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HIF-1? confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.

ABSTRACT: Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1? (HIF-1?), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain obscure. We recently identified an alternative mechanism of HIF-1? function by which HIF-1? suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here, we show that this HIF-?-c-Myc pathway plays an essential role in mediating hypoxic effects on malignant progression via genetic alterations, resulting in the formation of malignant tumors with aggressive local invasion and epithelial-mesenchymal transition. We show an absolute requirement of the HIF-?-c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1? alone is insufficient and seemingly dispensable. This study indicates that HIF-1? induction of genetic alteration is the underlying cause of tumor progression, especially by the hypoxic microenvironment.

SUBMITTER: Yoo YG

PROVIDER: S-EPMC3041864 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.

Yoo Young-Gun YG Christensen Jared J Huang L Eric LE

Cancer research 20110208 4

Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain ...[more]

PMID: 21303984

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Project description:BackgroundWe have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple erbB receptors with distinct functional characteristics and it is not clear which of these receptors drive MPNST pathogenesis. Here, we test the hypothesis that altered erbB4 expression promotes MPNST pathogenesis by uniquely activating key cytoplasmic signaling cascades.MethodsErbB4 expression was assessed using immunohistochemistry, immunocytochemistry, immunoblotting and real-time PCR. To define erbB4 functions, we generated mice that develop MPNSTs with floxed Erbb4 alleles (P0-GGFβ3;Trp53+/-;Erbb4flox/flox mice) and ablated Erbb4 in these tumors. MPNST cell proliferation and survival was assessed using 3H-thymidine incorporation, MTT assays, Real-Time Glo and cell count assays. Control and Erbb4-null MPNST cells were orthotopically xenografted in immunodeficient mice and the growth, proliferation (Ki67 labeling), apoptosis (TUNEL labeling) and angiogenesis of these grafts was analyzed. Antibody arrays querying cytoplasmic kinases were used to identify erbB4-responsive kinases. Pharmacologic or genetic inhibition was used to identify erbB4-responsive kinases that drive proliferation.ResultsAberrant erbB4 expression was evident in 25/30 surgically resected human MPNSTs and in MPNSTs from genetically engineered mouse models (P0-GGFβ3 and P0-GGFβ3;Trp53+/- mice); multiple erbB4 splice variants that differ in their ability to activate PI3 kinase and nuclear signaling were present in MPNST-derived cell lines. Erbb4-null MPNST cells demonstrated decreased proliferation and survival and altered morphology relative to non-ablated controls. Orthotopic allografts of Erbb4-null cells were significantly smaller than controls, with reduced proliferation, survival and vascularization. ERBB4 knockdown in human MPNST cells similarly inhibited DNA synthesis and viability. Although we have previously shown that broad-spectrum erbB inhibitors inhibit Ras activation, Erbb4 ablation did not affect Ras activation, suggesting that erbB4 drives neoplasia via non-Ras dependent pathways. An analysis of 43 candidate kinases identified multiple NRG1β-responsive and erbB4-dependent signaling cascades including the PI3K, WNK1, STAT3, STAT5 and phospholipase-Cγ pathways. Although WNK1 inhibition did not alter proliferation, inhibition of STAT3, STAT5 and phospholipase-Cγ markedly reduced proliferation.ConclusionsErbB4 promotes MPNST growth by activating key non-Ras dependent signaling cascades including the STAT3, STAT5 and phospholipase-Cγ pathways. ErbB4 and its effector pathways are thus potentially useful therapeutic targets in MPNSTs.

Dataset Information

HIF-1? confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.

Publications

HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.

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