Hypoxia-inducible factors: a central link between inflammation and cancer

Triner, Daniel; Shah, Yatrik M.

doi:10.1172/jci84430

Cited by 152 publications

(126 citation statements)

References 148 publications

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“…The authors suggest that these results could partly be due to defective migration and invasion of macrophages with HIF-2α loss (111). For a more comprehensive discussion of myeloid HIF-αs in cancer, please refer to other reviews within this series (164,165).…”

Section: Hifs In Myeloid Cellsmentioning

confidence: 99%

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Lin¹,

Simon²

2016

Journal of Clinical Investigation

115

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Section: Hifs In Myeloid Cellsmentioning

confidence: 99%

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Lin¹,

Simon²

2016

Journal of Clinical Investigation

115

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“…HIF-α, including HIF-1α and HIF-2α, can form complexes with HIF-1β and bind to hypoxia-response elements in the promoter regions of a vast array of genes encoding proteins involved in angiogenesis, glycolysis, cell proliferation, metastasis and apoptosis to promote tumour development and even induce treatment resistance (7). As the most commonly investigated factor in hypoxic HCC responses, HIF-1α is highly associated with acute hypoxia, while overexpression of HIF-2α is also a common feature in HCC and can control tumour progression and therapy sensitivity (8,9).…”

Section: Introductionmentioning

confidence: 99%

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Dong

Liu

Zhi

et al. 2018

Clinical Cancer Research

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Tumor hypoxia and hypoxia-related sorafenib resistance adversely affected the prognosis of HCC patients. Hypoxia-inducible factor (HIF) s are defined as the central transcriptional mediator of hypoxic response. Recent efforts have identified HIF-2α that has been involved in sorafenib resistance. However, the regulatory mechanisms of HIF-2α activity in HCC remain obscure. Here, using both in vitro and in vivo HCC models, we show that the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) axis is a driver of HIF-2α expression and activity, which then promotes HCC growth, metastasis and angiogenesis. We further show that COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment by regulating the HIF-2α level and activity. These observations support further clinical developments of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.Research.

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“…Unlike HIF‐1α that has been extensively investigated,35 it is little known about the function of its regulatory partner HIF‐1β in cancer, including MM. To explore the functional role of HIF‐1β in MM, we first validated ARNT expression in a cohort of 40 MM patients.…”

Section: Resultsmentioning

confidence: 99%

“…Cross‐talk between HIF (HIF‐1α in particular) and NF‐κB is well‐established in certain physiological circumstances such as inflammation and immune response 35, 36, 39. As hypoxia‐induced expression of HIF‐1α and HIF‐1β was accompanied by NF‐κB activation (Figure 3), a possibility then arose that these 2 pathways might communicate to each other in MM cells, particularly under hypoxia within bone marrow microenvironment.…”

Section: Resultsmentioning

confidence: 99%

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ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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Hypoxia-inducible factors: a central link between inflammation and cancer

Cited by 152 publications

References 148 publications

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

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