FGFR2 mediates the progression of colorectal cancer by promoting the expression of HIF-1α via the PI3K/AKT/mTOR pathway.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy worldwide, and its progression is associated with dysregulated signaling pathways. Fibroblast growth factor receptor 2 (FGFR2) is frequently overexpressed in CRC and correlated with poor prognosis, but whether it mediates hypoxia-inducible factor-1α (HIF-1α) to promote tumor progression remains unclear. METHODS: The expression and prognostic value of FGFR2 and HIF-1α in CRC were analyzed via bioinformatics. Clinicopathological specimens were obtained and immunohistochemical staining was performed to explore the correlations between FGFR2 and HIF-1α expression and the clinicopathological features of CRC patients. Using CRC cell lines (HCT116 and NCI-H716), cell proliferation, transwell, wound healing, western blotting, gene activation and knockdown experiments were used to assess the effects of FGFR2 expression on cell proliferation, migration and invasion, as well as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway activity and HIF-1α expression level. A mouse xenotransplantation model was used to further clarify the regulatory effects of changes in FGFR2 expression on PI3K/AKT/mTOR pathway activity, HIF-1α expression level and CRC tumor growth in vivo. RESULTS: In this study, immunohistochemical staining of tumor tissues from 72 patients with CRC confirmed that the expression level of HIF-1α in cancer tissues was higher than that in normal tissues. Bioinformatics analysis and clinicopathological analysis confirmed that the overexpression of the FGFR2 and HIF-1α genes were the independent risk factors affecting the prognosis of CRC and that the overexpression of HIF-1α was positively correlated with the increase of tumor size and FGFR2 expression. The in vitro results of this study show that FGFR2 mediates HIF-1α and affects CRC cell proliferation, migration and invasion, which is consistent with the results of bioinformatics analysis. In vitro experiments involving FGFR2 overactivation and knockdown demonstrated that FGFR2 primarily functions in regulating the PI3K/AKT/mTOR signaling pathway, which was further verified by xenotransplantation mouse model. Knockdown of FGFR2 expression curbed the growth of CRC tumors through downregulating the PI3K/AKT/mTOR signaling pathway and HIF-1α expression level. CONCLUSION: FGFR2 mediates the expression of HIF-1α via activating the PI3K/AKT/mTOR signaling pathway, thereby enhancing the proliferation, migration, and invasion of CRC cells. These findings suggest that FGFR2 may serve as potential therapeutic targets for the treatment of CRC.