ArticleJournal of translational medicine2025
The Wnt/β-catenin-P2-HNF4α feedback loop facilitates colorectal tumorigenesis and malignancy.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed.
- The role of HNF4α in adenocarcinoma.Biochemical Society transactions · 2026Review
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11 authors.
Funding
Abstract
backgroundThe Wnt/β-catenin signaling pathway is a crucial regulator of colorectal cancer (CRC) development; however, its downstream targets and mechanistic contributions to tumorigenesis remain incompletely understood. Hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor primarily studied in liver function and hepatocarcinogenesis, has an unclear role in CRC. This study investigates the antagonistic and synergistic effects of HNF4α isoforms driven by the P1 and P2 promoters on Wnt/β-catenin signaling in colorectal cancer.
methodsWe assessed P1/P2-HNF4α expression and its regulation by Wnt/β-catenin signaling using bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), in vitro and in vivo CRC models, and clinical tumor samples. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to determine the regulatory effect of TCF7L1 on HNF4α. Clinical correlations between P1/P2-HNF4α levels and Wnt/β-catenin activity were analyzed using immunohistochemistry, RNA sequencing, and Spearman's rank correlation. Statistical significance was determined using Student's t-test and ANOVA.
resultsP2-HNF4α was significantly overexpressed in CRC tissues compared to normal controls and significantly promoted tumor growth in subcutaneous xenograft models using nude mice. Mechanistically, P2-HNF4α was transcriptionally activated by the Wnt/β-catenin/TCF7L1 axis, creating a positive feedback loop that amplified oncogenic Wnt signaling. Clinically, P2-HNF4α expression strongly correlated with Wnt/β-catenin pathway activation in patient samples (r = 0.58, p < 0.0001). Functionally, P1/P2-HNF4α knockdown suppressed CRC cell proliferation and inhibited Wnt-driven tumorigenesis.
conclusionsThis study identifies P2-HNF4α as a novel downstream effector of the Wnt/β-catenin pathway and a critical driver of CRC progression. The Wnt/β-catenin/HNF4α feedback loop identified here provides mechanistic insights into colorectal carcinogenesis and highlights P2-HNF4α as a potential therapeutic target. These findings may inform strategies to disrupt Wnt signaling hyperactivation in CRC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.