Abstract
BackgroundMounting 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.MethodsTransmission 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.ResultsIn 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.ConclusionsThese 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.
Highlights
The combination of surgery, chemotherapy, targeted therapy, and immunotherapy has partially improved the clinical efficacy of colorectal cancer (CRC) therapy, CRC still ranks third in terms of incidence and is the second leading cause of cancerrelated deaths worldwide [1, 2]
Elevated expression of miR‐934 positively correlates with cancer liver metastasis (CRLM) progression and poor prognosis of patients with CRLM To reveal the potential miRNAs involved in CRLM, we first compared the expression profiles of dysregulated miRNAs between stage I and stage IV CRC tumors using the latest colon adenocarcinoma CRC miRNASeq dataset from The Cancer Genome Atlas (TCGA) database
Each dot represents a sample. c, d Expression levels of miR-934 in tissues and serum of two groups of CRC patients classified on the basis of the presence (n = 50) or absence (n = 60) of liver metastasis. e Representative in situ hybridization assay for the detection of miR-934 in normal mucosa, CRC tissue without liver metastasis, and CRC tissue with liver metastasis. f, g Kaplan–Meier survival analysis with the log-rank test was used to determine the association of miR-934 with overall survival (OS) (e) and disease-free survival (DFS) (f) in 308 CRC patients (*p < 0.05; **p < 0.01; ***p < 0.001)
Summary
The combination of surgery, chemotherapy, targeted therapy, and immunotherapy has partially improved the clinical efficacy of colorectal cancer (CRC) therapy, CRC still ranks third in terms of incidence and is the second leading cause of cancerrelated deaths worldwide [1, 2]. Accumulating evidence suggests that exosomes play key roles in remodeling the TME and tumor metastasis by transferring signal peptides, noncoding RNAs, or DNA to neighboring cells or tissues [8, 9]. Tumor-associated macrophages (TAMs), which are considered to be M2-like, exist in the TME and influence the metastasis of various cancers by interacting with cancer cells [14]. The crosstalk between cancer cells and M2 macrophages has been investigated extensively; the mechanisms underlying the activation of M2 macrophages by tumor cells remain unclear in colorectal cancer and are even more obscure in CRLM. The molecular mechanisms by which tumorderived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown
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