Dataset Information

P53 functional states are associated with distinct aldehyde dehydrogenase transcriptomic signatures.

ABSTRACT: p53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; however, the relationship between these two mediators remains poorly defined. In this study, ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV-/p53HRmut cases (p?=?0.03). AVS and several individual ALDH isoforms were associated with prognosis in HPV16+/p53WT HNSCC but not in HPV-/p53HRmut HNSCC. Knockdown of the dominant ALDH isoform in high AVS HNSCC depleted the CIC pool in vitro and in vivo. Our results demonstrate that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures. Moreover, tumor ALDH profiling may provide insight on which ALDH isoform to target in high AVS HNSCC tumors to deplete the CIC population.

SUBMITTER: Gui S

PROVIDER: S-EPMC6978341 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Pediatric spinal ependymomas (SEPN) are important albeit uncommon malignant central nervous system tumors with limited treatment options. Our current knowledge about the underlying biology of these tumors is limited due to their rarity. To begin to elucidate molecular mechanisms that give rise to pediatric SEPN, we compared the transcriptomic landscape of SEPNs to that of intracranial ependymomas using genome-wide mRNA and microRNA (miRNA) expression profiling in primary tumour samples. We found that pediatric SEPNs are characterized by increased expression of genes involved in developmental processes, oxidative phosphorylation, cellular respiration, electron transport chain, and cofactor metabolic process. Next, we compared pediatric spinal and intracranial ependymomas with the same tumours in adults and found a relatively low number of genes in pediatric tumours that were shared with adult tumours (12.5%). In contrast to adult SEPN, down-regulated genes in pediatric SEPN were not enriched for position on chromosome 22. At the miRNA level, we found ten miRNAs that were perturbed in pediatric SEPN and we identified regulatory relationships between these miRNAs and their putative targets mRNAs using the integrative miRNA-mRNA network and predicted miRNA target analysis. These miRNAs include the oncomiR hsa-miR-10b and its family member hsa-miR-10a, both of which are upregulated and target chromatin modification genes that are down regulated in pediatric SEPN. The tumor suppressor, hsa-miR-124, was down regulated in pediatric SEPN and it normally represses genes involved in cell-cell communication and metabolic processes. Together, our findings suggest that pediatric SEPN is characterized by a distinct transcriptional landscape from that of pediatric intracranial EPNs or adult tumors (both SEPNs and intracranial EPNs). Although confirmatory studies are needed, our study reveals novel molecular pathways that may drive tumorigenesis and could serve as biomarkers or rational therapeutic targets.

Dataset Information

P53 functional states are associated with distinct aldehyde dehydrogenase transcriptomic signatures.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets