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PACAP and VIP regulate hypoxia-inducible factors in neuroblastoma cells exposed to hypoxia.

Neuropeptides. 2018 Jun;69:84-91. Epub 2018 Apr 17
Grazia Maugeri 1 , Agata Grazia D'Amico 2 , Daniela Maria Rasà 1 , Salvatore Saccone 3 , Concetta Federico 3 , Sebastiano Cavallaro 4 , Velia D'Agata 5
Grazia Maugeri 1 , Agata Grazia D'Amico 2 , Daniela Maria Rasà 1 , Salvatore Saccone 3 , Concetta Federico 3 , Sebastiano Cavallaro 4 , Velia D'Agata 5
+ et al

[No authors listed]

Author information
  • 1 Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
  • 2 Department of Human Science and Promotion of quality of Life, San Raffaele Open University of Rome, Italy.
  • 3 Section of Animal Biology, Department of Biological, Geological and Environmental Sciences, University of Catania, Italy.
  • 4 Institute of Neurological Sciences, National Research Council, Catania, Italy.
  • 5 Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy. Electronic address: vdagata@unict.it.

摘要


Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two related peptides acting as neurotransmitters/neuromodulators in central and peripheral nervous system. They are also involved in cancer showing a controversial role. Particulary, they are implicated in neuroblastoma differentiation (NB). This pediatric tumor can evolve to a malignant metastatic disease or spontaneously regress towards a benign form, known as ganglioneuroblastoma/ganglioneuroma. A negative hallmark of neoplasia progression is represented by hypoxic microenvironment. Low oxygen tension induces activation of hypoxia-inducible factors (HIFs) promoting cells proliferation and metastasis formation. Moreover, HIFs trigger vascular endothelial growth factor (VEGF) release favouring high-risk NB phenotype development. In the present work, we have investigated for the first time, if PACAP and VIP interfere with NB differentiation through modulation of hypoxic/angiogenic process. To this end, we analyzed their effect in malignant undifferentiated and all-trans retinoic acid (RA) differentiated SH-SY5Y cells, representing the benign form of this tumor. Our results have suggested tha both peptides, but predominantly VIP, induce NB differentiation into benign form by regulating HIFs, VEGF and VEGFRs expression and distribution. All these data give new insight regarding PACAP/VIP regulatory role in NB progression.

KEYWORDS: Hypoxia-inducible factors, Neuroblastoma, PACAP, VIP