Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.
Bottom Line: A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation.Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9.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.