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An miR-340-5p-macrophage feedback loop modulates the progression and tumor microenvironment of glioblastoma multiforme

Oncogene volume 38, pages 7399–7415 (2019)Cite this article

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Abstract

MicroRNAs (miRNAs) have been shown to be involved in the progression and tumor microenvironment of glioblastoma multiforme (GBM). Our previous research has indicated that miR-340-5p has an antitumor effect in vitro. However, the role of miR-340-5p in GBM has not been fully elucidated. Here, we show that downregulation of miR-340-5p in GBM is correlated with tumor size, recurrence, and poor survival. Moreover, we found that miR-340-5p levels are correlated with the density of tumor-associated macrophages (TAMs) and M2-polarized TAMs in GBM. Biofunctional investigations revealed that downregulation of miR-340-5p promoted TAM recruitment and M2-TAMs polarization in vitro and in vivo. In addition, we found that upregulation of miR-340-5p inhibited tumor growth and was associated with good prognosis in vivo. Through gene expression profiles and bioinformatics analysis, we showed that miR-340-5p directly targets POSTN, which recruited TAMs through integrin αvβ3. Downregulation of miR-340-5p in GBM did not induce the differentiation of TAMs into polarized M2 cells but was able to promote the M2 polarization of TAMs through directly targeting LTBP-1. Furthermore, we found that M2-TAMs promoted tumorigenesis and were associated with a poor prognosis in vivo. In an in vitro study, we demonstrated that M2-TAMs inhibited miR-340-5p expression in GBM cells by upregulation of TGFβ-1, which increased HMGA-2 expression in GBM. A ChIP assay confirmed that HMGA-2 transcriptionally suppressed miR-340-5p expression. Patients with low-miR-340-5p expression, high CD163, high POSTN, high LIBP1 levels, and high HMGA-2 had a poor prognosis with shorter overall survival, confirming data from the TCGA database. These findings suggest that an miR-340-5p-macrophage feedback loop modulates the progression and tumor microenvironment of GBM and may represent a prognostic biomarker and therapeutic strategy for GBM.

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Acknowledgements

We thank and acknowledge the patients for tumor tissue donation. We also thank SWQ and BH for their scientific support in some experiments. This work was supported by the National Natural Science Foundation of China (No. 81572481 to YP, 81502167 to XMR and 81502552 to LH), the key point program of Science & Technique plan for production, study, and research of Guangzhou city (201508020058). Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University and Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology.

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  1. These authors contributed equally: Yunyun Liu and Xiaoyu Li

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  1. Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China

    Yunyun Liu, Xiaoyu Li, Yuanpei Zhang, Hongxuan Wang, Xiongming Rong, Jialing Peng, Lei He & Ying Peng

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China

    Yunyun Liu, Xiaoyu Li, Yuanpei Zhang, Hongxuan Wang, Xiongming Rong, Jialing Peng, Lei He & Ying Peng

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Liu, Y., Li, X., Zhang, Y. et al. An miR-340-5p-macrophage feedback loop modulates the progression and tumor microenvironment of glioblastoma multiforme. Oncogene 38, 7399–7415 (2019). https://doi.org/10.1038/s41388-019-0952-x

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