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The Mirnas Role in Melanoma and in Its Resistance to Therapy

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The Mirnas Role in Melanoma and in Its Resistance to Therapy International Journal of Molecular Sciences Review The miRNAs Role in Melanoma and in Its Resistance to Therapy Francesca Varrone 1,* and Emilia Caputo 2,* 1 IRBM S.p.A., Via Pontina Km 30,600, I-00071 Pomezia, Italy 2 Institute of Genetics and Biophysics –I.G.B., Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche (CNR), Via Pietro Castellino, 111, I-80131 Naples, Italy * Correspondence: [email protected] (F.V.); [email protected] (E.C.); Tel.: +81-6132307 (F.V.); +81-6132307 (E.C.) Received: 13 December 2019; Accepted: 26 January 2020; Published: 29 January 2020 Abstract: Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10–15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and immunotherapeutic strategies has improved chances for patient survival, melanoma treatment still remains a big challenge for oncologists. Here, we collect recent data about the emerging role of melanoma-associated microRNAs (miRNAs) currently available treatments, and their involvement in drug resistance. We also reviewed miRNAs as prognostic factors, because of their chemical stability and resistance to RNase activity, in melanoma progression. Moreover, despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors. Keywords: melanoma; metastasis; drug resistance; miRNAs 1. Introduction 1.1. Melanoma: Its Progression and Metastasis Melanoma is the most malignant skin cancer and its incidence has been steadily increasing over the past three decades, accounting for the majority of skin cancer-related deaths worldwide [1]. Melanoma originates from an altered proliferation of melanocytes, a skin minority cell population, with a low proliferative potential, deriving from neural crest cell precursors. They produce melanin pigment, providing it to the nearby keratinocytes. UV exposure induces melanocytes to proliferate and produce melanin, by a finely tuned process, depending upon specific pathways of which alteration is associated to the melanocyte malignant transformation [2,3]. Melanomagenesis has been classically described as a process characterized by a linear progression of normal melanocytes through various precursor lesions and ultimately to melanoma [4]. The initial step is the formation of a nevus, which consists of the proliferation and aggregation of melanocytes located at the skin layer and epidermis; some of them could also show an altered growth pattern changing into a dysplastic nevus phenotype. However, it may arise from a preexisting melanocytic nevus or as a new lesion. This stage of progression is characterized by the disruption of the p16INK4a-retinoblastoma (Rb) pathway, mostly by inactivation of CDKN2A, due to its mutations [5,6]. Successively, the continuous and unchecked melanocyte proliferation allows them to penetrate into the epidermal/dermal junction or within the dermis by a radial growth phase (RGP). At this stage, neoplastic melanocytes show an immortal phenotype, achieved by the activation of human telomerase Int. J. Mol. Sci. 2020, 21, 878; doi:10.3390/ijms21030878 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 878 2 of 28 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 28 enterreverse into transcriptase the final step (hTERT) of progression [7]. Then, [4] cells. The may final grow stage into of the melanoma dermis, where, progression they interact is characterized with other bycell a types vertical and growth gain physical phase access(VGP), to requiring both lymphatics mutations and repressing blood vessels, apoptosis, and may which enter allow into thecells final to survivestep of progressionin the absence [4]. Theof keratinocytes final stage of melanomaas well as progressionPTEN loss, isover characterized-expression byof avarious vertical protein growth kinasesphase (VGP), or RAS requiring activation, mutations and β- repressingcatenin activation apoptosis, (reviewed which allow in Bennett cells to et survive al.) [8] in. The the absenceloss of E of- cadherinkeratinocytes along as with well the as PTENaberrant loss, expression over-expression of N-cadherin of various and protein αVβ3 integrin kinases orhave RAS also activation, been shown and toβ-catenin be crucial activation for the p (reviewedrogression in from Bennett RGP etto al.) VGP [8]. final The melanoma loss of E-cadherin progression along (reviewed with the in aberrant Miller etexpression al.) [9] (Figure of N-cadherin 1). and αVβ3 integrin have also been shown to be crucial for the progression from RGP to VGP final melanoma progression (reviewed in Miller et al.) [9] (Figure1). Figure 1. Schematic representation of melanoma onset and progression. Melanoma onset and progression described in the text was illustrated, underlining its clonal evolution, phenotype switching, Figure 1. Schematic representation of melanoma onset and progression. Melanoma onset and and high heterogeneity [10]. progression described in the text was illustrated, underlining its clonal evolution, phenotype switchingAlthough, and Clark high classification heterogeneity is [10] still. used for melanoma stadiation, substantial evidence suggests that melanomagenesis is not a result of a linear progression of alterations from nevus through all the differentAlthough phases Clark to the classification metastatic melanoma, is still used but for MMmelanoma can originate stadiation, from substantial each of the evidence described suggest phases,s thatwithout melanomagenesis necessarily passing is not througha result of all a of linear them. progression of alterations from nevus through all the differentIn fact, phases this to model the metastatic has been improvedmelanoma, from but MM the discovery can originate and from identification each of the of de cancerscribed stem phase cellss, without(CSCs). Itnecessarily has been demonstratedpassing through that all malignant of them. melanoma stem cells (MMSCs) are involved in the melanomaIn fact,origin, this model progression, has been andimproved metastasis from [ 11the]. discovery MMSCs are and similar identification to adult of stem cancer cells stem for theircells (CSCs).multipotency It has been and plasticdemonstrated phenotype that propertiesmalignant [m12elanoma–14]. These stem cells cells express (MMSCs) VE-cadherin, are involved and in the melanomareceptor tyrosine origin, kinaseprogression for ephrin, and (Eph),metastasis and [11] are. able MMSCs to induce are similar de novo to tumoradult stem angiogenesis cells for their by a multipotencyvasculogenic mimicryand plastic (VM) phenotype process.At properties the same [12 time,–14] the. These growth cells factors express produced VE-cadherin, from endothelial and the receptorcells and /tyroor fibroblastssine kinase present for ephrin in the microenvironment(Eph), and are able play to aninduce important de novo role tumor in melanoma angiogenesis progression, by a vasculogenicas well as immune mimicry cells (VM) infiltrating process the. At tumorthe same mass time and, the their growth cytokines factors [15 produced–18]. from endothelial cells Furthermore,and/or fibroblasts our growingpresent knowledgein the microenvironment about the epigenetic play an mechanisms important involvedrole in melanoma in cancer progressiondevelopment, as provide well as a immune more complex cells infiltrating picture of the melanoma tumor mass progression and their and cytoki metastasisnes [15– [1918],20. ]. Furthermore, our growing knowledge about the epigenetic mechanisms involved in cancer development1.2. Melanoma prov Riskide Factors a more complex picture of melanoma progression and metastasis [19,20]. Melanoma progression is a combination of environmental and genetic risk factors [21,22]. Among 1.2. Melanoma Risk Factors the environmental factors, the accumulation of sun exposure (or by UV radiation from tanning beds) is theMelanoma primary andprogression most common is a combination risk factor. Melanocytesof environmental are resistant and genetic to UV-induced risk factors apoptosis. [21,22]. AmongThey continue the environmental to grow and factors, accumulate the geneticaccumulation mutations, of sun leading exposure to the (or formation by UV radiation and growth from of tanninga melanoma beds) [ 23is ,the24]. prim Otherary environmental and most common risk factorsrisk factor for. melanoma Melanocytes have are been resistant demonstrated to UV-induced to be apoptosis.the skin pigmentation They continue phenotype to grow (fairand oraccumulate light skin) genetic as well mutations as the existence, leading of atypicalto the formation and multiple and growthnevi [25 –of28 ].a Amelanoma role of the circadian[23,24]. Other rhythm environmental in melanoma developmentrisk factors hasfor also melanoma been reported. have Itbeen has demonstratedbeen demonstrated to be thatthe melatonin,skin pigmen a majortation outputphenotype product (fair of or thee light circadian skin) as rhythm, well as plays the existence a protective of atypicalrole in melanoma and multiple [29]. nevi [25–28]. A role of the circadian rhythm in melanoma development has also been reported. It has been demonstrated that melatonin, a major output product of thee circadian rhythm, plays a protective role in melanoma [29]. Int. J. Mol. Sci. 2020, 21, 878 3 of 28 Along with the environmental risks,
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