Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.
Bottom Line: Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation.A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation.These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway.
Affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.Show MeSH
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Mentions: Wild type cells, chronic hypoxia-resistant PDAC cells (Ch-H-R cells), PDAC cells cultured under acute hypoxia (Ac-H cells) and reoxygenated Ch-H-R cells were used to investigate the change of phenotypes by reoxygenation. First, we evaluated HIF-1α, well known as one of the main hypoxic transcriptional factors, and its downstream protein CA9. CA9 positive cells were counted as described in Fig. S3. CA9 and HIF-1α were expressed in Ch-H-R cells and Ac-H cells. However, the amount of CA9 or HIF-1α positive cells in reoxygenated Ch-H-R cells was significantly lower than in Ch-H-R cells and Ac-H cells (Figs1a,S4), and CA9 and HIF-1α protein expression were also confirmed by western blotting analysis (Fig. S5). Next, we examined proliferation and invasiveness, factors of malignant potential. The ability of anchorage-dependent proliferation of reoxygenated Ch-H-R cells was the highest among the four types of cells both in AsPC-1 and SUIT-2 (Fig.1b). Invasiveness in Ch-H-R cells was significantly higher than that in Ac-H cells, and also significantly higher in reoxygenated Ch-H-R cells than in Ch-H-R cells both in AsPC-1 and SUIT-2 (Fig.1c). These results suggest that reoxygenation confers a more aggressive phenotype in PDAC cells.
Affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.