Transcriptional Repression of Raf Kinase Inhibitory Protein Gene by Metadherin during Cancer Progression

Raf kinase inhibitory protein (RKIP), also known as a phosphatidylethanolamine-binding protein 1 (PEBP1), functions as a tumor suppressor and regulates several signaling pathways, including ERK and NF-κκB. RKIP is severely downregulated in human malignant cancers, indicating a functional association with cancer metastasis and poor prognosis. The transcription regulation of RKIP gene in human cancers is not well understood. In this study, we suggested a possible transcription mechanism for the regulation of RKIP in human cancer cells. We found that Metadherin (MTDH) significantly repressed the transcriptional activity of RKIP gene. An analysis of publicly available datasets showed that the knockdown of MTDH in breast and endometrial cancer cell lines induced the expression RKIP. In addition, the results obtained from qRT-PCR and ChIP analyses showed that MTDH considerably inhibited RKIP expression. In addition, the RKIP transcript levels in MTDH-knockdown or MTDH-overexpressing MCF-7 cells were likely correlated to the protein levels, suggesting that MTDH regulates RKIP expression. In conclusion, we suggest that MTDH is a novel factor that controls the RKIP transcription, which is essential for cancer progression.

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Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice

Scientific Reports ◽

10.1038/s41598-021-01667-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuko Kondo-Takuma ◽

Masayuki Mizuno ◽

Yo Tsuda ◽

Yuta Madokoro ◽

Kengo Suzuki ◽

...

Keyword(s):

Knockout Mice ◽

Direct Reduction ◽

Explant Culture ◽

Precursor Protein ◽

Inhibitory Protein ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Peptide Precursor ◽

Hippocampal Network ◽

Phosphatidylethanolamine Binding Protein

AbstractThe cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

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Human Organoid and Supporting Technologies for Cancer and Toxicological Research

Frontiers in Genetics ◽

10.3389/fgene.2021.759366 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keisuke Sekine

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Cancer Metastasis ◽

Human Cancer ◽

Cancer Tissue ◽

Carcinogenic Activity ◽

Cultured Cell ◽

Human Cancer Cells ◽

Cell Culture Systems ◽

Different Genetic Background

Recent progress in the field of organoid-based cell culture systems has enabled the use of patient-derived cells in conditions that resemble those in cancer tissue, which are better than two-dimensional (2D) cultured cell lines. In particular, organoids allow human cancer cells to be handled in conditions that resemble those in cancer tissue, resulting in more efficient establishment of cells compared with 2D cultured cell lines, thus enabling the use of multiple patient-derived cells with cells from different genetic background, in keeping with the heterogeneity of the cells. One of the most valuable points of using organoids is that human cells from either healthy or cancerous tissue can be used. Using genome editing technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein, organoid genomes can be modified to, for example, cancer-prone genomes. The normal, cancer, or genome-modified organoids can be used to evaluate whether chemicals have genotoxic or non-genotoxic carcinogenic activity by evaluating the cancer incidence, cancer progression, and cancer metastasis. In this review, the organoid technology and the accompanying technologies were summarized and the advantages of organoid-based toxicology and its application to pancreatic cancer study were discussed.

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Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein

Oncotarget ◽

10.18632/oncotarget.18698 ◽

2017 ◽

Vol 8 (40) ◽

pp. 67439-67456 ◽

Cited By ~ 11

Author(s):

Sonja I. Buschow ◽

Matteo Ramazzotti ◽

Inge M.J. Reinieren-Beeren ◽

Lucie M. Heinzerling ◽

Harm Westdorp ◽

...

Keyword(s):

Dendritic Cell ◽

Metastatic Melanoma ◽

Binding Protein ◽

Dendritic Cell Vaccination ◽

Inhibitory Protein ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Melanoma Patients ◽

Phosphatidylethanolamine Binding Protein

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Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20215367 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5367

Author(s):

Madokoro ◽

Yoshino ◽

Kato ◽

Sato ◽

Mizuno ◽

...

Keyword(s):

Precursor Protein ◽

Inhibitory Protein ◽

Cholinergic Activity ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Peptide Precursor ◽

Hippocampal Network ◽

Medial Septal Nucleus ◽

Phosphatidylethanolamine Binding Protein ◽

Cholinergic Projection

The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network.

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