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The Role of Non-Coding Rnas in Uveal Melanoma

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The Role of Non-Coding Rnas in Uveal Melanoma cancers Review The Role of Non-Coding RNAs in Uveal Melanoma Manuel Bande 1,2,*, Daniel Fernandez-Diaz 1,2, Beatriz Fernandez-Marta 1, Cristina Rodriguez-Vidal 3, Nerea Lago-Baameiro 4, Paula Silva-Rodríguez 2,5, Laura Paniagua 6, María José Blanco-Teijeiro 1,2, María Pardo 2,4 and Antonio Piñeiro 1,2 1 Department of Ophthalmology, University Hospital of Santiago de Compostela, Ramon Baltar S/N, 15706 Santiago de Compostela, Spain; [email protected] (D.F.-D.); [email protected] (B.F.-M.); [email protected] (M.J.B.-T.); [email protected] (A.P.) 2 Tumores Intraoculares en el Adulto, Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; [email protected] (P.S.-R.); [email protected] (M.P.) 3 Department of Ophthalmology, University Hospital of Cruces, Cruces Plaza, S/N, 48903 Barakaldo, Vizcaya, Spain; [email protected] 4 Grupo Obesidómica, Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; [email protected] 5 Fundación Pública Galega de Medicina Xenómica, Clinical University Hospital, SERGAS, 15706 Santiago de Compostela, Spain 6 Department of Ophthalmology, University Hospital of Coruña, Praza Parrote, S/N, 15006 La Coruña, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-981951756; Fax: +34-981956189 Received: 13 September 2020; Accepted: 9 October 2020; Published: 12 October 2020 Simple Summary: The development of uveal melanoma is a multifactorial and multi-step process, in which abnormal gene expression plays a key role. Recently, several studies have highlighted the role of non-coding RNAs in the progression of uveal melanoma by affecting different signaling pathways. As important agents in the regulation of genes, non-coding RNAs have enormous potential to open up therapeutic pathways, predict response to treatment, and anticipate patient outcome for uveal melanoma. This review aims to provide a comprehensive view of what we know about ncRNAs in uveal melanoma currently. Abstract: Uveal melanoma (UM) is the most common primary intraocular tumor in adulthood. Approximately 50% of patients develop metastatic disease, which typically affects the liver and is usually fatal within one year. This type of cancer is heterogeneous in nature and is divided into two broad groups of tumors according to their susceptibility to develop metastasis. In the last decade, chromosomal abnormalities and the aberrant expression of several signaling pathways and oncogenes in uveal melanomas have been described. Recently, importance has been given to the association of the mentioned deregulation with the expression of non-coding RNAs (ncRNAs). Here, we review the different classes of ncRNAs—such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)—and their contribution to the development of UM. Special attention is given to miRNAs and their regulatory role in physiopathology and their potential as biomarkers. As important agents in gene regulation, ncRNAs have a huge potential for opening up therapeutic pathways, predicting response to treatment, and anticipating patient outcome for UM. Keywords: uveal melanoma; ncRNAs; miRNA; lncRNAs; review Cancers 2020, 12, 2944; doi:10.3390/cancers12102944 www.mdpi.com/journal/cancers Cancers 2020, 12, 2944 2 of 22 1. IntroductionCancers 2020, 12, x 2 of 22 The1. Introduction latest research on the human genome indicates that only 2% of human DNA is encodes proteins [1]. However, it is known that over 80% of the human genome contains elements linked The latest research on the human genome indicates that only 2% of human DNA is encodes to biochemical functions [2]. What was formerly considered junk DNA has more recently been proteins [1]. However, it is known that over 80% of the human genome contains elements linked to demonstratedbiochemical to functions be ncRNAs [2]. that What perform was formerly multiple considered biologic processesjunk DNA and has whose more deregulationrecently been may be associateddemonstrated with to multiple be ncRNAs diseases, that perform including multiple cancer biologic [3, 4processes]. In addition and whose to the deregulation well-known may types of ncRNA,be associated such as with tRNA multiple and rRNAdiseases, that including are involved cancer [3,4]. in protein In addition synthesis, to the well ncRNA‐known also types comprises of manyncRNA, new transcripts such as tRNA that and have rRNA been that identified are involved in the in protein last decade. synthesis, They ncRNA are divided also comprises into two many groups accordingnew transcripts to their size: that small have ncRNAbeen identified and long in ncRNA. the last Thedecade. size They of small are divided ncRNAs into is usually two groups less than 200 nucleotidesaccording to and their includes size: small miRNA, ncRNA PIWI-interacting and long ncRNA. RNA The size (piRNA), of small small ncRNAs nucleolar is usually RNA less (snoRNA), than and promoter-associated200 nucleotides and smallincludes RNA miRNA, (PASR) PIWI [5],‐ asinteracting summarized RNA in (piRNA), Figure1 .small nucleolar RNA (snoRNA), and promoter‐associated small RNA (PASR) [5], as summarized in Figure 1. FigureFigure 1. ncRNA 1. ncRNA categories. categories. RNAs RNAs are are divided divided intointo two major major classes: classes: messenger messenger RNA RNA (mRNA) (mRNA) and and non-codingnon‐coding RNA RNA (ncRNA). (ncRNA). Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. At Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. At present, present, using any of the conservative treatment options or combinations results in a degree of local using any of the conservative treatment options or combinations results in a degree of local control of control of greater than 90% after 5 years. Despite this success, metastatic disease appears in more than greater50% than of patients 90% after after 5 15 years. years Despite of local treatment. this success, This metastatic poor prognosis disease is associated appears inwith more clinical than and 50% of patientsmolecular after 15 factors years of of primary local treatment. UM, such Thisas tumor poor height, prognosis presence is associated of monosomy with 3, clinical and chromosome and molecular factors8 gain, of primary while 6p UM, gain suchprovides as tumor a protective height, effect presence [6]. Genetic of monosomy prognostic markers 3, and chromosomehave been found 8 gain, whilethat 6p gaincan be provides used to identify a protective patients eff atect risk [6]. of Genetic developing prognostic metastatic markers disease. have Gene been expression found profiles that can be used(GEPs) to identify are used patients to classify at risk UMs of developing for disease‐specific metastatic mortality disease. risk, Gene with class expression 1A being profiles very low (GEPs) risk are used(2% to classify risk at 5 UMs years), for class disease-specific 1B being low risk mortality (21% risk risk, at 5 with years), class and 1A class being 2 being very high low risk risk (72% (2% at risk5 at 5 years),years) class [7]. 1BLikewise, being tumor low risk‐specific (21% mutations risk at 5 years),have been and found class in 2 the being genes high GNAQ, risk GNA11, (72% at EIF1AX, 5 years) [7]. SF3B1, and BAP1 [8,9]. Likewise, tumor-specific mutations have been found in the genes GNAQ, GNA11, EIF1AX, SF3B1, In recent years, many studies have shown that ncRNAs play a key role in multiple biological and BAP1 [8,9]. processes in UM, such as tumorigenesis, proliferation, and metastasis. Some ncRNAs have also been Inidentified recent as years, biomarkers many for studies the clinical have diagnosis shown that and prognosis ncRNAs of play UM. a In key this role review, in multiple we summarize biological processesthe role in UM,and mechanisms such as tumorigenesis, of different ncRNAs proliferation, in the physiopathology and metastasis. of Some UM, ncRNAsincluding have those also that been identifiedmay have as biomarkers a clinical application for the clinical in the diagnosis and and prognosis prognosis of ofthis UM. type In of this cancer. review, we summarize the role and mechanisms of different ncRNAs in the physiopathology of UM, including those that may have a clinical application in the diagnosis and prognosis of this type of cancer. Cancers 2020, 12, 2944 3 of 22 Cancers 2020, 12, x 3 of 22 2. MicroRNAs in UM 2. MicroRNAs in UM OfOf all all the the types types ofof ncRNAs,ncRNAs, miRNAsmiRNAs are the best best-studied‐studied and and understood understood within within the the context context of of UMUM initiation initiation and and progression. progression. MicroRNAs—RNA MicroRNAs—RNA strands strands of about of 17–22about nucleotides—are 17–22 nucleotides—are estimated ableestimated to regulate able 60%to regulate of all protein-encoding 60% of all protein genes,‐encoding and agenes, single and miRNA a single can miRNA regulate can up regulate to 400 di ffuperent to mRNAs400 different [10]. TheymRNAs regulate [10]. They the expression regulate the of expression genes both of at genes the transcriptional both at the transcriptional and post-transcriptional and post‐ leveltranscriptional and are implicated level and in are several implicated physiological in several and physiological pathological and processes pathological in which processes they exertin which their regulatorythey exert etheirffects regulatory through binding effects
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