Differential Expression and Co-Variation of HERV-Associated Transcripts, IL-17 Cytokines, and NFκB in Paired Colorectal Cancer Tissues

Background: The mechanistic link between HERV-associated transcript expression and the inflammatory pathways involved in colorectal cancer (CRC), particularly the IL-17 axis, remains insufficiently characterized. We performed an exploratory paired-tissue study to investigate whether HERV-associated transcript deregulation in CRC aligns with a distinct local inflammatory signature, potentially consistent with endogenous retroviral re-expression linked to local immune activation and viral mimicry-related processes within the tumor microenvironment. Methods: Matched colorectal tumor tissue (T) and histologically tumor-free adjacent tissue (N) were obtained from 21 treatment-naive CRC patients. Expression of selected HERV-associated loci/transcripts (HERV-FRD, HERV-R, HERV-K, HERV-V1, HERV-1, HERV-H, and ERVWE1), HHLA1/HHLA2, IL-17 family members, and NFKB1 was assessed by RT–qPCR. Results: CRC tumors exhibited selective upregulation of HERV-FRD, HERV-R, HERV-K, HERV-V1, ERVWE1, HHLA1, and HHLA2, whereas HERV-1 and HERV-H showed no significant paired differences. IL-17E was also increased in tumor tissue, while NFKB1 did not show significant paired variation. Paired differential expression analysis [Δ(T−N)] identified a coordinated HERV/ERVWE1 signature that positively correlated with IL-17E after FDR correction, whereas HHLA1/HHLA2 displayed partially distinct behavior. No consistent associations were observed with clinicopathological variables. Conclusions: CRC appears to harbor a selective HERV/ERVWE1-associated transcriptional program linked to IL-17E, supporting a candidate inflammatory axis that may reflect a biologically relevant component of the tumor microenvironment. This expression pattern may also be compatible with a localized endogenous retroviral reactivation state linked to viral mimicry-related inflammatory signaling, although this interpretation remains indirect and requires mechanistic validation. These findings are associative and hypothesis-generating, but they provide a conceptual basis for future mechanistic validation and for exploring whether HERV-linked inflammatory signatures may have biomarker or therapeutic relevance in CRC.