HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog
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Tomohiro Katagiri1, Minoru Kobayashi1,2, Michio Yoshimura1, Akiyo Morinibu1,2, Satoshi Itasaka1, Masahiro Hiraoka1 and Hiroshi Harada1,2,3
1Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-Ku, Kyoto 606-8507, Japan
2Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe-Cho, Sakyo-Ku, Kyoto 606-8501, Japan
3Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Keywords: tumor hypoxia; hypoxia-inducible factor 1 (HIF-1); Sonic hedgehog signaling pathway; stromal fibroblasts; pancreatic cancers
Received: November 07, 2016 Accepted: January 04, 2018 Published: January 11, 2018
Hypoxic and stroma-rich microenvironments, characteristic features of pancreatic cancers, are strongly associated with a poor prognosis. However, whether and how hypoxia increases stromal compartments remain largely unknown. Here, we investigated the potential importance of a master regulator of the cellular adaptive response to hypoxia, hypoxia-inducible factor-1 (HIF-1), in the formation of stroma-rich microenvironments of pancreatic tumors. We found that pancreatic cancer cells secreted more Sonic hedgehog protein (SHH) under hypoxia by upregulating its expression and efficiency of secretion in a HIF-1-dependent manner. Recombinant SHH, which was confirmed to activate the hedgehog signaling pathway, accelerated the growth of fibroblasts in a dose-dependent manner. The SHH protein secreted from pancreatic cancer cells under hypoxic conditions promoted the growth of fibroblasts by stimulating their Sonic hedgehog signaling pathway. These results suggest that the increased secretion of SHH by HIF-1 is potentially responsible for the formation of detrimental and stroma-rich microenvironments in pancreatic cancers, therefore providing a rational basis to target it in cancer therapy.
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