Hepatic Stellate Cells Activated by Cancer Cell-derived AMIGO2-containing Small Extracellular Vesicles Promote Cancer Cell Migration by Producing IL-8Izutsu, Osaki, Seong
et alAnticancer Res (2025) 45 (4), 1435-1446
Abstract: Our previous studies have demonstrated that amphoterin-induced gene and open reading frame 2 (AMIGO2) functions as a driver gene for liver metastasis, regulating adhesion between cancer cells and liver endothelial cells. AMIGO2-containing small extracellular vesicles (sEVs) derived from gastric cancer (GC) cells were shown to enhance adhesion to hepatic endothelial cells, contributing to pre-metastatic niche formation. However, their role in promoting cancer cell migration into the liver parenchyma remained unclear. This study investigated whether AMIGO2-containing sEVs activate hepatic stellate cells (HSCs) and promote cancer cell migration.AMIGO2-over-expressing and control cell lines (MKN28) were established. sEVs isolated from each cell line were added to human HSCs (TWINT-1). The supernatant collected was added to MKN28 to quantitatively evaluate migration ability and nuclear translocation of NF-kB. A chemokine array identified secreted factors affected by sEV treatment.HSCs were activated by AMIGO2-containing EVs, resulting in increased IL-8 secretion through NF-kB nuclear translocation. This IL-8-rich supernatant significantly enhanced GC cell migration. Neutralizing IL-8 with antibodies suppressed this migration, confirming its pivotal role.AMIGO2-containing sEVs derived from GC cells actively modify the hepatic microenvironment by activating HSCs and inducing IL-8 secretion, which promotes GC cell migration into the liver parenchyma. This process contributes to the formation of a pre-metastatic niche, highlighting AMIGO2-containing sEVs as potential therapeutic targets for preventing liver metastasis.Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
MiR-18a-LncRNA NONRATG-022419 pairs targeted PRG-1 regulates diabetic induced cognitive impairment by regulating NGF\BDNF-Trkb signaling pathwayXiang, Lin, Tao
et alProteome Sci (2025) 23 (1), 1
Abstract: Diabetic encephalopathy (DE) is considered as one of the complications of diabetes,which is associated with cognitive impairment in the pathological process of development. Up to now, phospholipid phosphatase related 4 (Plppr4), also known as plasticity related gene 1 (PRG-1) has been revealed its important role in neuroplasticity. However, the underlying mechanisms of Plppr4 on the basis of diabetic-induced cognitive dysfunction (DCD) are still unknown. The aim of current study was to provide insight into molecular mechanism and cellular heterogeneity underlying DCD, and investigate the functional role of PRG-1 involved in this process.Combined Single-cell RNA sequencing (scRNA-seq) and RNA transcriptome analysis, the distinct sub-populations, functional heterogeneity as well as potential enriched signaling pathways of hippocampal cells could be elucidated.We identified the sub-cluster of type I spiral ganglion neurons expressed marker gene as Amigo2 in cluster8 and Cnr1 in cluster 9 of hippocampal cells from DCD and the effect of those on neuronal cells interaction. We also found that PRG-1 was involved in the synaptic plasticity regulation of hippocampus via NGF\BDNF-Trkb signaling pathway. In high glucose induced HT22 cells injury model in vitro, we investigated that down-regulated PRG-1 along with down-regulated BDNF and also decreased expression of synapsin-1, PSD-95, SYN which are related to synaptic plasticity; Meanwhile, the Prg-1 targeted miR-18a-LncRNA NONRATG-022419 pairs related with significantly down-regulated expression of PRG-1.This study revealed the synaptic plasticity regulation of PRG-1 in DCD, and might provide the therapeutic target and potential biomarkers for early interventions in DCD patients.© 2025. The Author(s).
Perineuronal Nets on CA2 Pyramidal Cells and Parvalbumin-Expressing Cells Differentially Regulate Hippocampal-Dependent MemoryAlexander, Nikolova, Stöber
et alJ Neurosci (2025) 45 (6)
Abstract: Perineuronal nets (PNNs) are a specialized extracellular matrix that surrounds certain populations of neurons, including (inhibitory) parvalbumin (PV)-expressing interneurons throughout the brain and (excitatory) CA2 pyramidal neurons in hippocampus. PNNs are thought to regulate synaptic plasticity by stabilizing synapses and as such, could regulate learning and memory. Most often, PNN functions are queried using enzymatic degradation with chondroitinase, but that approach does not differentiate PNNs on CA2 neurons from those on adjacent PV cells. To disentangle the specific roles of PNNs on CA2 pyramidal cells and PV neurons in behavior, we generated conditional knock-out mouse strains with the primary protein component of PNNs, aggrecan (Acan), deleted from either CA2 pyramidal cells (Amigo2 Acan KO) or from PV cells (PV Acan KO). Male and female animals of each strain were tested for social, fear, and spatial memory, as well as for reversal learning. We found that Amigo2 Acan KO animals, but not PV Acan KO animals, had impaired social memory and reversal learning. PV Acan KOs, but not Amigo2 Acan KOs, had impaired contextual fear memory. These findings demonstrate independent roles for PNNs on each cell type in regulating hippocampal-dependent memory. We further investigated a potential mechanism of impaired social memory in the Amigo2 Acan KO animals and found reduced input to CA2 from the supramammillary nucleus (SuM), which signals social novelty. Additionally, Amigo2 Acan KOs lacked a social novelty-related local field potential response, suggesting that CA2 PNNs may coordinate functional SuM connections and associated physiological responses to social novelty.Copyright © 2024 Alexander et al.
Perineuronal nets on CA2 pyramidal cells and parvalbumin-expressing cells differentially regulate hippocampal dependent memoryAlexander, Nikolova, Stöber
et albioRxiv (2024)
Abstract: Perineuronal nets (PNNs) are a specialized extracellular matrix that surround certain populations of neurons, including (inhibitory) parvalbumin (PV) expressing-interneurons throughout the brain and (excitatory) CA2 pyramidal neurons in hippocampus. PNNs are thought to regulate synaptic plasticity by stabilizing synapses and as such, could regulate learning and memory. Most often, PNN functions are queried using enzymatic degradation with chondroitinase, but that approach does not differentiate PNNs on CA2 neurons from those on adjacent PV cells. To disentangle the specific roles of PNNs on CA2 pyramidal cells and PV neurons in behavior, we generated conditional knockout mouse strains with the primary protein component of PNNs, aggrecan (Acan), deleted from either CA2 pyramidal cells (Amigo2 Acan KO) or from PV cells (PV Acan KO). Male and female animals of each strain were tested for social, fear, and spatial memory, as well as for reversal learning. We found that Amigo2 Acan KO animals, but not PV Acan KO animals, had impaired social memory and reversal learning. PV Acan KOs, but not Amigo2 Acan KOs had impaired contextual fear memory. These findings demonstrate independent roles for PNNs on each cell type in regulating hippocampal-dependent memory. We further investigated a potential mechanism of impaired social memory in the Amigo2 Acan KO animals and found reduced input to CA2 from the supramammillary nucleus (SuM), which signals social novelty. Additionally, Amigo2 Acan KOs lacked a social novelty-related local field potential response, suggesting that CA2 PNNs may coordinate functional SuM connections and associated physiological responses to social novelty.
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