Aryl hydrocarbon receptor promotes the proliferation and aggressive progression of colorectal cancer under high-fat diet via activating INPP4B/AKT/SGK3 signaling pathway.

INTRODUCTION: Epidemiological evidence confirms high-fat diet (HFD) as a key risk factor for colorectal cancer (CRC) progression. Aryl hydrocarbon receptor (AhR), a ligand-dependent nuclear transcription factor enriched in intestinal tissues, regulates intestinal metabolism and tumorigenesis. However, its role and mechanism in HFD-induced CRC progression remain unclear.

METHODS: Here, we constructed a HFD-induced obese CRC tumor-bearing mouse model and a free fatty acid (FFA)-treated CRC cell model to investigate AhR function and mechanism underlying in HFD-related CRC.

RESULTS AND DISCUSSION: We found that HFD significantly promoted CRC progression, accompanying with activation of AhR with upregulated level of kynurenine (KYN) synthesis-related enzymes and increased KYN levels in tumor tissue and peripheral blood. The specific inhibition of AhR alleviated tumor growth and metastasis in tumor-bearing mouse with HFD treatment. In vitro, FFA treatment induced AhR activation with high level of KYN secretion, which enhanced CRC cell growth, invasion and epithelial-mesenchymal transition (EMT). Genetic knockdown of AhR reversed FFA-induced malignant phenotypes. Quantitative proteomic analysis identified that inositol polyphosphate 4-phosphatase type II (INPP4B) might be a potential target for AhR function. Mechanistically, activated AhR directly transcriptionally upregulated INPP4B to trigger AKT/SGK3 pathway activation, and knockdown of INPP4B abolished AhR activation-induced oncogenic effects. In conclusion, AhR promotes HFD-related subcutaneous tumor growth and invasion/migration-related phenotypes of CRC via activating the INPP4B/AKT/SGK3 pathway, which may provide a potential target for the prevention or treatment of HFD-associated CRC.