Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma

Wu,Xiao; Liu,Bao‑Jun; Ji,Shumeng; Wu,Jing‑Feng; Xu,Chang‑Qing; Du,Yi‑Jie; You,Xiao‑Fang; Li,Bei; Le,Jing‑Jing; Xu,Hai‑Lin; Duan,Xiao‑Hong; Dong,Jing‑Cheng

doi:10.3892/mmr.2015.3559

Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma

Authors:
- Xiao Wu
- Bao‑Jun Liu
- Shumeng Ji
- Jing‑Feng Wu
- Chang‑Qing Xu
- Yi‑Jie Du
- Xiao‑Fang You
- Bei Li
- Jing‑Jing Le
- Hai‑Lin Xu
- Xiao‑Hong Duan
- Jing‑Cheng Dong
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Affiliations: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China, Department of Dermatology, Xintai People's Hospital, Xintai, Shandong 271200, P.R. China, Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China, Department of Childhood and Adolescence, Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, P.R. China
Published online on: March 27, 2015 https://doi.org/10.3892/mmr.2015.3559
Pages: 1405-1412

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Abstract

Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal‑regulated kinase (pERK), matrix metalloproteinase (MMP)‑2 and MMP‑9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor‑stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR‑2 and L1CAM mRNA as well as pERK, MMP‑2 and MMP‑9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP‑2 and MMP‑9 protein expression.

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