Hypoxia-inducible Transcription Factors Trigger Metastasis in Malignant Melanoma Tumors

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 (extracellular matrix) as well as genes that control motility and adhesion of tumor cells. HIF activity is upregulated by mutated RAS, a member of the KRAS family of oncogenes, and BRAF (v-raf murine sarcoma viral oncogene homolog B1) as well as loss-of-function mutations of the PTEN gene. PTEN (phosphatase and tensin homolog), which is missing in 60% to 70% of metastatic cancers in humans, is the name of a phospholipid phosphatase protein, and gene that encodes it. The PTEN gene acts as a tumor suppressor gene thanks to the role of its protein product in regulation of the cycle of cell division, preventing cells from growing and dividing too rapidly.

Investigators at the University of North Carolina (Chapel Hill, USA) examined the molecular basis for melanoma metastasis in a genetically engineered PTEN-deficient, BRAF-mutant mouse model. In this model the activities of HIF1 and HIF2, which are usually overexpressed in melanoma tumors, can be shut down.

Results published in the April 8, 2013, online edition of the Journal of Clinical Investigation revealed that inactivation of HIF1 or HIF2 prevented metastasis without affecting primary tumor formation. Both HIF1 and HIF2 independently activated the proto-oncogene tyrosine-protein kinase SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) using different signaling pathways.

The protein encoded by the SRC gene has been linked to several different cancers, and the identification of its role in melanoma may mean that existing drugs that target SRC may be adapted for treatment of malignant melanoma.

“What we are trying to do now is inhibit these pathways with drugs in the mice to see if we see a decrease of metastasis,” said first author Sara Hanna, a graduate student researcher at the University of North Carolina.

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