Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells

Abstract

BackgroundNon-small cell lung carcinoma (NSCLC) is a type lung cancer with high malignant behaviors. MicroRNAs (miRNAs) are known to be involved in progression of NSCLC. In order to explore potential targets for the treatment of NSCLC, bioinformatics tool was used to analyze differential expressed miRNAs between NSCLC and adjacent normal tissues.MethodsBioinformatics tool was used to find potential targets for NSCLC. Cell proliferation was investigated by Ki67 staining. Cell apoptosis was measured by flow cytometry. mRNA and protein expression in NSCLC cells were detected by RT-qPCR and Western-blot, respectively. Transwell assay was performed to test the cell migration and invasion. In order to investigate the function of exosomal miRNA in NSCLC, in vivo model of NSCLC was constructed.ResultsMiR-770 was identified to be downregulated in NSCLC, and miR-770 agomir could significantly inhibit NSCLC cell proliferation through inducing the apoptosis. Additionally, the metastasis of NSCLC cells was decreased by miR-770 agomir. MAP3K1 was identified to be the target mRNA of miR-770. Meanwhile, tumor cell-derived exosomal miR-770 inhibited M2 macrophage polarization via downregulation of MAP3K1, which in turn suppressed NSCLC cell invasion. Besides, tumor cell-derived exosomal miR-770 markedly decreased NSCLC tumor growth in vivo through suppressing M2 macrophage polarization.ConclusionTumor cell-derived exosomal miR-770 inhibits M2 macrophage polarization to inhibit the invasion of NSCLC cells via targeting MAP3K1. Thus, this study provided a new strategy for the treatment of NSCLC.

Macrophage-Related SPP1 as a Potential Biomarker for Early Lymph Node Metastasis in Lung Adenocarcinoma

“…It has been well documented that M2 macrophages promote tumor growth and metastasis ( Tao et al, 2020 ). On the other hand, many studies indicated tumor cells stimulate naive M0 macrophages to differentiate into M2 macrophages ( Liu et al, 2021 ). Macrophages are mainly M2 subtypes in tumor microenvironment, especially in advanced stage of tumors.…”

Predictive and Prognostic Biomarkers for Lung Cancer Bone Metastasis and Their Therapeutic Value

“…They act as gene regulator by binding to mRNAs and inhibiting their functions (205). Plenty of studies revealed that miRNAs play significant roles, including both oncogenes and tumor suppressors, during the progression and metastasis of lung cancer (206)(207)(208).…”

“…They act as gene regulator by binding to mRNAs and inhibiting their functions ( 205 ). Plenty of studies revealed that miRNAs play significant roles, including both oncogenes and tumor suppressors, during the progression and metastasis of lung cancer ( 206 – 208 ). Overexpression of the let-7 family, miR-486, miR-218, miR-34, and miR-200 were proved to inhibit the tumor cell proliferation, invasion and colony formation, though there is no specific article describing their relations with tumor cells bone migration ( 209 – 212 ).…”

Tumor-derived exosomes: immune properties and clinical application in lung cancer

“…On the other hand, TEXs can also indirectly transfer tumor antigen to antigen presenting cells, like DCs, and then activate the cytotoxic activity of CD8 + T cells and CD4 + T helper cells, so as to inhibit tumor growth [58] . Additionally, the enrichment of HSPs on TEXs such as Hsp70, can stimulate the activity of NK cells [59] and macrophages [60] , and induce MHC class I-restricted cytotoxic T cells activation [61] . Tumor cell-derived exosomal miR-770 could suppress M2 macrophage polarization via targeting MAP3K1, which in turn decreased NSCLC tumor growth [62] .…”

“…Tumor cell-derived exosomal miR-770 could suppress M2 macrophage polarization via targeting MAP3K1, which in turn decreased NSCLC tumor growth [62] . Tetraspanins on the exosome surface mainly mediate cell adhesion and participate in maintaining the optimal conformation of immune proteins like MHC class II, thus playing an important role in antitumor immunity through exosomal targeting to DCs [61,[63][64][65] .…”