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The role of HIF-1? in the TGF-?2-mediated epithelial-to-mesenchymal transition of human lens epithelial cells.

ABSTRACT: Human lens epithelial cells (HLE) undergo mesenchymal transition and become fibrotic during posterior capsule opacification (PCO), which is a frequent complication after cataract surgery. TGF-?2 has been implicated in this fibrosis. Previous studies have focused on the role of hypoxia-inducible factor-1? (HIF-1?) in fibrotic diseases, but the role of HIF-1? in the TGF-?2-mediated fibrosis in HLE is not known. TGF-?2 treatment (10?ng/mL, 48?h) increased the HIF-1? levels along with the EMT markers in cultured human lens epithelial cells (FHL124 cells). The increase in HIF-1? corresponded to an increase in VEGF-A in the culture medium. However, exogenous addition of VEGF-A (up to 10?ng/mL) did not alter the EMT marker levels in HLE. Addition of a prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG, up to 10?µM), enhanced the levels of HIF-1?, and secreted VEGF-A but did not alter the EMT marker levels. However, treatment of cells with a HIF-1? translational inhibitor, KC7F2, significantly reduced the TGF-?2-mediated EMT response. This was accompanied by a reduction in the ERK phosphorylation and nuclear translocation of Snail and Slug. Together, these data suggest that HIF-1? is important for the TGF-?2-mediated EMT of human lens epithelial cells.

SUBMITTER: Nahomi RB

PROVIDER: S-EPMC6605039 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The role of HIF-1α in the TGF-β2-mediated epithelial-to-mesenchymal transition of human lens epithelial cells.

Nahomi Rooban B RB Nagaraj Ram H RH

Journal of cellular biochemistry 20180425 8

Human lens epithelial cells (HLE) undergo mesenchymal transition and become fibrotic during posterior capsule opacification (PCO), which is a frequent complication after cataract surgery. TGF-β2 has been implicated in this fibrosis. Previous studies have focused on the role of hypoxia-inducible factor-1α (HIF-1α) in fibrotic diseases, but the role of HIF-1α in the TGF-β2-mediated fibrosis in HLE is not known. TGF-β2 treatment (10 ng/mL, 48 h) increased the HIF-1α levels along with the EMT marker ...[more]

PMID: 29693273

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Project description:BackgroundTumor 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.MethodsIFN 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.ResultsWe 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.ConclusionsOur 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.

Dataset Information

The role of HIF-1? in the TGF-?2-mediated epithelial-to-mesenchymal transition of human lens epithelial cells.

Publications

The role of HIF-1α in the TGF-β2-mediated epithelial-to-mesenchymal transition of human lens epithelial cells.

Similar Datasets

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