International journal of medical sciences
State-Dependent Decoupling of a CREM-Centric cAMP-Responsive Regulon and Survival in Hepatocellular Carcinoma
By Ling H and Hu Y.
Abstract
Background
The cAMP-responsive element modulator (CREM) has emerged as a cAMP-responsive transcriptional node associated with dysfunctional lymphocyte states in chronic hepatic infection and some immunosuppressive tumor microenvironments, but its regulatory output and isoform usage by specific cell-types remain insufficiently defined in hepatocellular carcinoma (HCC). Because CREM produces activating isoforms and repressive inducible cAMP early repressor (ICER) isoforms through alternative promoter usage, bulk or single-cell CREM mRNA abundance may not faithfully describe the net direction of downstream CRE-dependent transcriptional programs.
Methods
Single-cell RNA-seq datasets spanning 18,665 T cells from two independent, pathologically validated primary liver cancer cohorts (32 HCC and 5 iCCA patients) were integrated, with HCC-only sensitivity analyses confirming the primary findings. Using prior-knowledge transcriptional regulon frameworks cross-referenced with CRE-family genomic occupancy data (ENCODE), CREM mRNA expression was decoupled from its inferred downstream regulon activity at single-cell resolution. Validation was performed using a third-generation long-read direct RNA sequencing hepatic model and bulk TCGA clinical survival cohorts.