Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb 22;11(3):438.
doi: 10.3390/antiox11030438.

Redox-Related Proteins in Melanoma Progression

Larissa A C Carvalho  1 , Rodrigo G Queijo  1 , Alexandre L B Baccaro  2 , Ádamo D D Siena  3 , Wilson A Silva Jr  3 , Tiago Rodrigues  4 , Silvya Stuchi Maria-Engler  1
Affiliations

Redox-Related Proteins in Melanoma Progression

Larissa A C Carvalho et al. Antioxidants (Basel). .

Abstract

Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy.

Keywords: antioxidants; melanoma; oxidative stress; redox proteins; resistance.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nitric oxide synthase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, with *** p < 0.001, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 1
Figure 1
Nitric oxide synthase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, with *** p < 0.001, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 2
Figure 2
NADPH oxidases on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 2
Figure 2
NADPH oxidases on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 3
Figure 3
Superoxide dismutase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes are common nevus, yellow boxes are dysplastic nevus, green boxes are radial growth phase (RGP) melanoma, blue boxes are vertical growth phase (VGP) melanoma, and purple boxes are metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 3
Figure 3
Superoxide dismutase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes are common nevus, yellow boxes are dysplastic nevus, green boxes are radial growth phase (RGP) melanoma, blue boxes are vertical growth phase (VGP) melanoma, and purple boxes are metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 4
Figure 4
Catalase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 5
Figure 5
Glutathione-related enzymes on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05, when compared to common or dysplastic nevus. NS: Not significant.
Figure 5
Figure 5
Glutathione-related enzymes on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05, when compared to common or dysplastic nevus. NS: Not significant.
Figure 5
Figure 5
Glutathione-related enzymes on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05, when compared to common or dysplastic nevus. NS: Not significant.
Figure 6
Figure 6
Thioredoxins, thioredoxins reductase and thioredoxin interacting protein on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 6
Figure 6
Thioredoxins, thioredoxins reductase and thioredoxin interacting protein on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 6
Figure 6
Thioredoxins, thioredoxins reductase and thioredoxin interacting protein on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 7
Figure 7
Peroxiredoxins on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 7
Figure 7
Peroxiredoxins on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 7
Figure 7
Peroxiredoxins on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, *** p < 0.001, ** p < 0.01, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 8
Figure 8
Protein disulfide isomerase on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 9
Figure 9
Peroxidasin on melanoma. (A) Percentage of patients with altered genes and types of genetic alterations; (B) overall patient survival status, and (C) expression in the melanoma progression. Red boxes represent the common nevus, yellow boxes the dysplastic nevus, green boxes the radial growth phase (RGP) melanoma, blue boxes the vertical growth phase (VGP) melanoma, and purple boxes the metastatic melanoma. The statistical analysis was performed by ANOVA followed by Tukey test, ** p < 0.01 * p < 0.05 when compared to common or dysplastic nevus. NS: Not significant.
Figure 10
Figure 10
Expression of RNS/ROS-generating and detoxifying proteins in melanoma progression. Thin arrows indicate an increase (↑) or decrease (↓) of proteins in VGP and metastatic melanoma compared to 1 common nevus or 2 dysplastic nevus. RGP: radial-growth phase. VGP: vertical-growth phase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Shain A.H., Bastian B.C. From melanocytes to melanomas. Nat. Rev. Cancer. 2016;16:345–358. doi: 10.1038/nrc.2016.37. - DOI - PubMed
    1. Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer statistics, 2021. CA Cancer J. Clin. 2021;71:7–33. doi: 10.3322/caac.21654. - DOI - PubMed
    1. Cannavò S.P., Tonacci A., Bertino L., Casciaro M., Borgia F., Gangemi S. The role of oxidative stress in the biology of melanoma: A systematic review. Pathol. Res. Pract. 2019;215:21–28. doi: 10.1016/j.prp.2018.11.020. - DOI - PubMed
    1. Premi S., Wallisch S., Mano C.M., Weiner A.B., Bacchiocchi A., Wakamatsu K., Bechara E.J.H., Halaban R., Douki T., Brash D.E. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science. 2015;347:842–847. doi: 10.1126/science.1256022. - DOI - PMC - PubMed
    1. Liou G.Y., Storz P. Reactive oxygen species in cancer. Free Radic. Res. 2010;44:479–496. doi: 10.3109/10715761003667554. - DOI - PMC - PubMed