The Proliferation–Invasion Dichotomy: Transcriptomic Signatures of lncRNA and Ubiquitin–Proteasome Networks in Hypermutated Endometrial Cancer

Endometrial cancer incidence is markedly rising globally, posing an urgent need to elucidate the molecular mechanisms driving disease characterization and progression. Endometrial cancer evolution is driven by canonical Wnt and p53 pathway alterations, yet the mechanisms orchestrating the transition from localized proliferation to stromal invasion, the proliferation–invasion dichotomy, remain poorly understood. While long non-coding RNAs (lncRNAs) are emerging as critical correlates of divergent tumor phenotypes, their coordination with the broader ubiquitin–proteasome system (UPS), specifically E3 ligase and deubiquitinase (DUB) networks, during endometrial cancer progression is largely unexplored. Whole-transcriptome RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tissue from a clinical cohort of 38 patients, comprising 34 primary endometrial carcinomas across distinct molecular subtypes (MSI, POLE, p53abn, and NSMP) and four pre-cancerous endometrial intraepithelial neoplasia (EIN) lesions. To stringently control for baseline patient-specific confounding, differential gene expression and principal component analyses were executed using a strict, intra-patient, matched-pair design (Tumor vs. Adjacent Normal). A principal component analysis of the batch-corrected transcriptome revealed a profound divergence between tumor and paired adjacent normal phenotypes. This spatial divergence was heavily characterized by lncRNA signatures (including SOCS2-AS1) strongly associated with extracellular matrix (ECM) remodeling. Concurrently, we identified a critical, malignancy-specific transcriptomic dysregulation across the broader UPS network. Within this altered transcriptional landscape, the ubiquitin C-terminal hydrolase (UCHL) family emerged as a highly significant node. UCHL5 displayed robust, global upregulation across the pan-cancer cohort compared with matched controls (log2FC = 0.83, padj < 0.001). Strikingly, UCHL3 exhibited global upregulation (log2FC = 1.23, padj = 0.002) that was highly concentrated within the microsatellite instability (MSI) and polymerase epsilon (POLE) hypermutated subtypes, highlighting a potential compensatory transcriptomic response to the predicted cellular stress inherent to high mutational burdens. In an exploratory subset of pre-cancerous EIN lesions (n = 4), neither the invasive lncRNA networks nor profound UPS/UCHL dysregulation were observed, suggesting a preliminary trend that requires validation in larger precursor cohorts. Our paired transcriptomic mapping reveals that endometrial cancer progression is characterized by divergent transcriptomic programs: specific lncRNA networks are tightly coupled to the invasive remodeling of the ECM, while concurrent dysregulation of broad UPS networks reflects the altered proteostasis associated with this phenotypic shift. The pronounced upregulation of critical UPS nodes, such as UCHL3 in MSI/POLE tumors, highlights a landscape of novel, enzymatically targetable vulnerabilities in hypermutated endometrial cancers.