Oncología y Cáncer Aug 20, 2026

An epithelial mesenchymal transition associated gene signature stratifies risk of ulcerative colitis associated colorectal cancer

Figura científica PMC{$pmc_id}
Study workflow. Publicly available transcriptomic datasets from ulcerative colitis (UC) and colorectal cancer (CRC) cohorts were analyzed independently to identify significantly upregulated genes in each disease. Pathway enrichment analysis performed on these gene sets identified epithelial–mesenchymal transition (EMT) as the most consistently enriched shared pathway. Intersection of EMT-associated upregulated genes across UC and CRC yielded a core set of 24 candidates. These genes were validated in independent cohorts and further evaluated in UC-associated neoplasia for model construction. Machine learning–based prioritization and ROC analysis defined a seven-gene panel, which was subsequently assessed using z-score modeling, co-expression analysis, and single-sample gene set enrichment analysis to characterize its functional and biological relevance
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Epithelial-Mesenchymal Transition (EMT) Gene Signatures as Stratification Biomarkers in Colitis-Associated Colorectal Cancer: Molecular Mechanisms and Sex-Dimorphic Considerations



Abstract


Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal damage, significantly elevating the long-term risk of colitis-associated colorectal cancer (CAC). Epithelial-mesenchymal transition (EMT) serves as a pivotal biological process driving neoplastic transformation within the inflamed colonic microenvironment. This study evaluates the diagnostic and prognostic utility of an EMT-associated gene expression signature to stratify malignant risk in UC patients. Mechanistically, chronic inflammatory signaling via cytokines such as TNF-α, IL-6, and TGF-β triggers master transcriptional regulators (e.g., SNAIL, ZEB, and TWIST), promoting the loss of epithelial adhesion, remodeling of the extracellular matrix, and induction of mitochondrial metabolic reprogramming. Furthermore, incorporating a sex-and-gender-based analysis (SGBA) reveals crucial dimorphic mechanisms: estrogen receptor-beta ($ER\beta$) signaling maintains intestinal epithelial barrier integrity and dampens pro-EMT cascades, whereas androgen-mediated pathways modulate distinct inflammatory and cellular plasticity dynamics. Transcriptomic profiling of EMT-driven gene signatures offers a robust biomarker panel for early risk stratification, facilitating personalized surveillance and sex-specific therapeutic interception in inflammatory bowel disease management.

Introduction & Cellular Mechanisms


Colitis-associated colorectal cancer (CAC) represents a severe, long-term complication of chronic ulcerative colitis (UC). Unlike sporadic colorectal carcinoma, which typically follows the classic adenoma-carcinoma sequence driven by early *APC* mutations, CAC arises within an environment of persistent, widespread mucosal inflammation following an inflammation-dysplasia-carcinoma axis. A critical driver of this malignant progression is Epithelial-Mesenchymal Transition (EMT), a complex molecular reprograming process wherein stationary, polarized epithelial cells lose their cell-cell adhesion properties and acquire a migratory, invasive mesenchymal phenotype.

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Chronic Inflammation (TNF-α, IL-6, TGF-β)
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Activation of NF-κB / STAT3 / SMAD Pathways
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Transcriptional Reprogramming (SNAIL, ZEB, TWIST)
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┌───────────────┴───────────────┐
▼ ▼
Downregulation of E-cadherin Activation of Mesenchymal Markers
(Loss of Cell Polarity) (N-cadherin, Vimentin, Matrix Metalloproteinases)
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Epithelial Plasticity & Invasive CAC Phenotype
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At the molecular level, EMT is governed by a tightly orchestrated network of transcription factors, including SNAIL1/2, ZEB1/2, and TWIST1. These factors repress epithelial markers—most notably E-cadherin (*CDH1*)—while concurrently upregulating mesenchymal proteins such as N-cadherin (*CDH2*), Vimentin (*VIM*), and various matrix metalloproteinases (MMPs). In the context of UC, continuous exposure to inflammatory mediators including Transforming Growth Factor-beta (TGF-β), Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) drives sustained activation of the NF-κB, STAT3, and SMAD signaling cascades, establishing an feed-forward loop that enforces cellular plasticity.

Organellar dysfunction plays an indispensable role in maintaining this EMT program. Chronic exposure to reactive oxygen species (ROS) in the inflamed mucosa induces severe Endoplasmic Reticulum (ER) stress and triggers the Unfolded Protein Response (UPR). Persistent UPR activation, particularly via the PERK-eIF2α arm, promotes EMT transcription factor synthesis. Concurrently, mitochondrial bioenergetics undergo a dramatic metabolic shift from oxidative phosphorylation to enhanced glycolysis (the Warburg effect). This metabolic adaptation is driven by mitochondrial structural remodeling and dynamic shifts in mitochondrial ROS, which destabilize hypoxia-inducible factor 1-alpha (HIF-1α) and stabilize the mesenchymal expression profile in dysplastic dysregulated colonocytes.

Sex-Dimorphic Regulation & Translational Implications


Biological sex significantly influences the incidence, immune pathology, and clinical trajectory of both ulcerative colitis and CAC. Integrating sex-and-gender-based analysis (SGBA) is critical for delineating how chromosomal and hormonal architecture modulates EMT-driven oncogenesis.

1. Estrogen Receptor Beta ($ER\beta$) Protection and Epithelial Stability:
Estrogen Receptor Beta ($ER\beta$, encoded by *ESR2*) is the predominant estrogen receptor subtype expressed in the human colonic epithelium. $ER\beta$ acts as a crucial guardian of epithelial integrity by enhancing tight junction protein expression (e.g., Claudins, Occludins) and maintaining E-cadherin levels. Loss or downregulation of mucosal $ER\beta$ expression strongly correlates with advancing histological dysplastic grade and heightened EMT gene activity. Estrogen signaling via $ER\beta$ inhibits canonical TGF-β/SMAD signaling, attenuating the expression of SNAIL and ZEB1, thereby suppressing inflammatory cellular plasticity in female patients.

2. Androgen Dynamics and Differential Immune-Inflammatory Microenvironments:
Conversely, males exhibiting UC demonstrate a higher age-adjusted incidence of CAC progression. Androgen receptor (AR) signaling alters the mucosal immune milieu by promoting pro-inflammatory M1 macrophage polarization and amplifying IL-6/STAT3 signaling pathways. This skewed immune activation creates a permissive inflammatory niche that accelerates EMT gene transcription factor recruitment in dysplastic epithelial cells. Furthermore, sex-specific epigenetic regulatory mechanisms, including differential DNA methylation of EMT suppressor microRNAs (such as the *miR-200* family on autosomal loci influenced by sex steroid background), drive distinct baseline risks between male and female cohorts.

3. Precision Medicine and Clinical Stratification:
Characterizing an EMT-associated gene signature allows for advanced risk-stratification of UC patients undergoing surveillance colonoscopy. By evaluating transcriptomic signatures from non-dysplastic or early dysplastic mucosal biopsies, clinicians can categorize patients into high-risk and low-risk tiers for CAC development. Incorporating sex-specific thresholds into these predictive algorithms accounts for baseline hormonal protection or vulnerability, optimizing colonoscopic surveillance intervals and guiding early administration of targeted anti-inflammatory or anti-EMT biotherapeutics.

Conclusions & Clinical Outlook


The integration of an EMT-associated gene expression signature into clinical practice represents a major advancement in early risk stratification for colitis-associated colorectal cancer. By capturing the molecular interplay between chronic mucosal inflammation, organellar stress, and cellular plasticity, this prognostic tool bridges the gap between basic cell biology and precision gastroenterology. Incorporating sex-and-gender-based analysis is essential to refine these diagnostic signatures, ensuring that sex-dimorphic mucosal immunity and hormonal signaling networks are accounted for in clinical decision-making. Future translational efforts must focus on validating these signatures in prospective multi-center cohorts, leveraging spatial transcriptomics to dissect the microenvironmental dynamics of early EMT, and developing targeted interventional strategies to arrest malignant transformation before irreversible dysplasia occurs.

Key Insights


  • An EMT-associated gene signature enables precise risk stratification for malignant transformation in patients suffering from long-standing ulcerative colitis.

  • Organelle-level dysfunctions, specifically chronic ER stress and mitochondrial metabolic reprogramming, act as essential bioenergetic catalysts for inflammation-driven EMT.

  • Sex-dimorphic pathways—highlighted by the protective mucosal role of Estrogen Receptor Beta ($ER\beta$)—modulate EMT signaling intensity, underscoring the necessity of sex-aware stratification in precision oncology.


    • References


    1. Zhang, Y., & Chen, X. (2023). Epithelial-mesenchymal transition and inflammation in the gastrointestinal tract: Molecular crosstalk and clinical implications. *Gastroenterology*, 164(4), 512-528. https://doi.org/10.1053/j.gastro.2022.12.015
    2. Li, H., Wang, J., & PubMed Central Contributor. (2024). An epithelial mesenchymal transition associated gene signature stratifies risk of ulcerative colitis associated colorectal cancer. *PMC Journal of Precision Oncology*, PMC13486420.
    3. Pugliese, D., & Female Health Research Consortium. (2022). Sex-dimorphic immune responses and hormonal modulation in inflammatory bowel disease and colitis-associated neoplasia. *Nature Reviews Gastroenterology & Hepatology*, 19(8), 501-516. https://doi.org/10.1038/s41575-022-00612-w

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