Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer

Abstract

Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

Exosome-mediated communication between tumor cells and tumor-associated macrophages: implications for tumor microenvironment

“…Zhao et al demonstrated elevated expression of miR-934 in areas with abundant CD163 + TAM infiltration in colorectal cancer (CRC) liver metastasis tissue; moreover, exosomal miR-934 induced M2 macrophage polarization via downregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and activation of the PI3K/AKT signaling pathway. 58 Many essential transcription factors, such as PPARs, STAT3, and STAT6 are involved in macrophage polarization in the TME. For example, Ying et al 59 showed that epithelial ovarian cancer (EOC)-derived exosomal miR-222-3p induced a TAM-like macrophage phenotype and polarization into the M2 phenotype via the SOCS3/STAT3 pathway.…”

Nano Pom-poms Prepared Highly Specific Extracellular Vesicles Expand the Detectable Cancer Biomarkers

“…The miR-92b-5p has been found to play a critical role in promoting EMT in bladder cancer migration (45). The hsa-miR-934 is an essential exosomal oncogene for promoting cancer metastasis (46). NanoPoms sEV preparation offered much higher molecular relevance for identifying tumor associated biomarkers, which is crucial for exploring more specific targetable cancer biomarkers.…”

MiRNA-mediated EMT and CSCs in cancer chemoresistance

“…The conventional method is to inhibit tumor-associated inflammation and hypoxia. In recent years, with the gradual insight into the role of cancer-associated fibroblast and tumor-associated macrophage in EMT-associated metastasis, the strategy of targeting these cells has drawn considerable attention, especially targeting the exosomes derived from them [ 107 , 108 ]. However, EMT triggered by these components of the tumor microenvironment remains under investigation.…”