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: To confirm the observed increase in proliferation by reoxygenation in vitro, we investigated the tumorigenicity of reoxygenated Ch-H-R cells. Normal PDAC cells cultured under normoxia were used as a control in this experiment. Anchorage-independent proliferation in reoxygenated Ch-H-R cells was significantly higher than that in wild type PDAC cells (Fig.5a). Tumors from mice administered with reoxygenated Ch-H-R cells were significantly larger than those from mice injected with wild-type cells (Fig.5b). Gli1 positive cells in tumors from mice injected with reoxygenated Ch-H-R cells were significantly higher than those in the controls (Fig.5c). Next, the effect of Hh signaling in increased tumorigenicity by reoxygenation was examined. Anchorage-independent proliferation in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was significantly lower than that in the control (Fig.5d) in vitro. In vivo, tumors from mice injected with Gli1 siRNA-transfected-reoxygenated Ch-H-R cells were significantly smaller than those from mice injected with control siRNA-transfected cells (Fig.5e). These results suggest that Gli1 plays a pivotal role in tumorigenicity in reoxygenation in vivo.
Affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.