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CCL2-CCL5/CCR4 contributed to radiation-induced epithelial-mesenchymal transition of HPAEpiC cells via the ERK signaling pathways.

ABSTRACT: Radiation-induced lung toxicity, including radiation pneumonitis and pulmonary fibrosis, often occurs in patients receiving radiation therapy. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays critical roles in radiation-induced lung toxicity. In the present study, RNA sequencing was applied to examine the whole transcriptomes of human pulmonary AEC cells (HPAEpiC) with or without radiation treatment. We found that cytokine, chemokine and cell adhesion signaling pathways were enriched in radiation-treated cells. CCL2 (C-C Motif Chemokine Ligand 2), CCL5 and CCR4 (C-C Motif Chemokine Receptor 4) were among the top enriched genes in chemokine signaling pathway. The upregulation of CCL2, CCL5 and CCR4 in response to irradiation was confirmed at both mRNA and protein levels by real-time PCR, western blotting and enzyme-linked immunosorbent assay analyses. Ophiopogonin B, a bioactive ingredient of Radix Ophiopogon japonicas, was found to attenuate radiation-induced EMT in HPAEpiC cells as demonstrated by the alteration in cell morphology, and the expression of E-cadherin and Vimentin. Ophiopogonin B could also reduce radiation-induced expression of CCL2, CCL5, CCR4 and phosphorylated ERK (p-ERK). Moreover, CCR4 knockdown, U0126 (a MEK/ERK inhibitor) or ophiopogonin B also partially blocked the EMT promoting effects of CCL2 and CCL5. Our data suggested CCL2, CCL5 and CCR4 may be potential therapeutic targets for radiation-induced lung toxicity. Ophiopogonin B, which could down-regulate CCL2, CCL5 and CCR4, may be a useful radioprotective agent.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC6413271 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CCL2-CCL5/CCR4 contributed to radiation-induced epithelial-mesenchymal transition of HPAEpiC cells via the ERK signaling pathways.

Zhong Yazhen Y Lin Zechen Z Lu Jinhua J Lin Xianlei X Xu Wei W Wang Nan N Huang Siyu S Wang Yuanyuan Y Zhu Yuan Y Chen Zhu Z Lin Shengyou S

American journal of translational research 20190215 2

Radiation-induced lung toxicity, including radiation pneumonitis and pulmonary fibrosis, often occurs in patients receiving radiation therapy. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays critical roles in radiation-induced lung toxicity. In the present study, RNA sequencing was applied to examine the whole transcriptomes of human pulmonary AEC cells (HPAEpiC) with or without radiation treatment. We found that cytokine, chemokine and cell adhesion signaling p ...[more]

PMID: 30899375

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Project description:BackgroundThe inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNF? & IL-1? were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.MethodsThe expression of CCL2, CCL5, TNF? and IL-1? was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.ResultsCCL2, CCL5, TNF? and IL-1? were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNF? & IL-1? in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNF? & IL-1? expression. These results suggest progression-related roles for TNF? and IL-1? in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNF? and IL-1? compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNF? (and to some extent IL-1?) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1? acts jointly with other pro-malignancy factors to promote disease relapse.ConclusionsOur findings suggest that the coordinated expression of CCL2 & CCL5 and TNF? & IL-1? may be important for disease course, and that TNF? & IL-1? may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.

Dataset Information

CCL2-CCL5/CCR4 contributed to radiation-induced epithelial-mesenchymal transition of HPAEpiC cells via the ERK signaling pathways.

Publications

CCL2-CCL5/CCR4 contributed to radiation-induced epithelial-mesenchymal transition of HPAEpiC cells via the ERK signaling pathways.

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