p53 knockout drives stage-specific long non-coding RNA reprogramming during human neural differentiation and glioma organoid tumorigenesis.

Human researchers have uncovered a critical process in the development of glioma tumors, the most common and aggressive form of brain cancer. The study focused on the role of the p53 gene, which is often mutated in cancer cells, and its impact on long non-coding RNAs (lncRNAs) during early neural differentiation.

The researchers utilized induced pluripotent stem cells (iPSCs) that lacked the p53 gene, allowing them to differentiate these cells into neural progenitor cells and cerebral organoids. By comparing the RNA sequencing data from these samples with established glioblastoma cell lines (U87 and U118), the team identified distinct changes in lncRNA expression patterns associated with the loss of p53.

The results showed that p53 deficiency led to a progressive and stage-specific remodeling of the lncRNA landscape, with the most significant alterations occurring in neural progenitor cells that reached 40 days of differentiation. This late-stage profile closely resembled that of glioblastoma-like cells and was marked by the upregulation of five specific lncRNAs. These lncRNAs were found to be enriched in both p53-deficient neural models and glioma cells.

Principal component analysis revealed that these lncRNAs clustered with tumor-associated samples and showed strong co-expression with genes involved in mitosis, suggesting their potential role in promoting tumorigenesis. Among the five lncRNAs identified, LINC00973 and LINC01583 were notably expressed at higher levels in primary glioblastoma samples, while RP5-875H18.9 and RP11-1094H24.4 were previously unrecognized glioma-associated transcripts.

The findings of this study suggest that the loss of p53 triggers stage-dependent reprogramming of lncRNAs during neural differentiation, contributing to the emergence of glioma-associated transcriptional features. These results identify candidate lncRNAs that may play a role in early gliomagenesis, offering potential biomarkers for early detection and novel therapeutic targets for the treatment of glioblastoma.