Abstract
Regulations between NF-κB and HIF-1 have not been adequately addressed in previous research. Here, we report that hypoxia increased NF-κB in hepatocellular carcinoma cells. The HIF-1 protein level was rapidly induced by protein stabilization (by 2 hours) and then moderately decreased, whereas mRNA levels were reciprocally increased. We also found that NF-κB p50 and p65 (RelA), but not c-Rel, bound the HIF-1a promoter, thus increasing its transcription. In contrast, miR-199a-5p and miR-93, c-Rel downstream targets, decreased HIF-1α at both the mRNA and protein levels. Dicer1, a key enzyme in miRNA biogenesis, was decreased by acute hypoxia but was later increased by HIF-1, rather than by the above-mentioned NF-κB subunits. Thus, NF-κB both positively and negatively fine-tuned HIF-1 in hypoxic hepatocarcinoma cells.
Highlights
Hypoxia, a common feature of all solid tumors, plays essential roles in tumor initiation and development [1]
We aimed to evaluate the temporal expression of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB) subunits in hepatocellular carcinoma cells (HCC) under short-term and prolonged hypoxia and revealed the underlying regulatory mechanism
The level of HIF-1α protein substantially increased following hypoxia treatment for 0–4 h, and decreased subsequently under prolonged hypoxia (Figure 1C, 1D and S1B). These results demonstrate that HIF-1 and NF-κB are temporally and differentially regulated under short-term versus prolonged hypoxia
Summary
A common feature of all solid tumors, plays essential roles in tumor initiation and development [1]. A key development in the understanding of oxygen-sensing processes and of the mechanisms that regulate the cellular and tissular response to hypoxia came with the discovery of hypoxia-inducible factor-1 (HIF-1) which consists of an oxygen regulated α-subunit and a constitutive β-subunit [2]. Molecular oxygen is not available for hydroxylation; HIF-1α can accumulate in the cell, translocate into the nucleus, bind with HIF-1β, and promote the transcription of downstream target hypoxia responsive genes (HRGs) thereby playing a central role in tumorigenesis, including energy metabolism, angiogenesis, proliferation and metastasis [5,6,7]. Activation of NF-κB elevates mRNA and protein levels of HIF-1α in multiple cell lines [8, 9]. Understanding the correlation between HIF-1 and NF-κB under hypoxia may be of great importance in therapeutically targeting hypoxic tumorigenesis
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