METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification

Abstract

Spermine synthase (SMS) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that SMS is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive SMS reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, SMS was identified as the direct target of both methyltransferase like 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly bind to the m6A modification sites of SMS and inhibit mRNA degradation. Knockdown of METTL3 or IGF2BP3 significantly reduced the SMS protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.

Study on autophagy-related biomarkers in pancreatic cancer based on bioinformatics

“…SMS is spermine synthase. Excess SMS reduces spermidine accumulation by converting spermidine to spermidine, activating serine/threonine kinase (AKT) phosphorylation and epithelial-mesenchymal transformation (EMT) signaling pathways, thus inhibiting the proliferation and invasion of PC cells [47].CASP1 is a caspase 1 that plays a key role in cellular immunity as an inflammatory response initiator: Once activated by the formation of the inflammasome complex, it initiates the pro-inflammatory response by cutting the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines involved in the inflammatory response in various inflammatory processes [48][49]. NPC1 is npc intracellularcholesterol transporter 1, which works collaboratively with NPC2 and plays an important role in cholesterol excretion from endosomal/lysosomal compartments [50].…”

Characterization of polyamine metabolism predicts prognosis, immune profile, and therapeutic efficacy in lung adenocarcinoma patients

“…SMS is a highly specific aminopropyltransferase that catalyzes spermidine to generate spermine ( Pegg and Michael, 2010 ). Currently, SMS is correlated with tumorigenesis in many tumors, including pancreatic cancer ( Guo et al, 2022 ), breast cancer ( Hanash et al, 2020 ), and colorectal cancer ( Guo et al, 2020 ). However, it is unclear what role SMS may play in the occurrence and progression of LUAD.…”

FERMT1 Is a Prognostic Marker Involved in Immune Infiltration of Pancreatic Adenocarcinoma Correlating with m6A Modification and Necroptosis

“…In addition, only the high expression of IGF2BP2 and IGF2BP3 was linked to poor prognosis in PAAD. As the stabilizers of m 6 A methylation, IGF2BP2 and IGF2BP3 can enhance the stability of B3GNT6 and spermine synthase ( SMS ) mRNA and protein expression, respectively, to promote the progression of pancreatic cancer [ 39 , 40 ]. In light of these findings, we proposed that the FERMT1 may be modified by m 6 A to enhance mRNA stability, thereby accelerating the development of PAAD.…”