Multimodal Role of PACAP in Glioblastoma

D’Amico, Agata Grazia; Maugeri, Grazia; Vanella, Luca; Pittalà, Valeria; Reglődi, Dóra; D’Agata, Velia

doi:10.3390/brainsci11080994

Cited by 13 publications

(12 citation statements)

References 144 publications

(158 reference statements)

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“…PACAP plays a role in neuronal excitability (May et al 2021 ), urinary bladder activity (Girard et al 2021 ), gastrointestinal motility and secretion (Karpiesiuk and Palus 2021 ; Reglodi et al 2018 ; Rytel et al 2021 ), cartilage and bone formation (Jozsa et al 2021 ), and reproduction and embryonal growth (Koves et al 2020 ; Ross et al 2018 ; Shan et al 2021 ) and it also has immunomodulatory functions (Abad and Tan 2018 ). Several studies show that PACAP plays important roles in numerous pathological conditions such as tumor growth and proliferation (D’Amico et al 2021b , c ; Maugeri et al 2018a , 2021 ; Moody et al 2016 ) and nervous system disorders (Moody and Jensen 2021 ) like migraine, schizophrenia, anxiety, and depression (Eslami et al 2021 ; Kormos et al 2016 ; Martelle et al 2021 ; Ross et al 2020 ; Tiihonen et al 2021 ) as well as inflammatory conditions (Moody and Jensen 2021 ; Tamas et al 2021 ), sudden infant death syndrome (Shi et al 2021 ), and hearing loss (Fulop et al 2019 ; Ruel et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide with widespread distribution and diverse biological functions. Several studies show that PACAP has strong cytoprotective effects mediated mostly through its specific PAC1 receptor (PAC1-R) and it plays important roles in several pathological conditions. Its distribution and altered expression are known in various human tissues, but there is no descriptive data about PACAP and its receptors in the human eyebulb. Since PACAP38 is the dominant form of the naturally occurring PACAP, our aim was to investigate the distribution of PACAP38-like immunoreactivity in the human eye and to describe the presence of PAC1-R. Semiquantitative evaluation was performed after routine histology and immunohistochemical labeling on human eye sections. Our results showed high level of immunopositivity in the corneal epithelium and endothelium. Within the vascular layer, the iris and the ciliary body had strong immunopositivity for both PACAP and PAC1-R. Several layers of the retina showed immunoreactivity for PACAP and PAC1-R, but the ganglion cell layer had a special pattern in the immunolabeling. Labeling was observed in the neuropil within the optic nerve in both cases and glial cells displayed immunoreactivity for PAC1-R. In summary, our study indicates the widespread occurrence of PACAP and its specific receptor in the human eye, implying that the results from in vitro and animal studies have translational value and most probably are also present in the human eye.

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Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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“…In addition, a recent study conducted by Shen demonstrated that HIF-1α expression is parallel with VEGF expression, and both expressions are positively correlated with poor prognosis of ovarian cancer [ 7 ]. In contrast, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1R suppress angiogenic pathway and mesenchymal markers, such as vimentin and MMP-2 by inhibition of MAPK/PI3K/Akt signaling in the hypoxia niche of glioblastoma [ 8 , 9 ]. Maugeri et al indicated that caffeine exerts anti-tumor effects on glioblastoma multiforme (GBM), characterized by extensive hypoxia through significant downregulation of HIF-1α as well as VEGF [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Endoglin Modulates TGFβR2 Induced VEGF and Proinflammatory Cytokine Axis Mediated Angiogenesis in Prolonged DEHP-Exposed Breast Cancer Cells

et al. 2022

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Angiogenesis is the process of vascular network development and plays a crucial role in cancer growth, progression, and metastasis. Phthalates are a class of environmental pollutants that have detrimental effects on human health and are reported to increase cancer risk. However, the interplay between phthalate exposure and angiogenesis has not been investigated thoroughly. In this study, we investigated the effect of prolonged di (2-ethylhexyl) phthalate (DEHP) treatment on the angiogenic potential of triple-negative breast cancer. MDA-MB-231 cells were exposed to physiological concentrations of DEHP for more than three months. Prolonged DEHP exposure induced angiogenesis in breast cancer cells. Endoglin (ENG)/CD105 is a membrane glycoprotein and an auxiliary receptor of the TGFβ receptor complex. In endothelial cells, ENG is highly expressed and it is a prerequisite for developmental angiogenesis. A literature review highlights endoglin as a well-known mesenchymal stem cell marker responsible for vascular development and angiogenesis. NGS analysis showed that endoglin overexpression in DEHP-exposed MDA-MB-231 cells correlated with tumor development and growth. An in vivo zebrafish xenograft assay showed that VEGFA induced sprouting of the subintestinal vein (SIV) in embryos injected with DEHP-exposed cells. Endoglin knockdown reduced SIV sprouting and VEGFA expression in zebrafish embryos. An in vitro HUVEC tube formation assay showed that endoglin depletion reversed DEHP-induced VEGF-mediated HUVEC tube formation in coculture. DEHP-induced endoglin activated TGFβ/SMAD3/VEGF and MAPK/p38 signaling in MDA-MB-231 cells. A cytokine angiogenesis antibody array showed induced expression of the inflammatory cytokines IL1α, IL1β, IL6, and IL8, along with GMCSF and VEGF. Endoglin knockdown reversed DEHP-induced activation of the TGFβ/SMAD3/VEGF signaling axis, MAPK/p38 signaling, and cytokine regulation, limiting angiogenesis potential both in vivo and in vitro. Targeting endoglin might serve as a potential alternative treatment to control angiogenesis, leading to metastasis and limiting cancer progression.

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“…Glioma is one of the most common malignant tumors of the central nervous system. According to the glioma grading classification criteria of the World Health Organization (WHO), gliomas are divided into Grade 1, 2, 3, and 4 [ 1 , 2 ]. Grade 1 and 2 gliomas belong to low-grade gliomas (LGGs) while Grade 3 and 4 gliomas are high-grade gliomas (HGGs).…”

Section: Introductionmentioning

confidence: 99%

PTPRN Serves as a Prognostic Biomarker and Correlated with Immune Infiltrates in Low Grade Glioma

Chen

Yao

et al. 2022

Brain Sciences

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Background: Glioma is one of the most common malignant tumors of the central nervous system. Immune infiltration of tumor microenvironment was associated with overall survival in low grade glioma (LGG). However, effects of Tyrosine phosphatase receptor type N (PTPRN) on the progress of LGG and its correlation with tumor infiltration are unclear. Methods: Here, datasets of LGG were from The Cancer Genome Atlas (TCGA) and normal samples were from GTEx dataset. Gepia website and Human Protein Atlas (HPA) Database were used to analyze the mRNA and protein expression of PTPRN. We evaluated the influence of PTPRN on survival of LGG patients. MethSurv was used to explore the expression and prognostic patterns of single CpG methylation of PTPRN gene in LGG. The correlations between the clinical information and PTPRN expression were analyzed using logistic regression and Multivariate Cox regression. We also explored the correlation between PTPRN expression and cancer immune infiltration by TIMER. Gene set enrichment analysis (GSEA) was formed using TCGA RNA-seq datasets. Results: PTPRN mRNA and protein expression decreased in LGG compared to normal brain tissue in TCGA and HPA database. Kaplan-Meier analysis showed that the high expression level of PTPRN correlated with a good overall survival (OS) of patients with LGG. The Multivariate Cox analysis demonstrated that PTPRN expression and other clinical-pathological factors (age, WHO grade, IDH status, and primary therapy outcome) significantly correlated with OS of LGG patients. The DNA methylation pattern of PTPRN with significant prognostic value were confirmed, including cg00672332, cg06971096, cg01382864, cg03970036, cg10140638, cg16166796, cg03545227, and cg25569248. Interestingly, PTPRN expression level significantly negatively correlated with infiltrating level of B cell, CD4+ T cells, Macrophages, Neutrophils, and DCs in LGG. Finally, GSEA showed that signaling pathways, mainly associated with tumor microenvironment and immune cells, were significantly enriched in PTPRN high expression. Conclusion: PTPRN is a potential biomarker and correlates with tumor immune infiltration in LGG.

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Multimodal Role of PACAP in Glioblastoma

Cited by 13 publications

References 144 publications

Distribution of PACAP and PAC1 Receptor in the Human Eye

Distribution of PACAP and PAC1 Receptor in the Human Eye

Endoglin Modulates TGFβR2 Induced VEGF and Proinflammatory Cytokine Axis Mediated Angiogenesis in Prolonged DEHP-Exposed Breast Cancer Cells

PTPRN Serves as a Prognostic Biomarker and Correlated with Immune Infiltrates in Low Grade Glioma

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