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EGR1-CCL2 Feedback Loop Maintains Epithelial-Mesenchymal Transition of Cisplatin-Resistant Gastric Cancer Cells and Promotes Tumor Angiogenesis

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Abstract

Background

The mechanism of cisplatin resistance in gastric cancer (GC) is still elusive; several recent evidences proposed that chemoresistant tumor cells acquired aggressive behaviors.

Aims

This study was aimed to investigate the mechanism of epithelial-mesenchymal transition (EMT) and angiogenesis in chemoresistant GC.

Methods

Bioinformatics analysis and function or mechanism experiments including RT-qPCR, immunofluorescence, Western blot, luciferase reporter assay, Chromatin immunoprecipitation, Chicken chorioallantoic membrane assay and animal experiments were applied to evaluate the role of EGR1-CCL2 feedback loop.

Results

Compared with the parental cell line SGC7901, cisplatin resistant SGC7901R cells underwent EMT and showed increased angiogenic capabilities. Mechanistically, SGC7901R cells showed increased levels of EGR1, which could transcriptionally activate the angiogenic factor CCL2 and EMT regulator ZEB2. Reciprocally, CCL2 activated the CCR2-ERK-ELK1-EGR1 pathway, thus forming a positive feed-forward loop. Moreover, CCL2 in culture medium of SGC7901R cells promoted angiogenesis of Human Umbilical Vein Endothelial Cells (HUVECs). EGR1 expression was positively correlated with CCL2 and ZEB2 in clinical GC tissues, and the depletion of ERG1 could also decrease microvessel density and ZEB2 expression in metastatic nodules of nude mice.

Conclusions

EGR1-CCL2 feedback loop might exert critical roles on EMT and angiogenesis of chemoresistant GC.

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Funding

This work was supported by the Youth Fund Program of The First Affiliated Hospital of Zhengzhou University.

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Jie Yan, Yaping Gao, Shan Lin, Yi Li & Litong Shi

  2. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East, Zhengzhou, Henan, China

    Jie Yan & Quancheng Kan

Authors
  1. Jie Yan
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  2. Yaping Gao
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  3. Shan Lin
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  4. Yi Li
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Correspondence to Quancheng Kan.

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Yan, J., Gao, Y., Lin, S. et al. EGR1-CCL2 Feedback Loop Maintains Epithelial-Mesenchymal Transition of Cisplatin-Resistant Gastric Cancer Cells and Promotes Tumor Angiogenesis. Dig Dis Sci 67, 3702–3713 (2022). https://doi.org/10.1007/s10620-021-07250-5

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