Identification of Transcriptional Hippo Response Signature Connecting Inflammatory Bowel Disease and Colorectal Cancer Progression
- 1Comsats University Islamabad, Pakistan
Abstract
BackgroundInflammatory bowel disease (IBD) has been linked to a two- to eightfold increase in colorectal cancer (CRC) risk. However, particular genes that bridge intestinal dysbiosis and oncogenic transcriptional reprogramming remain unclear. The Hippo/YAP pathway is a major regulator of intestinal epithelial homeostasis whose effector YAP is hyperactivated in CRC, but its transcriptional engagement in IBD mucosa and its link to specific cancer-risk genes has not been thoroughly mapped.
MethodsBulk RNA-seq data were integrated from two independent cohorts: GSE235236 (IBD colon mucosa; UC/CD vs. healthy controls; n = 56) and TCGA-COAD/READ (CRC tumors stratified by YAP activity; n = 592). Differential expression analysis was conducted separately within each cohort using Welchs t-test with Benjamini-Hochberg FDR correction. YAP transcriptional activity was estimated per sample as the mean row-wise Z-score of seven canonical YAP target genes, and TCGA tumors were stratified into Hippo-High (Q4) and Hippo-Low (Q1) groups. Genes showing consistent dysregulation across both cohorts were identified and ranked to define a Dysbiosis-Hippo Response (DHR) module, which was further organized into functional gene archetypes.
ResultsIBD mucosa showed 2,848 significantly dysregulated genes (FDR < 0.05). Comparison with the CRC cohort identified 120 genes showing concordant dysregulation, forming the DHR module. These genes were significantly enriched in TNF-alpha signaling via NF-kB (adjusted p = 0.006), inflammatory response (adjusted p = 0.013), and Myogenesis (adjusted p = 0.013). DHR gene classification revealed three functional archetypes: (i) innate immune activation (SPI1, OSM, IL11, LILRA2, SLC11A1) reflecting convergent myeloid reprogramming; (ii) epithelial-mesenchymal transition (TWIST1, SNAI1, PRRX2, MMP9) priming invasive potential before malignancy; and (iii) tumor microenvironment immune regulation (TN-FRSF4, TNFRSF18, PDCD1, VASN, SPON2) shaping immune tolerance. Interestingly, the canonical YAP target genes (CTGF, CYR61, ANKRD1, AMOTL2, and FSTL1), sharply upregulated in Hippo-High CRC, were essentially unchanged in IBD mucosa. This signifies that the shared DHR programme operates through non-canonical YAP effectors. And yet, YAP target scores are positively correlated with DHR module expression across IBD samples (Spearman rho = 0.726, p = 2.5 x 10-10).
ConclusionsOur findings define a three-archetype DHR module that links gut dysbiosis to YAP-driven oncogenesis at single-gene resolution. The programme shared between IBD and CRC is driven by innate immune activation, EMT priming, and remodeling of the immune microenvironment, not by the canonical CTGF/CYR61 YAP target axis, which appears only at the CRC stage. This gene-level framework provides tractable mechanistic targets for chemoprevention and biomarker development at the inflammation-to-cancer transition.
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BibTeX
@misc{noor2026identification,
title = {{Identification of Transcriptional Hippo Response Signature Connecting Inflammatory Bowel Disease and Colorectal Cancer Progression}},
author = {S. Noor and K. S. Vignaish and P. Joshi},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363887},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Identification of Transcriptional Hippo Response Signature Connecting Inflammatory Bowel Disease and Colorectal Cancer Progression
AU - S. Noor
AU - K. S. Vignaish
AU - P. Joshi
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363887
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1
AB - BackgroundInflammatory bowel disease (IBD) has been linked to a two- to eightfold increase in colorectal cancer (CRC) risk. However, particular genes that bridge intestinal dysbiosis and oncogenic transcriptional reprogramming remain unclear. The Hippo/YAP pathway is a major regulator of intestinal epithelial homeostasis whose effector YAP is hyperactivated in CRC, but its transcriptional engagement in IBD mucosa and its link to specific cancer-risk genes has not been thoroughly mapped. MethodsBulk RNA-seq data were integrated from two independent cohorts: GSE235236 (IBD colon mucosa; UC/CD vs. healthy controls; n = 56) and TCGA-COAD/READ (CRC tumors stratified by YAP activity; n = 592). Differential expression analysis was conducted separately within each cohort using Welchs t-test with Benjamini-Hochberg FDR correction. YAP transcriptional activity was estimated per sample as the mean row-wise Z-score of seven canonical YAP target genes, and TCGA tumors were stratified into Hippo-High (Q4) and Hippo-Low (Q1) groups. Genes showing consistent dysregulation across both cohorts were identified and ranked to define a Dysbiosis-Hippo Response (DHR) module, which was further organized into functional gene archetypes. ResultsIBD mucosa showed 2,848 significantly dysregulated genes (FDR < 0.05). Comparison with the CRC cohort identified 120 genes showing concordant dysregulation, forming the DHR module. These genes were significantly enriched in TNF-alpha signaling via NF-kB (adjusted p = 0.006), inflammatory response (adjusted p = 0.013), and Myogenesis (adjusted p = 0.013). DHR gene classification revealed three functional archetypes: (i) innate immune activation (SPI1, OSM, IL11, LILRA2, SLC11A1) reflecting convergent myeloid reprogramming; (ii) epithelial-mesenchymal transition (TWIST1, SNAI1, PRRX2, MMP9) priming invasive potential before malignancy; and (iii) tumor microenvironment immune regulation (TN-FRSF4, TNFRSF18, PDCD1, VASN, SPON2) shaping immune tolerance. Interestingly, the canonical YAP target genes (CTGF, CYR61, ANKRD1, AMOTL2, and FSTL1), sharply upregulated in Hippo-High CRC, were essentially unchanged in IBD mucosa. This signifies that the shared DHR programme operates through non-canonical YAP effectors. And yet, YAP target scores are positively correlated with DHR module expression across IBD samples (Spearman rho = 0.726, p = 2.5 x 10-10). ConclusionsOur findings define a three-archetype DHR module that links gut dysbiosis to YAP-driven oncogenesis at single-gene resolution. The programme shared between IBD and CRC is driven by innate immune activation, EMT priming, and remodeling of the immune microenvironment, not by the canonical CTGF/CYR61 YAP target axis, which appears only at the CRC stage. This gene-level framework provides tractable mechanistic targets for chemoprevention and biomarker development at the inflammation-to-cancer transition.
ER -