Abstract
5-Fluorouracil (5-Fu) is one of the basic drugs in colorectal cancer (CRC) chemotherapy, and its efficacy is mainly limited by the acquisition of drug resistance. However, the underlying mechanisms remain unclear. In this study, hypoxia inducible factor 1α (HIF1α) was screened for high expression in 5-Fu resistant HCT115 cells, which displayed epithelial–mesenchymal transition (EMT) phenotype. Suppression of HIF1α reversed EMT phenotype, reduced glucose transporter 1 (Glut1) expression, a key molecule mediated drug resistance. Moreover, we unveiled that vascular endothelial growth factor (VEGF) was regulated by HIF1α and mediated HIF1α-maintained malignant phenotype of 5-Fu resistant cells. Further studies verified that AKT/GSK3β signaling was activated in resistant cells and controlled HIF1α expression. Interestingly, we demonstrated that VEGF could feedback up-regulate HIF1α via AKT/GSK3β signaling. Clinically, HIF1α and VEGF were high expressed and associated with survival and prognosis in CRC patients. In conclusion, our findings proposed that HIF1α/VEGF feedback loop contributed to 5-Fu resistance, which might be potential therapeutic targets.
Highlights
Colorectal cancer (CRC) is common malignancy with increasing incidence and leading rate of mortality (Jemal et al, 2011)
We demonstrate that hypoxia inducible factor 1α (HIF1α) is upregulated in 5-Fu resistant HCT115 cells, and HIF1α maintains resistant phenotype by regulating vascular endothelial growth factor (VEGF)/glucose transporter 1 (Glut1)
To gain further insight into how HIF1α induces colorectal cancer (CRC) progression, we examined the effect of HIF1α on many microenvironmental genes, including TGF-β, TNF-α, VEGF, EGF, PDGF, b-FGF, HGF, and IGF, which have been implicated in promoting tumor development
Summary
Colorectal cancer (CRC) is common malignancy with increasing incidence and leading rate of mortality (Jemal et al, 2011). Despite that the substantial diagnostic and therapeutic strategies have been improving, the mortality rate of CRC remains high (Sun et al, 2020a). The patients’ response rates to therapy remain low due to the development of drug resistance. Hypoxia, controlled by transcription factor hypoxia-inducible factor-1α (HIF-1α), plays important roles in the pathobiology of inflammation and pathology, including regulation of tumor progression (Semenza, 2012). Hypoxia activates the HIF-1α enabling it to trigger transcription and induce an adaptive response (Hong et al, 2020). The role of HIF1α in cancer development extends a broad spectrum of biological functions, such as promoting metastasis, reprograming metabolism, regulating cell proliferation and survival, and increasing therapeutic
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