Human endogenous retroviruses (HERVs) are remnants of ancient infections integrated into the primate germ line. HERV transcriptional reactivation has been observed in several diseases, including cancer, where it may reflect epigenetic deregulation, cellular stress, inflammation, and infections. Hepatocellular Carcinoma (HCC) is one of the most diffuse and deadly cancers worldwide, with chronic hepatitis infections as major etiological factors. In this context, the activation of specific HERV loci in HCC and their relationship with the broader tumor-associated transcriptional landscape remain poorly defined. Here, we characterized the expression of ∼3300 HERVs in a public RNA-seq dataset comprising HCC samples, predominantly of viral etiology, and non-HCC liver controls. We identified 185 differentially expressed HERVs, predominantly upregulated in HCC (n = 145): comparisons with GTEx healthy liver transcriptomes, inflammatory gene profiling, and covariate-adjusted analyses supported the consistency of this HCC-associated transcriptional signature. Aggregate expression scores of upregulated and downregulated HERVs showed significant associations with histological grade, with opposite trends across G1–G3 tumors. 16 HERV loci were consistently upregulated in all tumor tissues, and their aggregate expression increased significantly with histological grade, supporting their prioritization as a candidate HCC-associated signature. HERV-correlated pathway analyses revealed grade-associated patterns involving metabolic, inflammatory, interferon-related, and proliferative transcriptional programs. De novo transcript reconstruction identified candidate HERV-derived transcripts requiring experimental validation. Overall, the study provides a comprehensive characterization of HERV modulation in a predominantly viral-associated HCC cohort and identifies conserved HERV signatures embedded within the broader transcriptomic remodeling, for future independent and functional studies of their potential relevance to liver cancer biology.
Effective triage of HPV-positive women remains challenging, as conventional cytology often yields excessive colposcopy referrals due to limited specificity. We evaluated HPV integration status-a key molecular marker associated with cervical carcinogenesis-as a novel triage biomarker within the Fujian-Hubei Screening Cohort (N = 31,628). Among 949 prospectively enrolled HPV-positive women with concurrent HPV integration testing (HIVID), genotyping, and cytology, HPV integration emerged as the strongest independent predictor of CIN3+ (aOR = 68.1). As a standalone triage tool, HPV integration detection significantly outperformed cytology, demonstrating superior specificity (97.0% vs. 64.3%; p < 0.001) and PPV (57.1% vs. 10.4%; p < 0.001) while maintaining comparable sensitivity (66.7% vs. 68.5%). Critically, our combined strategy integrating HPV16/18 genotyping with integration detection achieved optimized performance: it enhanced specificity by 25.2% (69.5% vs. 44.3%) and yielded a higher PPV (14.7% vs. 9.1%) compared to standard cytology + genotyping, with no significant sensitivity loss (87.0% vs. 92.6%; p = 0.526). This approach identified a large low-risk subgroup (NILM/integration-negative; 59.2% of cohort) with minimal CIN3+ risk (0.7%), enabling an 82% reduction in colposcopy referrals versus cytology triage (6.6% vs. 37.6%; p < 0.001). These results position HPV integration as a robust biomarker for precision risk stratification. The combined use of HPV genotyping and integration detection offers an efficient, clinically actionable strategy to minimize unnecessary procedures while maintaining high-grade lesion detection.
Beta human papillomaviruses (betaHPVs) act as cofactors in keratinocyte carcinogenesis, but how they reprogram host gene regulation remains unclear. Here, we combined transcriptomic, small RNA and epigenomic profiling to dissect the impact of betaHPV8 oncogene expression on keratinocytes. The viral E6 protein emerged as the major driver of host gene regulatory reprogramming, repressing epidermal differentiation programs, whereas E7 induced fewer, complementary changes. Small RNA sequencing revealed E6-dependent remodeling of the microRNA (miRNA) landscape, and integrative analyses linked miRNA regulation to reciprocal changes in target gene expression, indicating a role for epigenetic post-transcriptional regulation in the E6-driven phenotype. Whole-genome bisulfite sequencing showed widespread E6-dependent DNA methylation changes at promoters, enhancers, and gene bodies. Motif enrichment analysis showed that hypermethylation silenced nuclear receptor and developmental regulators, while hypomethylation was associated with enrichment of AP1 and STAT3 binding motifs. Analysis of clinical specimens further revealed that betaHPV DNA was enriched in actinic keratoses and cutaneous squamous cell carcinomas displaying stem cell-like methylation profiles, linking viral activity to progenitor-associated tumorigenesis. Together, our data define a multilayered mechanism by which HPV8 destabilizes keratinocyte lineage identity which may create a cellular state permissive for malignant progression.
Human T-cell Leukemia Virus type 1 (HTLV-1) drives Adult T-cell Leukemia/Lymphoma (ATLL) through sustained expression of the viral oncoprotein HBZ. Although HBZ is known to reshape host transcriptional programs, its role in post-transcriptional regulation in ATLL remains poorly understood. Here, we uncover a mechanism by which HBZ reprograms circular RNA (circRNA) biogenesis to support leukemic cell survival. Comprehensive circRNA profiling across ATLL subtypes revealed extensive circRNA remodeling, with distinct signatures associated with aggressive ATLL subtypes. Among these, circAFF2(3) is markedly upregulated in aggressive ATLL, and functional analyses show that its expression enhances, whereas its silencing reduces, the survival of HTLV-1-transformed T cells. Mechanistically, we show that HBZ interacts with the RNA helicase DHX9 and inhibits its helicase activity at intronic double-stranded RNA structures flanking circularized exons. Using both endogenous and synthetic circRNAs, we demonstrate that this inhibition allows RNA duplexes to persist, thereby promoting back-splicing and the accumulation of DHX9-sensitive circRNAs, including circAFF2(3). Together, these findings reveal that HTLV-1 hijacks host RNA helicase activity to reprogram circRNA biogenesis, identifying the HBZ-DHX9 axis as a novel post-transcriptional mechanism contributing to ATLL development.
IL-33, an alarmin cytokine binding to IL1RL1 (ST2) receptor, plays a multifaceted role in cancer. Using an HPV16-E7 oncoprotein-mediated murine model of squamous intraepithelial hyperplasia, a pre-stage of squamous cell carcinoma (SCC), we characterised the interactions of hyperproliferative epithelial cells and immune cells regulated by IL-33 and IL1RL1. We show that basal epithelial cells in epithelial hyperplasia co-express IL-33 and genes involved in MHC class II antigen presentation and in epithelial stress response. Using spatial transcriptomics, we demonstrate that IL1RL1+Foxp3+Tregs are in close proximity to IL-33-expressing cells, in both the murine model and in human cervical intraepithelial neoplastic tissues. Cytoplasmic location of IL-33 is associated with its bioactivity, and we show that a subset of epithelial cells in epithelial hyperplasia contains high levels of cytoplasmic IL-33. Genetic deletion of the IL1RL1 gene led to partial rejection of HPV16-E7-expressing skin grafts, demonstrating that IL1RL1 plays a functional role in mediating immune suppression in epithelial hyperplasia. IL1RL1-deletion further led to a significant reduction in Tregs in epithelial hyperplasia. The IL1RL1 signalling pathway, therefore, represents a potential therapeutic target for intraepithelial hyperplasia and SCC.
