Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway
Journal
Journal of Experimental and Clinical Cancer Research
Journal Volume
37
Journal Issue
1
Date Issued
2018
Author(s)
Abstract
Background: Tumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development. Methods: IFN was used to induce inflammation response and HIF-1α expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1α in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation. Results: We showed for the first time that IFN induced functional HIF-1α expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1α pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1α, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1α is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1α-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay. Conclusions: Our mechanistic study showed an induction of HIF-1α and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1α may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1α programming. ? 2018 The Author(s).
Subjects
Epithelial-to-mesenchymal transition; HIF-1α; Inflammatory hypoxia; Interferon; Oncogenesis; Tumor microenvironment
SDGs
Other Subjects
hypoxia inducible factor 1alpha; interferon; Janus kinase; mammalian target of rapamycin; mitogen activated protein kinase; mitogen activated protein kinase kinase; mitogen activated protein kinase p38; phosphatidylinositol 3 kinase; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; protein kinase B; Ras protein; biological marker; hypoxia inducible factor 1alpha; interferon; Janus kinase; phosphatidylinositol 3 kinase; protein kinase B; protein kinase inhibitor; Ras protein; target of rapamycin kinase; Akt signaling; anchorage independent growth; angiogenesis; animal experiment; animal model; apoptosis; Article; cancer cell line; cancer growth; carcinogenesis; cell structure; clonogenic assay; controlled study; epithelial mesenchymal transition; female; gene expression; gene silencing; human; human cell; immunoblotting; inflammation; luciferase assay; mouse; nonhuman; priority journal; protein expression; tumor hypoxia; tumor invasion; tumor microenvironment; tumor xenograft; wound healing; biological model; drug effect; gene expression regulation; genetics; hypoxia; MAPK signaling; metabolism; neoplasm; pathology; signal transduction; Apoptosis; Biomarkers; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Interferons; Janus Kinases; MAP Kinase Signaling System; Models, Biological; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; ras Proteins; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment
Publisher
BioMed Central Ltd.
Type
journal article