The Interplay between HGF/c-met Axis and Nox4 in BRAF Mutated Melanoma.
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
Middle Aged
Mutation
NADPH Oxidase 4
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Proto-Oncogene Proteins c-met
/ metabolism
Reactive Oxygen Species
HGF
NADPH oxidases
melanoma
oxidative stress
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
13 Jan 2021
13 Jan 2021
Historique:
received:
16
12
2020
revised:
07
01
2021
accepted:
08
01
2021
entrez:
16
1
2021
pubmed:
17
1
2021
medline:
10
4
2021
Statut:
epublish
Résumé
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). 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 33451139
pii: ijms22020761
doi: 10.3390/ijms22020761
pmc: PMC7828605
pii:
doi:
Substances chimiques
Reactive Oxygen Species
0
Hepatocyte Growth Factor
67256-21-7
NADPH Oxidase 4
EC 1.6.3.-
NOX4 protein, human
EC 1.6.3.-
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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