Regulation of angiogenin expression and epithelial-mesenchymal transition by HIF-1α signaling in hypoxic retinal pigment epithelial cells

Lai, Kairan; Luo, Chenqi; Zhang, Xiaobo; Ye, Panpan; Zhang, Yidong; He, Jiliang; Yao, Ke

doi:10.1016/j.bbadis.2016.05.023

Cited by 29 publications

(36 citation statements)

References 42 publications

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“…On the other hand, an antioxidant defense that prevents oxidative damage to the body can be imbalanced and cause oxidative stress as a feedback mechanism. This includes accumulation of oxygen free radicals in the eye fluids and the tissues of the epithelial cells (Figure 2 17 where an increase in vimentin expression was observed in the condition of hypoxic stress as obtained in our results with oxidative stress (Figure 2(c)).…”

Section: Discussionsupporting

confidence: 81%

Inhibition of histone deacetylase protects the damaged cataract via regulating the NF-κB pathway in cultured lens epithelial cells

Yin

2019

Eur J Inflamm

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Induction of oxidative damage by the activation of histone deacetylase (HDAC) is an integral event that causes major membrane damage of ocular tissues and leads to the pathogenesis of cataract. It is elucidated that nuclear factor-κB is a mediator in the process of cataract development. However, studies on the role played by epigenetic proteins in regulating cataract pathogenesis are limited. Hence, in the current investigation, ARPE-19 human retinal epithelial cells were used as an experimental model to elucidate the role of HDAC inhibition and its mechanism behind the cataract pathogenesis. ARPE-19 cells were exposed to H 2 O 2 , with and without Trichostatin A (TSA), a pan-HDAC inhibitor, and maintained along with control cells without any treatment. On exposure to H 2 O 2 , cells were susceptible to oxidative stress as it is evident from the reduced expression levels of superoxide dismutase (SOD), catalase, and GSH levels. Simultaneously, H 2 O 2 -exposed cells showed the nuclear translocation of NF-κB with the activation of inflammatory cytokines such as CXCL1 and IL-6. In addition, the mRNA expression analysis revealed that the GADD45α, COX-2, MCP-1, and ICAM-1 expressions were increased in H 2 O 2 group. Moreover, the activity of HDAC was increased to 2-fold with a significant reduction in the histone acetyltransferase (HAT) activity in cells that were maintained under oxidative conditions. However, TSA was able to inhibit the critical cytokines' expression with attenuated HDAC activity and limited NF-κB translocation. Furthermore, pre-treatment of TSA significantly suppressed the transcript levels of upregulated inflammatory markers in cells. Together, these findings offer new insight into the role of HDACs in regulating cellular processes involved in the pathogenesis of cataract as well as the potential use of HDAC inhibitors as therapeutics for controlling the disease progression.

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Section: Discussionsupporting

confidence: 81%

Inhibition of histone deacetylase protects the damaged cataract via regulating the NF-κB pathway in cultured lens epithelial cells

Yin

2019

Eur J Inflamm

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“…Moreover, HIF‐1α was shown to induce EMT in many types of cancer tissues. HIF‐1α expression profile was correlated with the expression levels of E‐cadherin, N‐cadherin, and vimentin (Lai et al, ). Based on these findings, HIF‐1α/VEGF signal pathway is considered to be an important target for the treatment of angiogenesis‐related diseases including metastasis of cancer.…”

Section: Introductionmentioning

confidence: 99%

HIF‐1α/VEGF signaling‐mediated epithelial–mesenchymal transition and angiogenesis is critically involved in anti‐metastasis effect of luteolin in melanoma cells

Wang

Shen

et al. 2019

Phytotherapy Research

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Tumor metastasis is still the leading cause of melanoma mortality. Luteolin, a natural flavonoid, is found in fruits, vegetables, and medicinal herbs. The pharmacological action and mechanism of luteolin on the metastasis of melanoma remain elusive. In this study, we investigated the effect of luteolin on A375 and B16‐F10 cell viability, migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells. Epithelial–mesenchymal transition (EMT) markers and pivotal molecules in HIF‐1α/VEGF signaling expression were analysed using western blot assays or quantitative real‐time polymerase chain reaction. Results showed that luteolin inhibits cellular proliferation in A375 and B16‐F10 melanoma cells in a time‐dependent and concentration‐dependent manner. Luteolin significantly inhibited the migratory, invasive, adhesive, and tube‐forming potential of highly metastatic A375 and B16‐F10 melanoma cells or human umbilical vein endothelial cells at sub‐IC 50 concentrations, where no significant cytotoxicity was observed. Luteolin effectively suppressed EMT by increased E‐cadherin and decreased N‐cadherin and vimentin expression both in mRNA and protein levels. Further, luteolin exerted its anti‐metastasis activity through decreasing the p‐Akt, HIF‐1α, VEGF‐A, p‐VEGFR‐2, MMP‐2, and MMP‐9 proteins expression. Overall, our findings first time suggests that HIF‐1α/VEGF signaling‐mediated EMT and angiogenesis is critically involved in anti‐metastasis effect of luteolin as a potential therapeutic candidate for melanoma.

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“…Recent studies indicate that CNV is a complex process in which the degeneration of retinal blood vessels in the elderly leads to tissue ischemia and hypoxia; therefore, hypoxia-mediated signaling is thought to be involved in the progression of the wet form of AMD [2]. A key transcriptional regulator of the hypoxic response is hypoxia-inducible factor (HIF), which consists of HIF-1α and HIF-1β subunits.…”

Section: Introductionmentioning

confidence: 99%

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Sun¹,

Cai²,

Liu³

2017

Cell Physiol Biochem

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Background/Aims: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells. Methods: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2. Results: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib. Conclusions: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.

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Regulation of angiogenin expression and epithelial-mesenchymal transition by HIF-1α signaling in hypoxic retinal pigment epithelial cells

Cited by 29 publications

References 42 publications

Inhibition of histone deacetylase protects the damaged cataract via regulating the NF-κB pathway in cultured lens epithelial cells

Inhibition of histone deacetylase protects the damaged cataract via regulating the NF-κB pathway in cultured lens epithelial cells

HIF‐1α/VEGF signaling‐mediated epithelial–mesenchymal transition and angiogenesis is critically involved in anti‐metastasis effect of luteolin in melanoma cells

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

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