The revelation of immune cell interaction and the building of a prognostic model in diffuse large B-cell lymphoma under Hedgehog signaling abnormalities based on single-cell data

Abstract

The Hedgehog (Hh) signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL) and helps facilitate tumor cell survival and proliferation. Currently, the role of the Hh signaling pathway in the prognosis of DLBCL has yet to be thoroughly investigated. RNA-Seq data and scRNA-seq data of DLBCL were collected from the UCSC Xena and GEO databases. A prognostic model related to Hh signaling pathway genes was constructed, and risk stratification was performed. The immune microenvironment characteristics, Hh scores, and drug sensitivity differences of different risk groups were systematically compared. The potential immune regulatory ligand-receptor pairs were screened through cell communication analysis. On this basis, the gene RABEP1, which contributed significantly to the model, was knocked down in SU-DHL-4 cells. Combined with a nude mouse subcutaneous xenograft tumor model, its tumor-promoting effect and impact on Hh signaling activity were verified in vivo and in vitro, as well as at the pathway level. We constructed an 11-gene prognostic model based on Tregs, Tfh and CD8 + T cells with high Hh scores, which demonstrated good stability and predictive ability in multiple datasets. RABEP1, with a prominent contribution to the risk score, was highly expressed in the high-risk group of DLBCL and negatively correlated with the sensitivity of AC220. In vitro and in vivo experiments showed that knockdown of RABEP1 could inhibit tumor growth and promote apoptosis by suppressing Hh signaling (GLI1/PTCH1). By integrating multi-omics data, we developed a prognostic model based on Hh-related genes. Based on an analysis of cell communication among immune cells, we identified several key receptor-ligand pairs. These findings not only provide new molecular biomarkers for predicting DLBCL prognosis but also offer fresh perspectives for therapeutic research targeting the Hh signaling pathway.