulators that are involved in a wide variety of cellular activities [62], including prolactin signaling [63].…”

Section: Resultsmentioning

confidence: 99%

Differential effects of follicle-stimulating hormone glycoforms on the transcriptome profile of cultured rat granulosa cells as disclosed by RNA-seq

Zariñán,

Espinal-Enriquez,

De Anda-Jáuregui

et al. 2023

Preprint

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It has been documented that variations in glycosylation on glycoprotein hormones, confer distinctly different biological features to the corresponding glycoforms when multiple in vitro biochemical readings are analyzed. We here applied next generation RNA sequencing to explore changes in the transcriptome of rat granulosa cells exposed for 0, 6, and 12 h to 100 ng/ml of four highly purified follicle-stimulating hormone (FSH) glycoforms, each exhibiting different glycosylation patterns: human pituitary FSH18/21 and equine FSH (eqFSH) (hypo-glycosylated), and human FSH24 and chinese-hamster ovary cell-derived human recombinant FSH (recFSH) (fully-glycosylated). Total RNA from triplicate incubations was prepared from FSH glycoform-exposed cultured granulosa cells obtained from DES-pretreated immature female rats, and RNA libraries were sequenced in a HighSeq 2500 sequencer (2 x 125 bp paired-end format, 10-15 x 106 reads/sample). The computational workflow focused on investigating differences among the four FSH glycoforms at three levels: gene expression, enriched biological processes, and perturbed pathways. Among the top 200 differentially expressed genes, only 4 (0.6%) were shared by all 4 glycoforms at 6 h, whereas 118 genes (40%) were shared at 12 h. Follicle-stimulating hormone glycocoforms stimulated different patterns of exclusive and associated up regulated biological processes in a glycoform and time-dependent fashion with more shared biological processes after 12 h of exposure and fewer treatment-specific ones, except for recFSH, which exhibited stronger responses with more specifically associated processes at this time. Similar results were found for down-regulated processes, with a greater number of processes at 6 h or 12 h, depending on the particular glycoform. In general, there were fewer downregulated than upregulated processes at both 6 h and 12 h, with FSH18/21 exhibiting the largest number of down-regulated associated processes at 6 h while eqFSH exhibited the greatest number at 12 h. Signaling cascades, largely linked to cAMP-PKA, MAPK, and PI3/AKT pathways were detected as differentially activated by the glycoforms, with each glycoform exhibiting its own molecular signature. These data extend previous observations demonstrating glycosylation-dependent differential regulation of gene expression and intracellular signaling pathways triggered by FSH in granulosa cells. The results also suggest the importance of individual FSH glycoform glycosylation for the conformation of the ligand-receptor complex and induced signalling pathways.

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“…Receptors of NPY, ghrelin, GLP‐1 and GIP among other gut hormones are present in the hypothalamus, pituitary, adrenal glands or ovaries of women. Expression of NPY and its receptors Y1, Y2, Y4 and Y5 have been reported in ovarian granulosa cells regulating their proliferation and apoptosis 63 . Ghrelin and its receptor GHSR‐1a are found in human and animal ovaries 64 .…”

Section: Gut Hormones In Infertilitymentioning

confidence: 99%

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment

Sridhar,

Khan,

Moffett

2023

Diabet Med

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Obesity poses an enormous threat to life expectancy and quality of life in people with associated metabolic comorbidities. Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and polycystic ovarian syndrome (PCOS). Recently, gut hormones and their receptors have been identified in various reproductive organs indicating their potential regulatory effects on reproductive function. This review focuses on modifications during obesity, diabetes and related infertility with an emphasis on gut hormones and their therapeutic potential. Evidence suggests that bariatric surgery has positive effects on fertility and PCOS where major alterations in metabolism occurs through restoration of gut hormone levels. This is thought to be due to the indirect effect weight loss and regulation of blood glucose has on the hypothalamic‐pituitary‐ovarian and hypothalamic‐pituitary‐adrenal axis influencing reproduction. Further research is required to elucidate the cellular mechanisms involved in the direct effects of gut hormone receptor activation on reproductive tissues. Current observations suggest a therapeutic role for gut hormones in infertility/PCOS associated with metabolic pathophysiology.

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Neuropeptide Y regulates proliferation and apoptosis in granulosa cells in a follicular stage-dependent manner

Cited by 16 publications

References 39 publications

The Novel Methylation Biomarker NPY5R Sensitizes Breast Cancer Cells to Chemotherapy

The Novel Methylation Biomarker NPY5R Sensitizes Breast Cancer Cells to Chemotherapy

Differential effects of follicle-stimulating hormone glycoforms on the transcriptome profile of cultured rat granulosa cells as disclosed by RNA-seq

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment

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