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

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Azienda Ospedaliero Universitaria Policlinico, 41124 Modena, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 761;
Received: 16 December 2020 / Revised: 7 January 2021 / Accepted: 8 January 2021 / Published: 13 January 2021
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. View Full-Text
Keywords: melanoma; HGF; oxidative stress; NADPH oxidases melanoma; HGF; oxidative stress; NADPH oxidases
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MDPI and ACS Style

Beretti, F.; Farnetani, F.; Reggiani Bonetti, L.; Fabbiani, L.; Zavatti, M.; Maiorana, A.; Pellacani, G.; Maraldi, T. The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma. Int. J. Mol. Sci. 2021, 22, 761.

AMA Style

Beretti F, Farnetani F, Reggiani Bonetti L, Fabbiani L, Zavatti M, Maiorana A, Pellacani G, Maraldi T. The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma. International Journal of Molecular Sciences. 2021; 22(2):761.

Chicago/Turabian Style

Beretti, Francesca, Francesca Farnetani, Luca Reggiani Bonetti, Luca Fabbiani, Manuela Zavatti, Antonino Maiorana, Giovanni Pellacani, and Tullia Maraldi. 2021. "The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma" International Journal of Molecular Sciences 22, no. 2: 761.

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