FSTL3 promotes colorectal cancer by activating the HIF1 pathway

Abstract

Follistatin-like 3 (FSTL3) is a glycoprotein known to promote tumor growth, invasion, and angiogenesis in various cancers. However, its role in Colorectal Cancer (CRC), particularly concerning the hypoxia-inducible factor 1α (HIF1α) signaling pathway, remains unclear. The HIF1α pathway is critical in CRC progression, enabling tumor cells to adapt to hypoxia through angiogenesis, Epithelial-Mesenchymal Transition (EMT), and metabolic reprogramming. Analysis of The Cancer Genome Atlas (TCGA) and GSE39582 datasets revealed that FSTL3 is significantly upregulated in CRC tissues and correlates with poor Overall Survival (OS), Progression-Free Survival (PFS), and aggressive features such as venous, lymphatic, and perineural invasion. In vitro experiments demonstrated that FSTL3 overexpression in HCT15 and HCT116 cells promoted proliferation, migration, and cell cycle progression, whereas knockdown in LOVO and Caco2 cells suppressed these processes and induced apoptosis. Transcriptome sequencing and western blot analysis indicated that FSTL3 activated the HIF1α pathway by upregulating HIF1α, ANGPT2, and HK3, which are key regulators of angiogenesis and glycolysis. Importantly, treatment with the HIF1α inhibitor KC7F2 reversed the oncogenic effects of FSTL3 overexpression both in vitro and in vivo. In xenograft and tail vein metastasis models, KC7F2 suppressed tumor growth, reduced pulmonary metastasis, and restored lung tissue integrity, further downregulating FSTL3 and HIF1α expression. These findings suggest that FSTL3 promotes CRC progression via the HIF1α pathway and highlight its potential as a prognostic biomarker and therapeutic target for CRC treatment.