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

ABSTRACT: BACKGROUND:Tumor-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. METHODS:The 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. RESULTS:Linc00514 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. CONCLUSION:Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.

SUBMITTER: Tao S

PROVIDER: S-EPMC7500027 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Tao Sifeng S Chen Qiang Q Lin Chen C Dong Haiying H

Journal of experimental & clinical cancer research : CR 20200917 1

<h4>Background</h4>Tumor-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.<h4>Methods</h4>The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional as ...[more]

PMID: 32943090

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Project description:Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR‑382 expression was significantly downregulated in tumor‑associated macrophages (TAMs) and M2‑polarized macrophages in breast cancer. In vitro, macrophage polarization toward the M2 phenotype and M2‑type cytokine release were inhibited by transfection with miR‑382‑overexpressing lentivirus. Similarly, the overexpression of miR‑382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) was identified as the downstream target of miR‑382 and it was found that PGC‑1α affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC‑1α restored the phenotype and cytokine secretion of miR‑382‑overexpressing macrophages. Furthermore, PGC‑1α expression reversed the miR‑382‑induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the in vivo growth and metastasis of 4T1 cells were inhibited by miR‑382‑overexpressing TAMs. Taken together, the results of the present study suggest that miR‑382 may alter the metabolic status of macrophages by targeting PGC‑1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.

Dataset Information

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

Publications

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

Similar Datasets

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