LncRNA RP3-525N10.2-NFKB1-PROS1 triplet-mediated low PROS1 expression is an onco-immunological biomarker in low-grade gliomas: a pan-cancer analysis with experimental verification

Abstract

Background: Glioma is the most common cancer in the central nervous system, and low grade gliomas are notorious for many types of tumors and heterogeneity. PROS1 not only plays an important role in the blood coagulation system, and recent studies have found that it was correlated with the development of tumors, especially related to tumor immune infiltration. However, the study of underlying role and mechanism of PROS1 in gliomas, especially in low-grade gliomas, is almost absent. Methods: We integrated the information of patients with LGG in The Cancer Genome Atlas (TCGA) cohort and Chinese Glioma Genome Atlas (CGGA) cohort. Then, we systematically demonstrated the differences and prognostic prognosis value of PROS1 based on multi-omics analyses. In addition, Cell counting kit-8 (CCK-8) assay, colony formation assay, 5-Ethynyl-2’-deoxyuridine (EdU) incorporation assay, and Transwell assays were performed to evaluate cell proliferation and invasion. qRT-PCR and immunohistochemistry were used to evaluate the expression of PROS1 in LGG. Results: Various bioinformatics approaches revealed that PROS1 was a valuable prognostic marker and may influence tumour development via distinct mechanisms, including expression of DNA methyltransferase, RNA modification, and DNA mismatch repair system genes, copy number variation, single nucleotide variation frequency, genomic heterogeneity, cancer stemness, DNA methylation, and alternative PROS1 splicing. Our analyses indicated that the long non-coding RNA RP3-525N10.2 may “decoy” or “guide” the transcription factor NFKB1 and prevent its association with PROS1, thereby reducing PROS1 expression and improving poor LGG prognosis. PROS1 expression was also closely associated with tumour infiltration by immune cells, especially tumour-associated macrophages, as well as the expression of various immune checkpoint inhibitors, immunomodulators, and immune cell markers. Conclusion: long non-coding RNA RP3-525N10.2-NFKB1-PROS1 triplet-mediated PROS1 expression could serve as a biomarker for cancer diagnosis, prognosis, therapy selection, and follow-up in LGG patients.