Cancer progression depends on the communication between
tumor cells and tumor microenvironment. Cancer-associated fibroblasts (CAFs) are a major component of stromal cells. CAFs promote
cancer metastasis; however, it has not been evaluated whether
N6-methyladenosine (m6A) modification is responsible for CAFs' role in
metastasis. In the present study, we found that CAFs promoted migration and invasion of
non-small cell lung cancer (NSCLC) cells by elevating
m6A modification in NSCLC cells.
Methyltransferase-like 3 (METTL3) in NSCLC cells mediated CAFs' effect on
m6A modification, and was regulated by CAFs-secreted
vascular endothelial growth factor A (VEGFA). METTL3 knockdown in NSCLC cells dramatically inhibited cell migration and invasion, and suppressed
tumor growth in vivo. Database analysis revealed that METTL3 was associated with poor prognosis of
lung cancer. The mechanism study showed that METTL3 increased
m6A level of RAC3
mRNA, resulting in increased stability and translation of RAC3
mRNA. RAC3 was responsible for the CAFs' promoting effect on cell migration via the AKT/NF-κB pathway. This study established a CAF-METTL3-RAC3
m6A modification-dependent regulation system in NSCLC
metastasis, suggesting potential candidates for
metastasis treatment.