HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog

Tomohiro Katagiri, Minoru Kobayashi, Michio Yoshimura, Akiyo Morinibu, Satoshi Itasaka, Masahiro Hiraoka, Hiroshi Harada

    Research output: Contribution to journalArticle

    8 Scopus citations

    Abstract

    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 stromarich 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.

    Original languageEnglish (US)
    Pages (from-to)10525-10535
    Number of pages11
    JournalOncotarget
    Volume9
    Issue number12
    DOIs
    StatePublished - Jan 1 2018

    Keywords

    • Hypoxia-inducible factor 1 (HIF-1)
    • Pancreatic cancers
    • Sonic hedgehog signaling pathway
    • Stromal fibroblasts
    • Tumor hypoxia

    ASJC Scopus subject areas

    • Oncology

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