Oncogenic Peptide Encoded by Noncoding RNA of <i>FOXM1</i> Promotes Pancreatic Cancer Malignancy Through PI3K/AKT Signaling

Alternative splicing of FOXM1 produces different isoforms, which have been proven to exist and have complex functions. One of the isoforms of FOXM1, isoform ENST00000535350, is a short noncoding RNA sequence, designated as FOXM1s here. We determined the function and mechanism of FOXM1s-encoded peptide, FOXM1s, in the development and progression of pancreatic cancer. The expression of FOXM1s as noncoding RNA in pancreatic cancer tissues and cell lines was analyzed by RT-PCR. Gene expression and its association with clinicopathologic characteristics of patients with PDAC were analyzed using IF and bioinformatics. The effects on cell proliferation, migration, invasion, tumor stemness, and on PI3K/AKT signaling were evaluated through in vitro biology methods and functionally validated in mouse models by using overexpression and knockdown approaches. The expression of FOXM1s in human pancreatic cancer tissues and cell lines was significantly increased. The overexpression of FOXM1s had a promoting effect on pancreatic cancer, while the mutation of FOXM1s attenuated its effect, indicating that FOXM1s exerted its role potentially through ORF2-encoded a peptide. The specific antibody #FOXM1s was used to validate that FOXM1s expressed a predicted peptide, FOXM1s, and its expression was upregulated in pancreatic cancer. FOXM1s significantly promoted the proliferation, migration, and invasion of pancreatic cancer cells, facilitated liver metastasis, and upregulated the expression of stem-related genes in pancreatic cancer. Mechanistically, the FOXM1s peptide encoded by FOXM1s activated the PI3K/AKT signaling pathway. FOXM1s encodes a FOXM1s peptide and exhibits oncogenic function in the pancreatic cancer development progression at least in part through activating PI3K/AKT signaling pathway. This novel molecule could serve as a potential therapeutic target.