Abstract
The rising incidence and mortality rate associated with the metastatic ability of cutaneous melanoma represent a major public health concern. Cutaneous melanoma is one of the most invasive human cancers, but the molecular mechanisms are poorly understood. Moreover, currently available therapies are not efficient in avoiding melanoma lethality. In this context, new biomarkers of prognosis, metastasis, and response to therapy are necessary to better predict the disease outcome. Additionally, the knowledge about the molecular alterations and dysregulated pathways involved in melanoma metastasis may provide new therapeutic targets. Members of the Ras superfamily of small GTPases regulate various essential cellular activities, from signaling to membrane traffic and cytoskeleton dynamics. Therefore, it is not surprising that they are differentially expressed, and their functions subverted in several types of cancer, including melanoma. Indeed, Ras small GTPases were found to regulate melanoma progression and invasion. Hence, a better understanding of the mechanisms regulated by Ras small GTPases that are involved in melanoma tumorigenesis and progression may provide new therapeutic strategies to block these processes. Here, we review the current knowledge on the role of Ras small GTPases in melanoma aggressiveness and the molecular mechanisms involved. Furthermore, we summarize the known involvement of these proteins in melanoma metastasis and how these players influence the response to therapy.
Highlights
Melanoma derives from the malignant transformation of melanocytes, which are melanin-producing cells located in the epidermis, eyes, meninges, esophagus, and mucous membranes (Ali et al, 2013)
Referred to as melanoma, represents the most lethal skin neoplasm, leading to 60–75% of the mortality rate related to skin malignancies, even though it accounts for only 5% of all skin tumors (Bandarchi et al, 2010; Potrony et al, 2015; Esteva et al, 2017)
Considering the role of these proteins in melanoma invasion and the observation that RAB27A and RAB38 expression were associated with shorter overall survival (OS) of melanoma patients, these GTPases were proposed as drivers of melanoma metastasis (Huang et al, 2018; Guo et al, 2019) (Table 1)
Summary
Melanoma derives from the malignant transformation of melanocytes, which are melanin-producing cells located in the epidermis, eyes, meninges, esophagus, and mucous membranes (Ali et al, 2013). Ras small GTPases control crucial physiological functions in cell homeostasis, several superfamily members are involved in the aberrant activation of signaling cascades that play a central role in a broad spectrum of human diseases, including cancer (Aspenström, 2018; Casalou et al, 2020; Gopal Krishnan et al, 2020). The imminent role of NRAS mutations in melanoma aggressiveness and response to therapy has been well established, much is still to discover about the impact of the remaining Ras family members in melanoma pathophysiology and as putative therapeutic targets.
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