Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway

Sifeng Tao,Chen Lin,Qiang Chen,Haiying Dong

doi:10.1186/s13046-020-01676-x

Abstract

BackgroundTumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear.MethodsThe candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity.ResultsLinc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages.ConclusionLinc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.

Highlights

Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment
Expressed linc00514 promotes breast cancer malignancy In the GEO database, we used ‘breast cancer’ as a key word to screen out the data of dysregulated Long non-coding RNA (lncRNA) in breast cancer tissues
Among the 13 lncRNAs, we found that 9 of them were aberrantly expressed in clinical breast cancer tissues, and that linc00514, linc00964, and Clorf81 had the correlation with the clinical characteristics of the breast cancer patients (Fig. 1a & S1A)

Summary

Introduction

Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. The potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment (TME) [2]. Their functions are widely restricted and regulated by the other components in TME, such as tumor cells. By the interactions between TAMs and tumor cells, TAMs are widely involved in the tumorigenicity, including proliferation and invasion of tumor cells, promoting tumor growth and metastasis [3]. Recent studies have revealed that the M2 polarization of TAMs can be induced by tumor cells in breast cancer. The interplay between TAMs and tumor cells has been established, the mechanisms of tumor cells modulating TAM polarization remain unclear

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Conclusion