Knockdown of p53 Enhances LncRNA A2M‐AS1 Inhibition of Pancreatic Cancer Progression via Regulating MAPK Pathway

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PURPOSE: Rapid progression in late-stage is a characteristic of pancreatic cancer (PC), leading to mortality. The critical role of lncRNA A2M-AS1 (long non-coding RNA alpha-2-macroglobulin antisense RNA 1) is involved in cancer progression, but the upstream regulator of A2M-AS1 in the PC progression phenotype remains elusive. METHODS: We conducted an integrated analysis using bioinformatics, in vitro experiments, and in vivo studies. Human PC tissues were analyzed for A2M-AS1 and p53 expressions. The PANC-1 and BxPC-3 cell lines were used for functional assays, including cell proliferation, apoptosis, migration, and invasion assays. The role of p53 in regulating A2M-AS1 was investigated through overexpression and knockdown studies, along with using a MAPK pathway inhibitor. RESULTS: We found that A2M-AS1 is downregulated in PC tissues and that its high expression correlates with a better prognosis. p53 was identified as a negative regulator of A2M-AS1, with its knockdown leading to increased A2M-AS1 expression and decreased PC cell invasiveness. Mechanistically, p53 was shown to bind to the A2M-AS1 promoter, modulating its transcriptional activity. The MAPK pathway was revealed as a downstream effector of the p53-A2M-AS1 axis, with its inhibition reversing the effects on PC cell behavior. CONCLUSION: High A2M-AS1 expression is associated with a better PC prognosis. A2M-AS1 overexpression subdues PC cell development. Our study unveils a new mechanism by which p53 decreases A2M-AS1 expression.

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