M2 Macrophage-Extracellular Vesicle-Derived lncRNA-NEAT1 Regulates miR-204-5p/RRS1-mediated Cell Cycle to Promote the Occurrence and Development of Colorectal Cancer

Colorectal Cancer (CRC) is a prevalent malignancy of the digestive system. Here, we explored the role of M2 macrophage-derived extracellular vesicles (EVs) carrying long non-coding RNA-nuclear paraspeckle assembly transcript 1 (lncRNA-NEAT1) in promoting CRC progression via regulation of the miR-204-5p/regulator of ribosome synthesis 1 (RRS1) axis and cell cycle dynamics. Firstly, we differentiated WTHP-1 cells into M0 and M2 macrophages and transfected M2 macrophages with sh-NEAT1 lentivirus plasmids. EVs were isolated from M2 macrophages and administered to SW480 cells along with miR-204-5p inhibitors or si-RRS1 for 24 h. M2-EVs-derived lncRNA-NEAT1 enhanced CRC cell proliferation, migration, invasion, and viability while reducing Apoptosis. This was accompanied by increased expression of RRS1, Wee1 G2 checkpoint kinase (Wee1), cyclin-dependent kinase 1 (CDK1), and CyclinB1, reduced miR-204-5p levels, and a lower proportion of cells in the G2/M phase. Knockdown of lncRNA-NEAT1 in M2 macrophages reversed these effects. Mechanistically, M2-EVs-derived lncRNA-NEAT1 functioned as a competing endogenous RNA (ceRNA), sponging miR-204-5p to upregulate RRS1 expression. In summary, M2 macrophage-derived EVs carrying lncRNA-NEAT1 promote CRC development by modulating the miR-204-5p/RRS1 axis, influencing the cell cycle and Apoptosis. These findings provide insights into the tumor-promoting mechanisms of macrophage-derived EVs in CRC.

M2 macrophages; colorectal cancer; extracellular vesicles; human regulator of ribosome synthesis 1; long noncoding RNA‐nuclear paraspeckle assembly transcript 1; miR‐204‐5p.