Journal
CANCER SCIENCE
Volume 105, Issue 3, Pages 324-333Publisher
WILEY-BLACKWELL
DOI: 10.1111/cas.12348
Keywords
Hedgehog; invasiveness; pancreatic cancer; proliferation; reoxygenation
Categories
Funding
- Japan Society for the Promotion of Science Kakenhi [24390303]
- Grants-in-Aid for Scientific Research [24390303, 23659616] Funding Source: KAKEN
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Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated under hypoxic condition for 3-6months and reoxygenation experiments were performed using these chronic-hypoxia-resistant PDAC cells in invivo-mimicking conditions. Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation. 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. Moreover, inhibition of Sonic Hh and Smoothened abrogated reoxygenation induced increases in proliferation and invasiveness. These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway. Therefore, the Hh signaling pathway may be a therapeutic target for refractory PDAC in metastatic processes induced by reoxygenation.
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