Cen Yu, Luo Yihui, Nan Yi, Kuang Wenxi, Zhang Xianglian, Lu Jiexia, Xie Chunxiao, Xie Mingzhi, Chen Enran, Jiang Haixing, Qin Shanyu
Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Gastroenterology, Liuzhou People's Hospital, Liuzhou, China.
Cancer Med. 2025 Jul;14(13):e70956. doi: 10.1002/cam4.70956.
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.
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.
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.
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.
晚期快速进展是胰腺癌（PC）的一个特征，可导致死亡。长链非编码RNA A2M-AS1（α-2-巨球蛋白反义RNA 1）在癌症进展中起关键作用，但其在PC进展表型中的上游调节因子仍不清楚。
我们使用生物信息学、体外实验和体内研究进行了综合分析。分析了人PC组织中A2M-AS1和p53的表达。使用PANC-1和BxPC-3细胞系进行功能测定，包括细胞增殖、凋亡、迁移和侵袭测定。通过过表达和敲低研究以及使用丝裂原活化蛋白激酶（MAPK）途径抑制剂，研究了p53在调节A2M-AS1中的作用。
我们发现A2M-AS1在PC组织中表达下调，其高表达与较好的预后相关。p53被确定为A2M-AS1的负调节因子，其敲低导致A2M-AS1表达增加和PC细胞侵袭性降低。机制上，p53被证明与A2M-AS1启动子结合，调节其转录活性。MAPK途径被揭示为p53-A2M-AS1轴的下游效应器，其抑制可逆转对PC细胞行为的影响。
高A2M-AS1表达与较好的PC预后相关。A2M-AS1过表达抑制PC细胞发育。我们的研究揭示了一种p53降低A2M-AS1表达的新机制。
