N6-Methyladenosine Methylation Regulator RBM15 is a Potential Prognostic Biomarker and Promotes Cell Proliferation in Pancreatic Adenocarcinoma

Abstract

RNA binding motif protein 15 (RBM15) is a key regulatory factor involved in N6-methyladenosine (m6A) methylation. It has been reported that RBM15 plays an important role in the progress of laryngeal squamous cell carcinoma (LSCC), promoting LSCC migration and invasion. However, the role of RBM15 in human different cancers remains unknown. This study aims to analyze the prognostic value of RBM15, and to demonstrate the correlation between RBM15 expression and tumor immunity, as well as to provide clues for further mechanism research. The results showed that RBM15 was mutated or copy number varied in 25 types of cancer. RBM15 mRNA was abnormally up-regulated across various cancers. Survival analysis suggested high expression of RBM15 was associated with poor prognosis in many cancer types. Among these, it affected patients’ overall survival (OS) in 10 cancer types, disease-free interval (DFI) in 8 cancer types, progression-free interval (PFI) in 12 cancer types and disease-specific survival (DSS) in 7 cancer types. Importantly, in pancreatic adenocarcinoma (PAAD), overexpression of RBM15 is associated with patients’ OS, DFI, PFI, or DSS. In addition, RBM15 expression was positively correlated with immune infiltrating cells in kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and PAAD. Moreover, RBM15 expression showed a strong correlation with immune checkpoint markers in PAAD. Cell counting kit-8 (CCK-8) assay showed that knockdown of RBM15 significantly inhibited the proliferation of pancreatic cancer cells. PPI analysis showed USP10, USP24, SMG1, NRAS were closely connected with RBM15 alterations. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that many biological processes (BP), cellular components (CC), molecular functions (MF), cancer related pathways including “sister chromatid cohesion”, “peptidyl-serine phosphorylation”, “cell division”, “nucleoplasm”, “nucleus”, “protein binding”, “protein serine/threonine kinase activity”, “T cell receptor signaling pathway”, “Cell cycle” were regulated by RBM15 alterations. Taken together, pan-cancer analysis of RBM15 suggested it may be served as a prognostic biomarker and immunotherapeutic target for PAAD.

Integrated Analyses of m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pan-Cancer

“…Kaplan-Meier curves were generated according to the low-expression and high-expression groups, and patients in the low-expression group had a significant survival advantage ( Figure S1 ). This is consistent with previous studies, which found that high expression of RBM15 is significantly associated with tumor progression and poor prognosis in a variety of cancers, including LSCC, COAD, LIHC, and PAAD [ 26 , 27 , 28 , 29 ]. Most m 6 A regulators were significantly positively correlated, while IGF2BP1, IGF2BP2, and IGF2BP3 were weakly correlated with other regulatory factors.…”

Effect of the m6ARNA gene on the prognosis of thyroid cancer, immune infiltration, and promising immunotherapy

“…RBM15 expression was positively correlated with immune-infiltrating cells in renal clear cell carcinoma (KIRC), brain low-grade glioma (LGG), and pancreatic adenocarcinoma (PAAD). In addition, RBM15 expression was strongly correlated with immune checkpoint markers in PAAD ( 65 ). In addition, some studies have found that downregulation of FTO in the chorionic villi destroys immune tolerance and angiogenesis at the maternal-fetal interface, leading to abnormal methylation and oxidative stress and ultimately to spontaneous abortion ( 66 ).…”

RBM15 condensates modulate m6A modification of STYK1 to promote tumorigenesis

“…Although the high expression level of RBM15 had been recurrently observed in several different types of cancers [58] , [59] , [60] , [61] , whether the abundant RBM15 altered the m 6 A status of related transcripts, and how they influenced the cancer progression remains unclear. In this work, we first revealed that endogenous RBM15 formed “liquid-like” phase-separated condensates dispersed in the nucleus, which were different from other known membrane-less subnuclear bodies, and underwent dynamic fusion and fission activities.…”