Regulation of neuropeptide Y mRNA expression in cultured human pheochromocytoma cells

Liu, Jianqi; Kahri, A I; Heikkilä, Päivi; Voutilainen, Raimo

doi:10.1530/eje.0.1410431

Cited by 11 publications

(7 citation statements)

References 22 publications

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“…3A, right). This decline is consistent with previous findings that treatment with dexamethasone reduced NPY messenger ribonucleic acid accumulation in cultured human pheochromocytoma cells (30). Targeted ablation of the GR in the nervous system of transgenic mice results in a significant increase of NPY expression (31).…”

Section: Discussionsupporting

confidence: 93%

Neuropeptide Y (NPY)

Zhang

Rao

Miramontes-González

et al. 2012

Journal of the American College of Cardiology

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Objectives This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. Background The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. Methods Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. Results Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇−880Δ (2-bp TG/—, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h2) stress traits: higher NPY secretion (h2 = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇−880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele −880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter −880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same −880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. Conclusions We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇−880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

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Section: Discussionsupporting

confidence: 93%

Neuropeptide Y (NPY)

Zhang

Rao

Miramontes-González

et al. 2012

Journal of the American College of Cardiology

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“…We did not observe any correlation between NPY and PCa grade and stage. However, lower NPY had already been found to be associated with less differentiated tumors ( 74 , 75 ). Additionally, Gleason score of ≤7 and low pro-NPY expression were associated with a lower risk of death than high NPY expression or high Gleason score in one study ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors

et al. 2021

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BackgroundCancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear.MethodsThe present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients’ age, tumor stage, grade, angioinvasion, and ERG status were examined.ResultsThe study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression.ConclusionsThe analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.

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“…In parallel with high concentrations of circulating NPY immunoreactivity, in these tumors, especially in the malignant forms, there is also an increase in NPY mRNA levels. The extent of NPY expression, however, does not always correlate with malignancy, indicating that it is not a reliable marker for distinguishing malignant from benign pheochromocytomas [74].…”

Section: Pheochromocytomamentioning

confidence: 98%

Relevance of the Neuropeptide Y System in the Biology of Cancer Progression

Ruscica¹,

Dozio²,

Motta³

et al. 2007

CTMC

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The peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure, known as PP-fold. Within this family of peptides, NPY, a highly conserved 36-aminoacid residue peptide, is involved in the regulation of a wide range of physiological functions, such as food intake and energy metabolism, as well as in the promotion of some remarkable aspects of tumor progression, including cell proliferation, matrix invasion, metastatization, and angiogenesis. NPY exerts its biological effects through five G-protein coupled receptors, named Y1-, Y2-, Y4-, Y5-, and y6-R, which appear associated with different aspects of oncogenesis. Y1-R seems involved in the modulation of cancer cell proliferation, whereas Y2-R activation appears to promote angiogenesis. The development of NPY receptor subtype selective analogs has helped to elucidate the physiological and pathophysiological role and localization of each receptor and may contribute to a better understanding of the receptor-ligand interaction. The NPY system appears to be variously associated with specific tumors, including neural crest-derived tumors, breast and prostate cancers. In addition to NPY, PYY is also able to affect cancer cell growth in a dose-dependent manner and through Y-Rs. In conclusion, peptides of the NPY family and the related receptors play an important role in the progression of different cancer types, with some molecular specificity according to each step of this process. On this basis, future studies may be directed to the implementation of novel diagnostic and therapeutic approaches targeting this system.

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Regulation of neuropeptide Y mRNA expression in cultured human pheochromocytoma cells

Cited by 11 publications

References 22 publications

Neuropeptide Y (NPY)

Neuropeptide Y (NPY)

Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors

Relevance of the Neuropeptide Y System in the Biology of Cancer Progression

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