HIF1? and HIF2? 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 HIF1? or HIF2? abrogates metastasis without affecting primary tumor formation. HIF1? and HIF2? drive melanoma invasion and invadopodia formation through PDGFR? 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 HIF1? and HIF2? activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.

SUBMITTER: Hanna SC 

PROVIDER: S-EPMC3635738 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature