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.
摘要:
黑色素瘤是最具侵袭性的皮肤癌类型。尽管有可用的治疗方法,最小残留病仍难治。活性氧和氮(ROS和RNS)在黑色素瘤中起着双重作用,其中氧化还原失衡涉及从起始到转移和抵抗。氧化还原蛋白通过控制免疫反应中的ROS/RNS水平来调节疾病,扩散,入侵,和复发。化疗药物如BRAF和MEK抑制剂促进氧化应激,但高ROS/RNS量与强大的抗氧化系统允许细胞适应和合作到无毒水平。这些蛋白质可以作为生物标志物和可能的靶标。通过了解适应和寻找新的靶标以使细胞更容易受到治疗的复杂机制,这种疾病可能会被克服。因此,探索氧化还原敏感蛋白的作用和氧化还原稳态的调节可能为新疗法提供线索.这项研究分析了从黑色素瘤患者的公共队列中获得的有关疾病阶段黑色素瘤中氧化还原生成和解毒蛋白表达的信息。遗传改变,和患者总体生存状况。根据我们的分析,66%的同工型在黑素瘤进展中呈现差异表达:NOS2,SOD1,NOX4,PRX3,PXDN和GPX1在黑素瘤进展期间增加,而CAT,GPX3、TXNIP、和PRX2减少。此外,疾病的阶段也可能影响结果。PRX1、PRX5和PRX6的水平可以根据阶段而增加或降低。我们发现所有分析的同工型都在基因上表现出一些遗传改变,其中大多数(78%)为mRNA表达增加。有趣的是,34%的黑色素瘤患者在TRX1上表现出遗传改变,多半为mRNA表达下降。此外,对于改变的组(PRX3,PRX5,TR2和GR)和未改变的组(NOX4),15%的同种型显示出患者总体生存状态的显着降低。虽然还没有这种特定的抗氧化疗法被批准用于黑色素瘤,这些氧化还原敏感蛋白的抑制剂或模拟物已经取得了非常有希望的结果。我们预计,即将进行的有关这些蛋白质调节的研究将为癌症治疗带来重大进展。