TNF 受体 2 基因敲除小鼠通过降低 TrkB 依赖性 BDNF 水平,减少了肺癌生长和类似精神分裂症的行为

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-04-09 DOI:10.1007/s12272-024-01487-0
In Jun Yeo, Ji Eun Yu, Sung-Hyun Kim, Dae Hwan Kim, Miran Jo, Dong Ju Son, Jaesuk Yun, Sang-Bae Han, Jin Tae Hong
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引用次数: 0

摘要

精神分裂症(SCZ)与癌症发展之间的关系仍存在争议。基于疾病基因关联平台,研究发现肿瘤坏死因子受体(TNFR)可能是癌症和精神分裂症发展的重要介导因素。TNF-α还能增加脑源性神经营养因子(BDNF)和肌钙蛋白受体激酶B(TrkB)在SCZ和肿瘤发生发展过程中的表达,但TNFR在介导两种疾病关联中的作用仍不清楚。我们利用A549肺癌细胞异种移植TNFR2基因敲除小鼠研究了TNFR2在肿瘤进展和SCZ样行为中的重要作用。与野生型小鼠相比,TNFR2基因敲除小鼠的肿瘤大小和重量以及精神分裂症样行为均明显减少。与肿瘤生长和类似精神分裂症行为的减少相一致,TNFR2基因敲除小鼠肺部肿瘤组织和前额叶皮层中的TrkB和BDNF表达水平也明显下降。然而,给TNFR2基因敲除小鼠静脉注射BDNF(160 μg/kg)4周后,肿瘤生长和SCZ样行为以及TrkB的表达均有所增加。体外研究发现,在 A549 肺癌细胞中转染 siTNFR2 后,细胞生长和 TrkB 及 BDNF 的表达均明显下降。然而,在 TNFR2 siRNA 转染的 A549 肺癌细胞中加入 BDNF(100 ng/ml)后,细胞生长和 TrkB 的表达均得到恢复。这些结果表明,TNFR2可能是通过增加依赖于TrkB的BDNF水平来介导肺肿瘤生长和SCZ发展的一个重要因素。
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TNF receptor 2 knockout mouse had reduced lung cancer growth and schizophrenia-like behavior through a decrease in TrkB-dependent BDNF level

The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 μg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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