Temporal regulation of HIF-1 and NF-κB in hypoxic hepatocarcinoma cells

Jiang, Yuan; Zhu, Ying; Wang, Xinxin; Gong, Jian; Hu, Chunyan; Guo, Bo; Zhu, Bo; Li, Yongsheng

doi:10.18632/oncotarget.3352

Cited by 52 publications

(42 citation statements)

References 32 publications

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“…In addition, we found that hypoxia-and Iono-enhanced p300 phosphorylation and HIF-1 accumulation (both mRNA and protein) could be inhibited by inhibitors of SOCE, CaMKII, and p300. Since p300 contributes to the stability and translocation of HIF-1a, and because HIF-1 transcripts several targets, including NF-kB, which also upregulate HIF-1a (Jiang et al, 2015), our findings suggest that STIM1-mediated SOCE promotes HIF-1a transcription and prevents HIF-1a degradation. Of interest, YC-1 significantly reduced STIM1 expression in HCCs and suppressed tumorigenesis, which could be partially reversed by STIM1 or HIF-1a overexpression.…”

Section: -Driven Tumorigenesismentioning

confidence: 70%

STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1

Guo

Xie

et al. 2015

Cell Reports

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Hypoxia and intracellular Ca(2+) transients are fundamental traits of cancer, whereas the route and regulation of Ca(2+) mobilization in hypoxic tumorigenesis are unknown. Here, we show that stromal-interaction molecule 1 (STIM1), an ER Ca(2+) sensor, correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCCs) and is upregulated during hepatocarcinoma growth. HIF-1 directly controls STIM1 transcription and contributes to store-operated Ca(2+) entry (SOCE). STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCCs via activation of Ca(2+)/calmodulin-dependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1α partially reverses impaired growth of tumors treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca(2+) mobilization and hypoxic tumor growth and highlight a potential target for early hypoxia-related intervention.

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Section: -Driven Tumorigenesismentioning

confidence: 70%

STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1

Guo

Xie

et al. 2015

Cell Reports

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“…These results suggested important roles of p‐AKT and p‐ERK and potential interplay and cooperation between NF‐κB and HIF‐1α in regulation of PD‐L1 expression by EGFR mutants in NSCLC cells. It has been reported that activated NF‐κB can directly bind to the promoter of HIF‐1α and promote HIF‐1α transcription under hypoxia or normoxia conditions in multiple cells, including cancer cells . Notably, some studies have revealed a positive feedback loop between HIF‐1α and NF‐κB pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia‐inducible factor‐1α can induce transcription of IKKβ through the hypoxia response element present in the promoter of the IKKβ gene and mediate consequent nuclear translocation and activation of NF‐κB . Hypoxia‐inducible factor‐1α has also been reported to directly transcript NF‐κB expression under hypoxia . Based on previous research reports and our existing research findings, we developed a possible model for PD‐L1 expression regulation by EGFR mutants (Figure ).…”

Section: Discussionmentioning

confidence: 99%

“…47 Hypoxia-inducible factor-1α has also been reported to directly transcript NF-κB expression under hypoxia. 45,48 Based on previous research reports and our existing research findings, we developed a possible model for PD-L1 expression regulation by EGFR mutants ( Figure 5). To investigate the correlations among EGFR mutants, pivotal EGFR signaling effectors, and PD-L1 expression, we further examined EGFR status and protein levels of p-IκBα, HIF-1α, and PD-L1 in 149 human NSCLC tissues.…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

Wang

et al. 2019

Cancer Science

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Some driver gene mutations, including epidermal growth factor receptor ( EGFR ), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 ( PD ‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD ‐L1 expression regulation in non‐small‐cell lung cancer ( NSCLC ) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD ‐L1 overexpression and phosphorylation of AKT and ERK , especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD ‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR . Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK / ERK , PI 3K/ AKT , mTOR /S6, IκBα, and HIF ‐1α indicated strong accordance among protein levels of PD ‐L1, p‐IκBα, and HIF ‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF ‐1α, and PD ‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF ‐1α, and PD ‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR . Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF ‐1α positive staining were more likely to possess elevated PD ‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF ‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF ‐κB and HIF ‐1α in PD ‐L1 expression regulation by EGFR mutants in NSCLC .

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“…Several studies have described miR-199a as a type of miRNA associated with hypoxia-adaptation (36)(37)(38)(39). It was demonstrated that miR-199a-5p downregulation is AKT-dependent (39,40) and may be antagonized by the β-adrenergic receptor (40).…”

Section: Discussionmentioning

confidence: 99%

miR-199a-5p regulates HIF-1α and OSGIN2 and its expression is correlated to soft-tissue sarcoma patients' outcome

et al. 2016

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Abstract. Soft tissue sarcomas are a heterogeneous group of malignant neoplasms of mesenchymal origin. Partly due to hypoxia, an aggressive and radioresistant phenotype frequently develops, resulting in poorer patient outcome. microRNAs (miRNAs) are tiny, non-coding regulators of gene expression and in situations of cellular stress situations may predict clinical progression and patient outcome. In the present study, hypoxia-associated miR-199a-5p expression in 96 soft tissue sarcoma samples was analysed by reverse transcription-quantitative polymerase chain reaction and associations between miR-199a-5p expression and patient clinicopathological characteristics and survival were measured. Additionally, luciferase reporter assays analyzed the post-transcriptional regulation of hypoxia-associated genes hypoxia-inducible factor 1α (HIF-1α), oxidative stress induced growth inhibitor 2 (OSGIN2) and vascular endothelial growth factor (VEGF) by miR-199a-5p. Survival analyses indicated that low expression of miR-199a-5p was significantly correlated with poorer tumor-specific survival (univariate Cox's-Regression analyses; relative risk=1.92, P=0.029). Furthermore, it was demonstrated that the 3'UTR of HIF-1α and OSGIN2 genes were regulated by miR-199a-5p in-vitro, although the 3'UTR of VEGF was not. To the best of our knowledge, this is the first report demonstrating the regulation of the 3'untranslated region of the OSGIN2 gene by miR-199a-5p and a significant correlation between low miR-199a-5p expression and a poor outcome of patients with soft tissue sarcoma. IntroductionMicroRNAs (miRNAs) are small (18-25 nt), non-coding RNAs of endogenous origin. To date, >2,500 different mature miRNA species have been detected in humans (1). Following maturation, double-stranded miRNAs are immediately bound to Argonaute proteins and unwound. In the single-stranded conformation, they build up the active component of the RNA-induced silencing complex (RISC) (2,3). miRNAs bind to complementary sequences in the 3'untranslated region (UTR) of their target mRNAs, thus acting as translational repressors. This action is primarily performed by a hexamer sequence at the 5'UTRs called the seed sequence and the subsequent translocation to the P-bodies (processing bodies), which are specialized cellular components for RNA silencing and decay (4,5). Due to the simple target recognition sequence and the vast number of different species of miRNA, it is estimated that ~60% of the human protein-coding genes are regulated post-transcriptionally by miRNAs (6). Due to their high abundance and immense impact on cellular gene expression profiles, miRNAs serve an important role in cellular proliferation and differentiation processes. Furthermore, they contribute to the adaptation to cellular stress, including stress caused by an acidic or hypoxic environment (7,8).Hypoxia, the state of decreased oxygen saturation in a tissue, is a major problem in the treatment of solid tumors. Due to rapid growth, regions in solid tumors tend to be cut off from oxygen ...

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Temporal regulation of HIF-1 and NF-κB in hypoxic hepatocarcinoma cells

Cited by 52 publications

References 32 publications

STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1

STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

miR-199a-5p regulates HIF-1α and OSGIN2 and its expression is correlated to soft-tissue sarcoma patients' outcome

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