The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma

Int J Mol Sci. 2021 Jan 13;22(2):761. doi: 10.3390/ijms22020761.


Background: Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have a role in the development and progression of melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor (HGF)/c-met axis is emerging as a critical player because it can play a role in drug resistance. Indeed, 50% of melanoma patients present BRAF mutations, however, all responders develop resistance to the inhibitors typically within one year of treatment. Interestingly, BRAF inhibitors induce reactive oxygen species (ROS) in melanoma cells, therefore, the aim of this study was to investigate a possible interplay between HGF/c-met and ROS sources, such as NADPH oxidases (Nox).

Methods: The expression of c-met and Nox were quantified in 60 patients with primary cutaneous melanoma. In vitro experiments on melanoma primary cells and the cell line were performed to dissect the underpinned molecular mechanism.

Results: The outcome of interest was the correlation between the high positivity for both Nox4 and c-met and metastasis occurring at least 1 year later than melanoma diagnosis in BRAF mutated patients, in contrast to nonmutated. In vitro experiments demonstrated that the axis HGF/c-met/Nox4/ROS triggers the epithelial-mesenchymal transition.

Conclusions: The observed correlation suggests an interplay between c-met and Nox4 in promoting the onset of metastasis. This study suggests that Nox4 inhibitors could be associated to the current therapy used to treat melanoma patients with BRAF mutations.

Keywords: HGF; NADPH oxidases; melanoma; oxidative stress.

MeSH terms

  • Adult
  • Aged
  • Cell Line, Tumor
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunohistochemistry
  • Male
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Middle Aged
  • Mutation*
  • NADPH Oxidase 4 / genetics*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Reactive Oxygen Species


  • Reactive Oxygen Species
  • Hepatocyte Growth Factor
  • NADPH Oxidase 4
  • NOX4 protein, human
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins B-raf