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Metastatic potential of peroxyredoxin 2 in NRAs-mutated Melanomas

Abstract

When diagnosed early, cutaneous melanoma is a curable neoplasm, but it is associated with a worse evolution in advanced disease. Melanoma lesions in sun-exposed sites and associated with a high mutational load and aberrant epigenetic regulation contribute to the development and progression of the disease. This is the type of skin cancer with the highest metastatic potential, which leads to its high mortality rate. The main mutations occur in the MAPKs pathway: 50% of patients have alterations in BRAF, 15-20% in NRAS and the rest in NF1 or wild-type triple. Target-directed therapy has revolutionized the treatment of melanoma with the use of BRAF and MEK inhibitors, but intrinsic and acquired resistance leads to treatment failure. In this sense, mutations in NRAS characterize an even more aggressive tumor and without specific therapeutic options, relating this mutation to a worse prognosis. Intratumoral heterogeneity occurs as a consequence of the phenotypic plasticity of cells, which assume and transit through different transcriptional states controlled by MITF levels, making cells more proliferative or invasive. Such an event is related to metastasis and therapy failure. Thus, alternative pathways should be explored as potential options for the treatment of patients with NRAS mutations. Given that one of the factors limiting the effectiveness of targeted therapy is resistance to oxidative stress, the control of redox homeostasis is an interesting starting point.Hydrogen peroxide plays a central role in redox signaling, being involved in all hallmarks of cancer, from proliferation to metabolism, angiogenesis and immune system escape. In addition, hydrogen peroxide is capable of altering MITF levels. In this context, molecules that control their action are of substantial interest. Peroxiredoxins (PRDXs) are the main hydrogen peroxide-consuming enzymes in cells due to their high expression and catalytic capacity. Several studies report the action of antioxidant enzymes on redox homeostasis and tumorigenesis. In addition to the exceptional role of PRDXs in removing the oxidant from the medium, when they become oxidized and inactive, they allow hydrogen peroxide to react directly or indirectly with other targets, thus regulating the cell's redox signaling. Due to their central role in the control of hydrogen peroxide, PRDXs are directly involved in different types of cancer. In fact, the PRDX2 isoform is epigenetically silenced in some cancers and our group recently demonstrated that it is also reduced in patients with melanoma metastasis, reinforcing its involvement with the invasion process. In this sense, it was demonstrated that PRDX2 is capable of inducing the stability of adherent junctions in melanomas with BRAF mutation. However, there are still no studies that relate PRDXs to mutation in NRAS, therefore, we observed that melanoma cell lines with mutation in NRAS showed different proliferative and invasive profiles, corresponding to the difference in PRDX2 expression. Thus, our proposal is to investigate the role of PRDX2 in the phenotypic plasticity of NRAS-mutated melanomas. For this, the silencing of this protein by gene editing (shRNA) and by a pharmacological inhibitor of PRDXs (Conoidin A) will be studied, in addition to the effect of its restoration by the use of gliotoxin, a PRDX mimetic. Functional parameters such as proliferation, colony formation capacity, migration and invasion in 3D skin models will be evaluated. Such observations reinforce our hypothesis that PRDX2 may be a new target in the search for more specific drugs for NRAS-mutated melanomas. (AU)

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