Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation

Imtiyaz, Hongxia Z.; Williams, Emily; Hickey, Michele M.; Patel, Shetal; Durham, Amy C.; Yuan, Lijun; Hammond, Rachel; Gimotty, Phyllis A.; Keith, Brian; Simon, M. Celeste

doi:10.1172/jci39506

Cited by 410 publications

(433 citation statements)

References 108 publications

(120 reference statements)

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“…VEGF protein and RNA expression in LMET and HMET cells was evaluated under normoxic and hypoxic conditions. Interleukin (IL)-6 mRNA expression was used as an additional control of hypoxic inducibility (16,17). Results presented in Fig.…”

Section: Vegf Expression Is Increased In Metastatic Hmet Cells Indepementioning

confidence: 99%

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

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Pancreatic cancer aggressiveness is characterized by its high capacity for local invasion, ability to promote angiogenesis, and potential to metastasize. Hypoxia is known to represent a crucial step in the development of aggressive malignant features of many human cancers. However, micrometastatic tumors are not typically subjected to hypoxic events during early stages of dissemination; therefore, it is unclear how these tumors are able to maintain their aggressive phenotype. Thus, the identification of regulators of hypoxia-related genes in aggressive/ metastatic tumors represents a fundamental step for the design of future therapies to treat pancreatic cancer. To this end, transcriptomic profiles were compared between the nonmetastatic pancreatic cancer cell line FG (LMET) and its angiogenic/metastatic derivate L3.6pl (HMET) under normoxic or hypoxic conditions. Cluster analysis revealed a number of transcripts that were induced by hypoxia in nonmetastatic cancer cells. Strikingly, this cluster was determined to be constitutively activated under normoxia in the metastatic cancer cells and could not be further induced by hypoxia. A subset of these transcripts were regulated by the transcription factor SOX9 in the aggressivemetastatic cells, but driven by hypoxia-inducible factor-1a (HIF-1a) in the parental nonmetastatic cell line. Moreover, these transcripts were enriched in cancer-related networks including: WNT, CXCR4, retinoic acid, and (FAK) focal adhesion kinase, gene PTK2 signaling pathways. In functional assays, inhibition of SOX9 expression in HMET cells led to increased apoptosis and reduced migration in vitro and a significant reduction in primary tumor growth, angiogenesis, and metastasis following orthotopic tumor cell injection. At the molecular level, the control of SOX9 expression was associated with changes in the methylation status of the SOX9 promoter. Finally, SOX9 upregulation was verified in a series of tumor specimens of patients with pancreatic carcinoma.

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Section: Vegf Expression Is Increased In Metastatic Hmet Cells Indepementioning

confidence: 99%

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

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“…Macrophages exposed to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in TAMs is specifically correlated with high-grade human tumors and poor prognosis. HIF-2α directly regulates proinflammatory cytokine/chemokine expression in macrophages activated in vitro [28]. This is of importance since in the majority of solid tumors, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-2α was observed in subsets of the tumor cells, and was also strongly expressed by subsets of tumor-associated macrophages.…”

Section: Tumor Associated Macrophagesmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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“…Most reports studying VHL/HIF transcriptional activation have focused on HIF-bound promoters (23)(24)(25)(26)(27)(28). However, recent evidence suggests an emerging role for distal enhancer elements in VHL/HIF transcriptional control ( 29,30 ).…”

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confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation

Cited by 410 publications

References 108 publications

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

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