Cancer-associated fibroblasts promote migration and invasion of non-small cell lung cancer cells via METTL3-mediated RAC3 m⁶A modification

Abstract

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 (m 6 A) 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 m 6 A modification in NSCLC cells. Methyltransferase-like 3 (METTL3) in NSCLC cells mediated CAFs' effect on m 6 A 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 m 6 A 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 m 6 A modification-dependent regulation system in NSCLC metastasis, suggesting potential candidates for metastasis treatment.

KDM5B/H3K4me3-mediated METTL14 regulates the function of LINC02747 through N6-methyladenosine modification in non-small cell lung cancer

“…Recently, the role of the m6A RNA modi cation, a key facet of posttranscriptional regulation, in regulating the expression of lung cancer genes has attracted increased amounts of attention [35,36]. In exploring METTL14's functional role, we utilized MeRIP-Seq data to identify LINC02747 as a likely target affected by METTL14.…”

The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications

“…METTL3 promotes the malignant behavior of LUSC cells through mediating m 6 A modification on COL10A1 mRNA and sustaining its high expression in CAFs ( 34 ). Moreover, it was discovered that CAFs-secreted vascular endothelial growth factor A (VEGFA) promoted the metastatic potential of NSCLC cells through METTL3-m 6 A-RAC3 mechanism ( 37 ).…”

Exploring the multifaceted role of direct interaction between cancer cells and fibroblasts in cancer progression

“…CAFs promote migration and invasion of non-small cell lung cancer (NSCLC) cells via miR-101-3p mediated VEGFA secretion and AKT/eNOS Pathway ( Guo et al, 2021 ). Another study established a CAF-METTL3-RAC3 m 6 A modification-dependent regulation system in NSCLC metastasis ( Chen et al, 2023 ).…”