HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases Journal Article

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Authors: Hanna, S. C.; Krishnan, B.; Bailey, S. T.; Moschos, S. J.; Kuan, P. F.; Shimamura, T; Osborne, L. D.; Siegel, M. B.; Duncan, L. M.; O'Brien, E. T., 3rd; Superfine, R.; Miller, C. R.; Simon, M. C.; Wong, K. K.; Kim, W. Y.
Article Title: HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases
Abstract: Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells. Using a Pten-deficient, Braf-mutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1alpha or HIF2alpha abrogates metastasis without affecting primary tumor formation. HIF1alpha and HIF2alpha drive melanoma invasion and invadopodia formation through PDGFRalpha and focal adhesion kinase-mediated (FAK-mediated) activation of SRC and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1alpha and HIF2alpha activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.
Journal Title: The Journal of clinical investigation
Volume: 123
Issue: 5
ISSN: 1558-8238; 0021-9738
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: 2078
End Page: 2093
Language: eng
DOI/URL:

10.1172/JCI66715
Notes: LR: 20150209; GR: 3P30CA016086/CA/NCI NIH HHS/United States; GR: 3P30ES010126/ES/NIEHS NIH HHS/United States; GR: CA 120964/CA/NCI NIH HHS/United States; GR: CA 122794/CA/NCI NIH HHS/United States; GR: CA 140594/CA/NCI NIH HHS/United States; GR: CA 141576/CA/NCI NIH HHS/United States; GR: CA 163896/CA/NCI NIH HHS/United States; GR: CA 166480/CA/NCI NIH HHS/United States; GR: P01 CA154303/CA/NCI NIH HHS/United States; GR: P30 CA016086/CA/NCI NIH HHS/United States; GR: P30 ES010126/ES/NIEHS NIH HHS/United States; GR: P30-DK-034987/DK/NIDDK NIH HHS/United States; GR: R01 CA122794/CA/NCI NIH HHS/United States; GR: R01 CA140594/CA/NCI NIH HHS/United States; GR: R01 CA142794/CA/NCI NIH HHS/United States; GR: R01 CA166480/CA/NCI NIH HHS/United States; GR: R33 CA155618/CA/NCI NIH HHS/United States; GR: T32 GM007092/GM/NIGMS NIH HHS/United States; GR: U54 CA151652/CA/NCI NIH HHS/United States; JID: 7802877; 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (RNA, Small Interfering); 0 (endothelial PAS domain-containing protein 1); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 3.1.3.48 (PTEN protein, human); EC 3.1.3.67 (PTEN Phosphohydrolase); OID: NLM: PMC3635738; 2012/09/12 [received]; 2013/02/08 [accepted]; 2013/04/08 [aheadofprint]; 2013/04/08 [epublish]; ppublish