Hepatocyte growth factor signaling regulates transactivation of genes belonging to the plasminogen activation system via hypoxia inducible factor-1.

Hepatocyte growth factor (HGF) plays an important role in tumor growth and progression also by regulating invasive/metastatic phenotype and angiogenesis. Here we report that a molecular mechanism possibly contributing to these functions of HGF may be hypoxia inducible factor-1 (HIF-1)-dependent expression of genes of the plasminogen activation system. The following findings support this conclusion: (1) HGF enhanced the activity of a luciferase reporter construct under the control of multiple HIF-1 responsive elements (HRE) in HepG2 cells, and the cotransfection of the dominant negative for the beta-subunit (ARNT) prevented this increase; (2) HGF activated uPA and PAI-1 promoters through HIF-1 activity regulated by PI3K/JNK1 transducers, as demonstrated by cotransfection with the reporter gene promoters and the dominant negative for ARNT, p85 subunit of PI3K or JNK1; (3) hypoxia was additive to HGF in increasing reporter vector activities, but probably through different transduction pathways; (4) JNK1 wild-type expression vector increased HIF-1alpha protein expression probably in a phosphorylated state and, thus, functional for transactivating activity; and (5) c-Jun did not seem to be involved in the activation of the luciferase construct containing multiple HREs because it was not prevented by expression of TAM-67, which is the dominant negative mutant form for c-Jun.