Dataset Information

Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial-Mesenchymal Transition in Glioblastoma.

ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial-Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regulate these events. Results have demonstrated that PACAP and its related receptor, PAC1R, are expressed in hypoxic area of human GBM colocalizing either in epithelial or mesenchymal cells. By using an in vitro model of GBM cells, we have observed that PACAP interferes with hypoxic/angiogenic pathway by reducing vascular-endothelial growth factor (VEGF) release and inhibiting formation of vessel-like structures in H5V endothelial cells cultured with GBM-conditioned medium. Moreover, PACAP treatment decreased the expression of mesenchymal markers such as vimentin, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) as well as CD44 in GBM cells by affecting their invasiveness. In conclusion, our study provides new insights regarding the multimodal role of PACAP in GBM malignancy.

SUBMITTER: Maugeri G

PROVIDER: S-EPMC8392618 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial-Mesenchymal Transition in Glioblastoma.

Maugeri Grazia G D'Amico Agata Grazia AG Saccone Salvatore S Federico Concetta C Rasà Daniela Maria DM Caltabiano Rosario R Broggi Giuseppe G Giunta Salvatore S Musumeci Giuseppe G D'Agata Velia V

Biomedicines 20210805 8

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial-Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regu ...[more]

PMID: 34440169

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Project description:Rationale: M2-like tumor-associated macrophages (TAMs) promote the malignant progression of glioblastomas. However, the mechanisms responsible for this phenomenon remain unclear. Methods: RT-PCR, Western blot and flow cytometry were used to evaluate the polarization status of macrophages. RT-PCR, western blot or/and immunohistochemistry was used to determine the expression of circ_0003137, PTBP1, PLOD3 and epithelial-mesenchymal transition (EMT) markers. Transwell assay was used to assess migration and invasion ability of tumor cells. RNA sequencing, bioinformatic analysis and Pearson correlation coefficient was performed to explore the relation between PTBP1 and circ_003137/PLOD3. In vivo experiment was used to determine the role of sh-circ_0003137-loaded nanoplatform. Results: Hypoxia promoted the polarization of macrophages towards M2-like TAMs in an HIF1α dependent manner. Then, M2-like TAMs could transport circ_0003137 enriched extracellular vesicles (EVs) to glioblastoma cells, upregulating circ_0003137 in glioblastoma cells. The circ_0003137 overexpression promoted the EMT of glioblastoma cells in vitro and in vivo. Mechanistically, circ_0003137 physically binds to polypyrimidine tract binding protein 1 (PTBP1), enhancing the stability of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and promoting the EMT of glioblastoma cells. Moreover, a liposome-based nanoplatform that delivers shRNAs was established and used to encapsulate sh-circ_0003137. The fluorescence microscope tracer and cell co-culture assays demonstrated that the nanoplatform encapsulated with sh-circ_0003137 was stable and could penetrate the blood-brain barrier (BBB), finally reaching the central nervous system (CNS). The intracranial in situ tumor model showed that injecting the sh-circ_0003137-loaded nanoplatform via the tail vein significantly inhibited glioblastoma progression and improved the nude mice's survival. Conclusions: Hypoxia can drive macrophage polarization towards M2-like TAMs. Polarized M2-like TAMs can transport circ_0003137 to glioblastoma cells through EVs. Then, circ_0003137 promotes the EMT of glioblastomas by targeting the PTBP1/PLOD3 axis. Hence, targeting circ_0003137 might be a novel therapeutic strategy against glioblastoma.

Dataset Information

Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial-Mesenchymal Transition in Glioblastoma.

Publications

Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial-Mesenchymal Transition in Glioblastoma.

Similar Datasets

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