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MDM2 induces EMT via the B‑Raf signaling pathway through 14‑3‑3.

ABSTRACT: MDM2 proto‑oncogene, E3 ubiquitin protein ligase (MDM2) is a well‑known oncogene and has been reported to be closely associated with epithelial‑to‑mesenchymal transition (EMT). The present study first demonstrated that the expression levels of MDM2 were markedly increased in TGF‑β‑induced EMT using quantitative PCR and western blotting. In addition, MDM2 was demonstrated to be associated with pathological grade in clinical glioma samples by immunohistochemical staining. Furthermore, overexpression of MDM2 promoted EMT in glioma, lung cancer and breast cancer cell lines using a scratch wound migration assay. Subsequently, the present study explored the mechanism by which MDM2 promoted EMT and revealed that MDM2 induced EMT by upregulating EMT‑related transcription factors via activation of the B‑Raf signaling pathway through tyrosine 3‑monooxygenase activation protein ε using RNA sequencing and western blotting. This mechanism depended on the p53 gene. Furthermore, in vivo experiments and the colony formation experiment demonstrated that MDM2 could promote tumor progression and induce EMT via the B‑Raf signaling pathway. Since EMT contributes to increased drug resistance in tumor cells, the present study also explored the relationship between MDM2 and drug sensitivity using an MTT assay, and identified that MDM2 promoted cell insensitivity to silibinin treatment in an EMT‑dependent manner. This finding is crucial for the development of cancer therapies and can also provide novel research avenues for future biological and clinical studies.

SUBMITTER: Ou M

PROVIDER: S-EPMC8129971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cortistatin-14 (CST-14), a recently discovered cyclic neuropeptide, can bind to all five cloned somatostatin receptors (SSTRs) and ghrelin receptor to exert its biological activities and co-exists with GABA within the cortex and hippocampus. However, the role of CST-14 in the control of depression processes is not still clarified. Here, we tested the behavioral effects of CST-14 in the in a variety of classical rodent models of depression [forced swimming test (FST), tail suspension test (TST) and novelty-suppressed feeding test]. In the models of depression, CST-14 produced antidepressant-like effects, and does not altered locomotor activity levels. And, we found that CST-14 mRNA and BDNF mRNA were significantly decreased in the hippocampus and cortex after mice exposed to stress. Further data show that i.c.v. administration of CST-14 produce rapid antidepressant effects, and does not altered locomotor activity levels. Then these antidepressant-like effects were significantly reversed by [D-Lys3]GHRP-6 (ghrelin receptor antagonist), but not c-SOM (SSTRs antagonist). Meanwhile, the effects of some neurotransmitter blockers indicates that only GABAA system, but not CRF1 receptor, ?/?-adrenergic receptor, is involved in the antidepressant effect of CST-14. The effects of the mTOR inhibitor (rapamycin), the PI3K inhibitor (LY294002) and the p-ERK1/2 inhibitor (U0126) suggesting that the ERK/mTOR or PI3K/Akt/mTOR signaling pathway is not involved in the antidepressant effects of CST-14. Interestingly, intranasal administration of CST-14 led to reducing depressive-like behavior, and near-infrared fluorescent experiments showed the real-time in vivo bio-distribution in brain after intranasal infusion of Cy7.5-CST-14. Taken all together, the results of present study point to a role for CST-14 in the modulation of depression processes via the ghrelin and GABAA receptor, and suggest cortistation may represent a novel strategy for the treatment of depression disorders. Highlights: -CST-14 and BDNF mRNA are decreased in hippocampus and cortex once mice exposed to stress.-i.c.v. or intranasal administration of CST-14 produce rapid antidepressant effects.-NIR fluorescence imaging detected the brain uptake and distribution after intranasal CST-14.-Antidepressant effects of CST-14 were only related to ghrelin and GABAA system.-Co-injection of CST-14 and NPS produce antidepressant effect, and do not impair memory.

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MDM2 induces EMT via the B‑Raf signaling pathway through 14‑3‑3.

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