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  2. Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway

Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway

  • J Exp Clin Cancer Res. 2018 Mar 27;37(1):70. doi: 10.1186/s13046-018-0730-6.
Yen-Hsiu Yeh 1 Ho-Fu Hsiao 2 Yen-Cheng Yeh 3 Tien-Wen Chen 1 Tsai-Kun Li 4 5 6
Affiliations

Affiliations

  • 1 Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, Republic of China.
  • 2 Department of Emergency Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan, Republic of China.
  • 3 Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, Republic of China.
  • 4 Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, Republic of China. [email protected].
  • 5 Center for Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China. [email protected].
  • 6 Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan, Republic of China. [email protected].
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.

Keywords

Epithelial-to-mesenchymal transition; HIF-1α; Inflammatory hypoxia; Interferon; Oncogenesis; Tumor microenvironment.

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