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HtrA3 Promotes Malignant Progression of Colorectal Cancer and Is Associated With PI3K ‐ AKT ‐ FOXO1 Signaling

Year: 2026

Type: article

Abstract: High-temperature requirement protease A3 (HtrA3) has been implicated in the progression of various carcinomas through tissue-specific mechanisms; however, its precise role in colorectal cancer (CRC) remains unclear. We initially identified the upregulation of HtrA3 in CRC tissues through Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomics, which was consistent with the analysis of the CPTAC dataset. Our research further confirmed that HtrA3 is significantly upregulated in CRC tissues and associated with reduced overall survival. Functional assays showed that HtrA3 overexpression enhanced CRC cell proliferation, migration, and invasion, while HtrA3 knockdown yielded opposite effects. In HtrA3-overexpressing HCT116 cells, increased phosphorylation of PI3K, AKT, and FOXO1 was observed, which was reduced upon treatment with the PI3K inhibitor LY294002. Conversely, in HtrA3-knockdown SW480 cells, these phosphorylation levels declined but were restored with the PI3K activator 740Y-P. In vivo, HtrA3 overexpression accelerated xenograft tumor growth. These findings suggest that HtrA3 promotes CRC cell proliferation, migration, and invasion, potentially involving PI3K-AKT-FOXO1 signaling, and support further investigation of HtrA3 as a potential prognostic biomarker and therapeutic target in CRC.

Source: Cancer Medicine

DOI: 10.1002/cam4.72496