Abstract
BACKGROUND: Colorectal liver metastasis (CRLM) is the main cause of death in colorectal cancer (CRC) patients worldwide. In the initial stage of metastasis, primary tumors provide the necessary conditions for metastasis by shaping the local microenvironment of the target organ, forming "premetastatic niches" (PMNs), and extracellular vesicles (EVs) play important roles in shaping PMNs. Therefore, investigating the EVs involved in the regulation of PMNs and their mechanism is highly valuable for the further understanding of CRLM. 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 the roles of MIR181A1HG in EVs in CRLM. RNA pull-down and dual-luciferase reporter assays were used to clarify the mechanism by which MIR181A1HG in EVs regulated the crosstalk between CRC cells and hepatic stellate cells (HSCs). RESULTS: We demonstrated that the lncRNA MIR181A1HG was progressively upregulated in tissues, serum EVs from healthy normal controls to CRC and paired liver metastatic groups. Additionally, we verified that HNRNPA2B1 mediated the packaging of MIR181A1HG into CRC cell-derived EVs, which in turn functioned as a ceRNA by sponging miR373-3p to activate HSCs via the TGFβRII/Smad2/3 signaling pathway. Furthermore, activated HSCs could secrete the chemokine CXCL12 to promote CRLM by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells in the liver, which resulted in liver metastasis. CONCLUSIONS: MIR181A1HG in EVs from highly metastatic CRC cells promoted CRLM by activating HSCs to form PMNs in the liver, which contributes to the further understanding of the mechanism of CRLM and provides potential predictive markers for CRLM.