RREB1 could act as an immunological and prognostic biomarker: From comprehensive analysis to osteosarcoma validation

The Ras-responsive element binding protein 1 (RREB1) is a transcription factor involved in various biological processes. Notably, RREB1 plays a role in tumor immunity by regulating tumor-related gene expression, shaping the tumor microenvironment, and modulating immune checkpoints. Given these functions, RREB1 has emerged as a potential regulatory target in tumor immunotherapy. However, a comprehensive pan-cancer analysis evaluating RREB1's prognostic value and its role in modulating the immune microenvironment remains unexplored, warranting further investigation to better understand its mechanisms across different cancer types and its implications for personalized immunotherapy.

We analyzed RREB1 expression across 33 cancer types using RNA sequencing data from the TCGA database. RREB1 alterations were further characterized using the cBioPortal database. Clinical and pathological features, along with prognostic significance, were assessed using TCGA clinical data. The involvement of RREB1 in the tumor microenvironment was evaluated using the CIBERSORT and ESTIMATE algorithms. Relationships between RREB1 expression and tumor mutation burden (TMB), as well as microsatellite instability (MSI), were investigated using Spearman's rank correlation coefficient. GSEA was applied to explore the biological functions of RREB1. Additionally, we assessed the link between RREB1 expression and the efficacy of PD-1/PD-L1 inhibitors. Finally, a series of in vitro experiments were performed to evaluate the impact of RREB1 expression on the malignant behavior of osteosarcoma (OS) and lung cancer cell lines.

RREB1 was overexpressed in several cancer types and correlated with patient prognosis. RREB1 expression was strongly associated with TMB, MSI, and immune cell infiltration, including regulatory T cells, CD8⁺ T cells, and macrophages. Furthermore, RREB1 expression was linked to immune responses and the efficacy of immunotherapy. In vitro experiments demonstrated that knockdown of RREB1 significantly inhibited the proliferation and migration of OS cells.

RREB1 shows potential as a prognostic marker for certain cancers and may predict the efficacy of immunotherapy. Additionally, RREB1 expression is related to immune-related markers, suggesting its role in prognosis and predicting responses to immune microenvironment therapies in specific tumors.