The Wnt/β-catenin-P2-HNF4α feedback loop facilitates colorectal tumorigenesis and malignancy

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• The Wnt/β-catenin pathway is integral to colorectal cancer (CRC) pathogenesis, but its downstream effectors remain partially elucidated.
• The role of Hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor typically associated with liver function, in CRC is not well-defined.
• Investigating HNF4α isoforms (P1 and P2) and their interplay with Wnt/β-catenin signaling in CRC is crucial for understanding tumorigenesis.

Purpose of the Study:

• To elucidate the role of HNF4α isoforms (P1 and P2) in colorectal cancer.
• To investigate the regulatory relationship between HNF4α and the Wnt/β-catenin signaling pathway in CRC.
• To identify potential therapeutic targets within the Wnt/β-catenin signaling axis in colorectal cancer.

Main Methods:

• Utilized bulk and single-cell RNA sequencing (RNA-seq), in vitro/in vivo CRC models, and clinical samples to assess P1/P2-HNF4α expression and regulation.
• Employed Chromatin immunoprecipitation sequencing (ChIP-seq) to determine TCF7L1's regulatory influence on HNF4α.
• Correlated P1/P2-HNF4α levels with Wnt/β-catenin activity in patient samples using immunohistochemistry and RNA sequencing.

Main Results:

• P2-HNF4α was significantly upregulated in CRC tissues and promoted tumor growth in xenograft models.
• The Wnt/β-catenin/TCF7L1 axis transcriptionally activated P2-HNF4α, establishing a positive feedback loop that enhanced oncogenic Wnt signaling.
• P2-HNF4α expression strongly correlated with Wnt/β-catenin pathway activation in patients (r=0.58, p<0.0001), and its knockdown inhibited CRC cell proliferation and tumorigenesis.

Conclusions:

• Identified P2-HNF4α as a novel downstream target of Wnt/β-catenin signaling and a key driver of CRC progression.
• Revealed a Wnt/β-catenin/HNF4α feedback loop, offering mechanistic insights into colorectal carcinogenesis.
• P2-HNF4α represents a promising therapeutic target for disrupting aberrant Wnt signaling in colorectal cancer.