Ruo-Si Zou, Jin-Gang He, Yang Zhao, Bing Zhou, Si-Long Deng, Jian-Guo Chen, Fang Wang
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引用次数: 0
Abstract
Rationale: Depression is commonly comorbid with cancer and affects therapeutic efficacy and outcome-of-disease. However, the molecular mechanism underlying cancer-induced depression (CID) remains poorly understood. Twist1 is a proto-oncogene driving tumor progression and metastasis, and chronic stress induces Twist1 expression in the medial prefrontal cortex (mPFC). This study aims to investigate the role and mechanisms of tumor-derived Twist1 in CID. Methods: shTwist1 stably expressing 4T1 cells were obtained through lentivirus transduction and puromycin selection. Tumor cells were subcutaneously inoculated into mice to establish a tumor-bearing mice model. Behavioral assays were used to assess depressive-like behaviors in mice. Ultra-high-speed centrifugation was employed to extract extracellular vehicles (EVs) in 4T1 cell medium or serum from tumor-bearing mice. Quantitative polymerase chain reaction and western blot were used to detect the levels of Twist1 mRNA and protein from tumor-derived EVs or mPFC tissue. Lentivirus was injected into the mPFC to knock down Twist1. Intravenous or intranasal administration of tumor or serum-derived EVs were used to investigate the role of EVs-packaged Twist1 in depressive-like behaviors in mice. Results: The present study demonstrated that tumor-derived EVs mediated the inter-organ communication between tumor cells and brain. Pharmacological inhibition of EVs secretion mitigated depressive-like behaviors in tumor-bearing mice. Intravenous or intranasal injection of EVs from tumor cells or serum from tumor-bearing mice into naïve mice induced a depressive-like phenotype. Further investigation identified tumor-derived EVs Twsit1 as a crucial mediator of cancer-induced dendritic atrophy and depressive-like behaviors in tumor-bearing mice. Knockdown of Twist1 in tumor cells significantly alleviated the detrimental effects of tumor-derived EVs on neuronal morphogenesis and prevented their pro-depressant effects. Conclusions: This study demonstrates that tumor-derived EVs containing Twist1 constitute a key pathological driver of cancer-induced depression, revealing a potential therapeutic target for clinical intervention.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.