Recurrence and metastasis are major factors associated with the poor prognosis of pancreatic cancer (PC). Previous studies have indicated that METTL3-mediated N6-methyladenosine (m6A) modification is closely associated with PC progression and prognosis. However, its underlying regulatory mechanisms remain unclear. In this study, we found that METTL3 was upregulated in PC tissues and cells and was associated with malignant tumor progression and poor progression-free survival in PC. Linc00662 was screened as a m6A-enriched RNA that promoted tumor growth and metastasis in PC cells and mouse models and was associated with poor clinical prognosis. Four m6A motifs were identified in Linc00662, which maintained the stability of Linc00662 in an IGF2BP3-coupled manner and were closely associated with the pro-tumor properties of Linc00662 in vitro and in vivo. ITGA1 was identified as a downstream gene regulated by Linc00662. Linc00662 recruites GTF2B to activate the transcription of ITGA1 in a m6A-dependent manner and initiates the formation of focal adhesions through the ITGA1-FAK-Erk pathway, thereby promoting malignant behavior in PC cells. The FAK inhibitor-Y15 obviously repressed tumor progression in Linc00662-overexpressing PC cells in vitro and in vivo. This study proposes a novel regulatory mechanism of Linc00662 in oncogene activation in PC and indicates that Linc00662 and its downstream genes are potential targets for PC therapy.
Keywords: FAK; ITGA1; Linc00662; N6-methyladenosine; Pancreatic cancer; focal adhesion.
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