Melanoma and Associated MicroRNAs


avatar Negin Afrang 1 , avatar Mehrnaz Imani 1 , avatar Maryam Honardoost 1 , *

Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran

how to cite: Afrang N, Imani M, Honardoost M. Melanoma and Associated MicroRNAs. J Skin Stem Cell. 2016;3(4):e63854. doi: 10.5812/jssc.63854.



Melanoma is an invasive type of skin cancer, with a rapidly increasing incidence. Therefore, new approaches are required to treat this aggressive cancer. MicroRNAs (miRNAs) are introduced as novel components in melanoma. This review study aimed to determine the relationship between melanoma and miRNAs.

Evidence Acquisition:

Prognostic, diagnostic, and therapeutic applications of miRNAs in skin cancer have been recently investigated from different aspects. Some of these studies on miRNAs were reviewed, and the mechanisms of some genetic modifications were determined in this study.


Since recommendations for miRNAs have increased in the past decades, and scientists have confirmed their great efficacy in multiple aspects of cancer treatment, different strategies have been developed considering their therapeutic effects. Therefore, further studies are required to confirm miRNA application in melanoma treatment.


This review study included various investigations concerning miRNA traces as molecular rearrangements in melanoma. It was revealed that multiple miRNAs are efficient in molecular signaling and can be used as prognostic, diagnostic, and therapeutic biomarkers. Although the exact relationship between aberrant expression of miRNAs and cancers has been confirmed, further studies are required to introduce more thorough and accurate applications of miRNAs in melanoma.

1. Context

Recently, skin cancers have become common in white populations. Melanoma is one of the prevalent and aggressive types of skin cancer, which is more common among the youth. Small noncoding regulatory RNA molecules (miRNAs) have been documented as primary biomolecules in cancer therapy, especially melanoma treatment. MiRNAs are responsible for several molecular modifications in abnormal cells. Involvement of miRNAs in melanoma has been approved by many researchers (1-4).

Some deregulated miRNAs are responsible for the progression and metastasis of melanoma. Although melanoma has been identified in recent years, there are no accurate treatments for this prevalent cancer. Evaluation of miRNAs in various studies in recent decades has shown their precise role in prognostic, diagnostic, and therapeutic processes. In this review, we aimed to evaluate the relationship between miRNAs and related targets involved in melanoma in order to elucidate the molecular mechanisms of this type of skin cancer.

2. Evidence Acquisition

In the past decades, prevalence of skin cancers, particularly melanoma, has grown worldwide. The incidence rate of melanoma has increased over the past 30 years, and the youth seem to be more vulnerable to this type of cancer. It is noteworthy that white populations are more at risk of this aggressive skin cancer (5, 6). Generally, this aggressive type of skin cancer has been identified for many years. However, there are no therapies for the malignant stages of this cancer. Therefore, novel procedures are required for the development of diagnostic and prognostic strategies (7, 8).

According to recent studies, molecular changes lead to modifications of normal cells into abnormal ones. In recent research, miRNAs have been implicated as liable biomarkers of molecular modifications in cancer. MiRNAs are short, noncoding RNAs containing 18 - 22 nucleotides, which bind to the 3’UTR region of target mRNA to prevent its translation into proteins. These new biological molecules can act as negative regulatory factors of gene expression by degrading targeted messenger RNA (mRNA) or inhibiting mRNA translation.

Recently, many studies have been performed on the role of miRNAs in the diagnosis, prognosis, and treatment of cancers, especially melanoma. Furthermore, these small biomolecules are essential for gene regulation in different types of cancers. MiRNA clusters, pre-miRNAs, and mature miRNAs have been examined in recent research and have been shown to regulate some functions in melanoma. In this review, we aimed to briefly elucidate the importance of these remarkable diagnostic, prognostic, and therapeutic biomarkers in melanoma (9-13).

2.1. MiRNA Upregulation in Melanoma

2.1.1. Cell-Cycle Regulatory Overexpressed miRNAs

There are several genes and mRNAs regulating cell proliferation, which can be modified by miRNAs. MiR-21, one of these regulatory factors, shows diverse expression patterns in melanoma cell lines at various stages. However, miR-182 has been shown to be methylated in all stages of melanoma. While miR-21 is upregulated in primary melanomas, its expression is prevented in other stages. Furthermore, this miRNA identifies phosphatase and tensin homolog (PTEN), Akt, Bax, and Bcl-2 proteins and induces cell proliferation through different processes, such as phosphorylation, inhibition, and overexpression (Figure 1).

Similar to miR-21, miR-195 is expressed differently in various stages of melanoma. For instance, it is downregulated in primary stages, whereas it is overexpressed in progressive stages to facilitate proliferation of melanoma cell lines. The small cell protein, WEE1 G2 checkpoint kinase (WEE1), as a mitotic inhibitor kinase, is another target of the cell cycle inhibitor, miR-195. As demonstrated by Watanabe et al. in 2013, depletion of WEE1 due to miR-195 attachment enhances cell proliferation (1, 14, 15). Furthermore, in a study by Felicetti et al. and Igoucheva et al., miR-221 and miR-222 were shown to be overexpressed. These upregulated miRNAs targeted P27, which is a cell cycle regulator adhering to cyclin D1. This regulator is downregulated in melanoma owing to increased miRNA expression. Tyrosine-protein kinase kit (c-kit), PTEN, and tissue inhibitor of metalloproteinase (TIMP) are other targets of miR-221/222 cluster (Figure 1). The level of c-kit is reduced due to miR-221 blocking process. In normal cells, c-kit modulates microphthalmia-associated transcription factor (MITF) and tyrosinase, which are mutated in melanoma cells. Depending on the cell stage of melanoma, it seems that miR-221 and miR-222 can have various targets (Table 1) (16-20).

Table 1. The miRNAs and Related Targets Involved in Melanoma
MiRNAValidated TargetReference
miR-21BRAF(1, 21, 22)
miR-195WEE1(1, 21, 22)
miR-221/222P27, C-KIT, TIMP, PTEN, BRAF(16-20)
Pre-miR-17-92BIM(1, 23, 24)
miR-506-514_(1, 23, 24)
miR-126_(1, 21, 22)
miR-155_(1, 21, 22)
miR-214_(1, 21, 22)
miR-786-3p_(1, 21, 22)
miR-210HOXA1, TP53I11, PTPN1(1, 21, 22)
miR-30/30b_(1, 21, 22)
miR-181PTEN(25, 26)
miR-182MITF, FOXO3, CASP2, PTEN, Akt, Bax, Bcl-2(1)
miR-let7-bCDK, BSG, MMP(1)
miR-205E2F1, E2F5(20)
miR-145C-myc, Erbb3(1)
miR-211MITF(1, 29, 30)
miR-199a-3pC-MET receptor(23)
miR-137YB1, MITF, c-MET(23)

There is some evidence on pre-miRNAs, triggering the alteration of mRNA expression. Upregulation of pre-miR-17 - 92 cluster, as reported by Levy et al., is an explicit example. This cluster is essential for inhibiting the proapoptotic moderator, Bcl-2L11 (BIM). Similar to this cluster, Georgantas et al. reported that miR-506-514 cluster on chromosome X is overexpressed in melanoma (1, 23, 24). Overall, several miRNAs have been reported as key regulators of cell production, including miR-786-3p, miR-214, miR-155, and miR-126 (1).

2.1.2. Immunosuppressive miRNAs

Several miRNAs have been introduced as mediators of immune responses in melanoma. MiR-210, miR-30, and miR-30b suppress immune responses through different processes. Upregulation of miR-210 targets immunosuppressive genes, namely Homeobox A1 (HOXA1), tumor protein P53 inducible protein 11 (TP53I11), and protein tyrosine phosphatase, non-receptor type 1 (PTPN1). Therefore, tumors remain undefined and cytotoxic T lymphocytes cannot destroy them (Table 1).

MiR-30 and miR-30b are overexpressed in melanoma, resulting in an increase in the expression of interleukin-10 (IL-10) and providing an immunosuppressive environment in combination with polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7), as a glycosylated protein. This gene modifies the cell surface of melanoma cells and affects cellular adherence; metastasis occurs due to discontinuity of cancerous cells. Therefore, miR-30b and miR-30 are accountable for metastasis in melanoma (1, 21, 22).

MiR-34a/c is another miRNA, which modulates immune responses in melanoma. These miRNAs downregulate UL16 binding protein 2 (ULBP2), a ligand for natural killer cells (NKCs) in the immune system. According to previous investigations, excess levels of miRNAs in melanoma remove ULBP2, and cancerous cells evade NKCs (1, 35).

2.2. Downregulated miRNAs in Melanoma

While there are overexpressed miRNAs in melanoma, reports have documented approximately 57 downregulated miRNAs. The mounting expression levels of target genes, owing to the reduction of miRNAs, trigger cellular mechanisms, including cell cycle, cell proliferation, and cell adhesion. Downregulation of miR-29c has been reported in metastatic melanoma (36); this study documented some of these miRNAs.

2.2.1. Cell-Cycle Regulatory Downregulated miRNAs

Adjustment of cell cycle is a key factor in arresting abnormal cell division. There are different molecules, which regulate cell cycle, and there are functional noncoding RNAs, which modulate these regulatory cell cycle factors. Different groups of miRNAs, including miR-let7-b and miR-193b, are examples of this short functional molecule. Loss of these miRNAs increases the expression and protein level of cyclin-dependent kinase D1 (CDK), which has been documented in the progression of melanoma (Table 1). In addition, melanoma metastasis decreases by miR-let-7b, which attenuates its essential target, basigin (BSG), and extracellular matrix metalloproteinase (MMP) (1, 37). Similarly, miR-206 reduces the proliferation and invasion of melanoma cell lines by targeting CDK4, cyclin D1, and cyclin C, which are downregulated in melanoma (Figure 1) (38-40).

MiR-205 is generally mutated because of its site (chromosome 1q), which is a hot spot in melanoma. Similar to other miRNAs, this biomolecule targets some cell proliferation mediators, ie, E2F transcription factors. E2F transcription factors are important cell-cycle regulators, upregulated in melanoma. While miR-205 is reduced, E2F1 and E2F5, as targets of miR-205, are overexpressed, thereby increasing cell proliferation.

It has been reported that injection of miR-205, as an in vivo or in vitro therapeutic marker, affects AKT and blocks the proliferation of melanoma cells (28, 41-43). On the other hand, inoculation of miR-205 increases the level of this essential biomolecule, which in turn decreases phosphorylated protein kinase B (PKB) sources by blocking melanoma cell proliferation. Considerably, these miRNAs perform their roles by reducing eukaryotic translation initiation factor (eIF4E) in melanoma cell lines (Table 1). MiR-145 is another moderator of cell cycle with different functions (1, 20, 43, 44). MiR-145 inhibits cell reproduction owing to the adherence of c-myc and Erbb3; this function is prevented due to miR-145 depletion (38-40).

Surface proteins play a key role in cell adhesion, inhibiting cell migration in cancer. E-cadherin is a vital surface protein, which is regulated by many types of miRNAs. MiR-9 is an essential miRNA, downregulated in melanoma. Lack of miR-9 results in the overexpression of NFkB and Snail. Eventually, E-cadherin is inhibited by the mentioned genes (28).

2.2.2. Epigenetic Regulatory miRNAs

Methylation is a regulatory factor for gene expression. Some miRNAs are downregulated, causing methylation. Based on a survey by Mazar et al., miR-375 is used in melanoma cell lines for methylation of demethylated CpG islands with some specific markers. In their study, different stages of melanoma were analyzed, and it was shown that miR-375 is methylated in stages II and III. Similar to miR-375, miR-34b is stage-dependently methylated, while miR-34b is methylated in stages III and IV (45).

MiR-31 is another miRNA, which is methylated and reduced in melanoma. This methylation could be due to the enhancement of zeste homolog 2 (EZH2)-mediated histone methylation or DNA methylation, which can silence genome expression. Chinnaiyan et al. reported reduced levels of genes, namely MET and SRC, which are targeted by miR-31, and recognized them as oncogenes in melanoma cell lines. Therefore, methylation of this miRNA induces melanoma cell proliferation (46).

2.3. Tumor Suppressor miRNAs

There are some tumor suppressor miRNAs, which inhibit oncogenes to prevent tumor metabolism. MiR-18b is one of these regulatory miRNAs, which moderates p53 expression. P53 is a key tumor suppressor in different types of cancers. Mouse double minute 2 homolog (MDM2), a p53 inhibitor, is reduced by miR-18b. The overexpression of p53 occurs through this attachment subsequent to apoptotic-cascade activation (Figure 1). As a result of miR-18b downregulation, p53 is blocked by MDM2 and apoptosis is inhibited (17, 19, 20, 43).

MiR-211 is another tumor suppressor in melanoma, which targets MITF, a significant gene in melanoma, and is downregulated in cancer (Figure 1) (1, 29, 30). Likewise, miR-196a suppresses the development of melanoma. Several targets have been introduced for miR-196a, such as HOX-B7, which is inversely regulated. Overexpression of this gene triggers the basic fibroblast growth factor (bFGF) signaling pathway. Finally, this signaling pathway increases the expression of ETS-1 transcription factor and bone morphogenetic protein-4 (BMP-4), inducing the progression of melanoma (1).

Other examples of tumor suppressor miRNAs include miR-34b, miR-34c, and miR-199a-3p. C-MET receptor is the target factor, which is overexpressed in many aggressive cancers (including melanoma) as a result of miRNA inhibition, leading to invasion and apoptosis inhibition. Another miRNA, known as miR-137, does not only target c-MET, but also targets MITF and Y-box binding protein 1 (YB1), which are modulatory members of cell reproduction and decrease in melanoma. Similarly, reduction of miR-199 and miR-34b/c increases the expression of target genes, c-MET, and consequently, melanoma migration is boosted (Table 1) (19, 23, 24, 47, 48).

Sun et al. introduced another new tumor suppressor, known as miR-216b. It has been reported that miR-216b concretes to Forkhead box M1 (FOXM1). Furthermore, in melanoma cell lines, miR-216b is reduced. Depletion of the mentioned miRNA leads to uncontrolled cell proliferation as a result of FOXM1 excess. Therefore, we could classify this miRNA in the category of tumor-suppressor miRNAs in melanoma (Table 1) (32). Moreover, NRAS, another oncogenic marker in melanoma, is downregulated by attachment of mir-let-7 family. As mentioned earlier, since this miRNA is decreased in melanoma by transfecting to melanoma cancer cells, apoptosis is induced and cell migration is ceased (Figure 1) (4, 49, 50).

2.4. OncomiRs

There are several pathways influenced by genetic mutations. In addition, there are numerous miRNAs requiring these mutations. BRAF mutation is the major mutant gene in most cancers, especially melanoma, which acts through MAPK signaling pathway and is stated to be the major affected pathway in melanoma (3, 4, 51). In a study by Pinto et al., various miRNAs and drugs were investigated to elicit the efficacy of miRNAs in the genetic mutation of melanoma, especially mutations in BRAF. They showed that miR-21, miR-101, miR-191, miR-221, and miR-338-3p bind to wild-type BRAF, while BRAF mutated genes decreased the expression level of these biological noncoding RNAs (Figure 1 and Table 1) (31, 52).

MiR-25, miR-181, miR-200b, and miR-92b are upregulated oncomiRs in melanoma. Similar to other miRNAs, they target particular genes, namely PTEN, a moderator gene of PI3K signaling pathway (25, 26). Multiple miRNAs, including miR-199a-5p and miR-1908, comprise the oncomiR group. Pencheva et al. studied this category and their targets and documented an essential marker, known as apolipoprotein E (ApoE), which is inhibited by the mentioned miRNAs. This protein plays its major role through suppressing metastasis. Due to the combination of ApoE and miRNAs, metastasis and angiogenesis are induced (27).

3. Results

As miRNAs play a key role in the adjustment of melanoma, recent studies have investigated their therapeutic applications. The findings have marked some of these miRNAs as therapeutic biomarkers. In a study by Segura et al. in 2011, miR-182 was investigated in melanoma cell lines of mice. Cells were inoculated by anti-miR-182, which targets miR-182. MITF, FOXO3, and CASP2, as miR-182 targets, increased the levels of gene expression and proteins. Consequently, overexpression of CASP2, a proapoptotic gene in the caspase family, induced melanoma cell apoptosis (Table 1) (1, 53).

Another study on the expression level of miR-219-5p showed that this miRNA could be used as a therapeutic factor in melanoma. MiR-219-5p targets Bcl-2, and its target is overexpressed as it is downregulated in melanoma. However, prevention of melanoma metastasis and cell proliferation is accompanied by miR-219-5p overexpression. Long et al. suggested this miRNA as an option for melanoma treatment (33).

In a study by Li et al. miR-625 was investigated given its role in various cancers, including prostate, breast, and gastric cancers. Considering some assumptions about miR-625 function in melanoma, Li et al. examined its accurate role in melanoma. They reported miR-625 downregulation in melanoma cancerous cells, which caused metastasis. Therefore, it was hypothesized that this miRNA could be used as a diagnostic and therapeutic biomolecule.

Likewise, another miRNA, miR-625, has its own target, namely sex-determining region Y-box 2 (SOX-2). SOX-2 stimulates cell proliferation and invasion when miR-625 is decreased. These findings, along with other prior investigations, represent the possibility of therapeutic application of miR-625 for melanoma (Table 1) (34).

Since drugs used for melanoma treatment are not sufficiently efficacious, more studies have been performed to determine novel methods of therapy. Therefore, importance of miRNAs in the efficacy of drugs (which develop drug-resistant and drug-sensitive cells) was underlined for treatment purposes. Among these miRNAs, miR-125a was introduced as a major biomarker in previous research.

Furthermore, Koetz-Ploch et al. showed that miR-125a was upregulated in melanoma and subsequently prevented apoptotic pathways by inhibiting proapoptotic elements. In addition, overexpression of miR-125a affected other signaling pathways, including TGF-β signaling pathway. They suggested this miRNA as a treatment component in melanoma cell lines, which are resistant to drugs (54).

4. Conclusions

MiRNAs are preferable in the diagnosis of primary and aggressive stages of melanoma. Although previous research has focused on these biomolecules and their efficacy in diagnosis, several investigations have aimed to introduce treatment methods for melanoma considering its rising incidence. In addition to their application in drugs, as mentioned earlier, several studies have documented multiple therapeutic miRNAs, including miR-625, miR-219-5p, and anti-miR-182 (1, 33, 34). Moreover, some diagnostic miRNAs can be used in therapy. For instance, in previous studies, miR-155, which is downregulated in melanoma, was injected in melanoma cell lines to increase its expression (1, 21, 22). Similar procedures can be executed for miR-193b as a practical therapeutic option (1). Considering the affirmative results of miRNA application in recent surveys and introduction of these small noncoding RNAs as feasible therapeutic markers, these molecular techniques should replace traditional methods according to research in this area.


  • 1.

    Aftab MN, Dinger ME, Perera RJ. The role of microRNAs and long non-coding RNAs in the pathology, diagnosis, and management of melanoma. Arch Biochem Biophys. 2014;563:60-70. doi: 10.1016/ [PubMed: 25065585].

  • 2.

    Cancer Genome Atlas N. Genomic Classification of Cutaneous Melanoma. Cell. 2015;161(7):1681-96. doi: 10.1016/j.cell.2015.05.044. [PubMed: 26091043].

  • 3.

    Masliah Planchon J, Garinet S, Pasmant E. RAS-MAPK pathway epigenetic activation in cancer: miRNAs in action. Oncotarget. 2016;7(25):38892-907. doi: 10.18632/oncotarget.6476. [PubMed: 26646588].

  • 4.

    Richtig G, Ehall B, Richtig E, Aigelsreiter A, Gutschner T, Pichler M. Function and Clinical Implications of Long Non-Coding RNAs in Melanoma. Int J Mol Sci. 2017;18(4). doi: 10.3390/ijms18040715. [PubMed: 28350340].

  • 5.

    Davar D, Tarhini AA, Gogas H, Kirkwood JM. Advances in adjuvant therapy: potential for prognostic and predictive biomarkers. Methods Mol Biol. 2014;1102:45-69. doi: 10.1007/978-1-62703-727-3_4. [PubMed: 24258973].

  • 6.

    Nikolaou V, Stratigos AJ, Tsao H. Hereditary nonmelanoma skin cancer. Semin Cutan Med Surg. 2012;31(4):204-10. doi: 10.1016/j.sder.2012.08.005. [PubMed: 23174490].

  • 7.

    Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-7. doi: 10.1001/archdermatol.2010.19. [PubMed: 20231499].

  • 8.

    Yamaguchi Y, Hearing VJ. Melanocytes and their diseases. Cold Spring Harb Perspect Med. 2014;4(5). doi: 10.1101/cshperspect.a017046. [PubMed: 24789876].

  • 9.

    Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8):1039-49. doi: 10.1200/JCO.2012.45.3753. [PubMed: 23401433].

  • 10.

    Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010;11(7):537-61. doi: 10.2174/138920210793175895. [PubMed: 21532838].

  • 11.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-97. [PubMed: 14744438].

  • 12.

    Tjwa M, Gu W, Wang X, Zhai C, Zhou T, Xie X. Biological basis of miRNA action when their targets are located in human protein coding region. PLoS ONE. 2013;8(5):63403. doi: 10.1371/journal.pone.0063403.

  • 13.

    Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5' UTR as in the 3' UTR. Proc Natl Acad Sci U S A. 2007;104(23):9667-72. doi: 10.1073/pnas.0703820104. [PubMed: 17535905].

  • 14.

    Satzger I, Mattern A, Kuettler U, Weinspach D, Niebuhr M, Kapp A, et al. microRNA-21 is upregulated in malignant melanoma and influences apoptosis of melanocytic cells. Exp Dermatol. 2012;21(7):509-14. doi: 10.1111/j.1600-0625.2012.01510.x. [PubMed: 22716245].

  • 15.

    Noguchi S, Mori T, Otsuka Y, Yamada N, Yasui Y, Iwasaki J, et al. Anti-oncogenic microRNA-203 induces senescence by targeting E2F3 protein in human melanoma cells. J Biol Chem. 2012;287(15):11769-77. doi: 10.1074/jbc.M111.325027. [PubMed: 22354972].

  • 16.

    Felicetti F, Errico MC, Segnalini P, Mattia G, Care A. MicroRNA-221 and -222 pathway controls melanoma progression. Expert Rev Anticancer Ther. 2008;8(11):1759-65. doi: 10.1586/14737140.8.11.1759. [PubMed: 18983236].

  • 17.

    Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, et al. The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. Cancer Res. 2008;68(8):2745-54. doi: 10.1158/0008-5472.CAN-07-2538. [PubMed: 18417445].

  • 18.

    Igoucheva O, Alexeev V. MicroRNA-dependent regulation of cKit in cutaneous melanoma. Biochem Biophys Res Commun. 2009;379(3):790-4. doi: 10.1016/j.bbrc.2008.12.152. [PubMed: 19126397].

  • 19.

    Bennett PE, Bemis L, Norris DA, Shellman YG. miR in melanoma development: miRNAs and acquired hallmarks of cancer in melanoma. Physiol Genomics. 2013;45(22):1049-59. doi: 10.1152/physiolgenomics.00116.2013. [PubMed: 24046283].

  • 20.

    Sun V, Zhou WB, Majid S, Kashani-Sabet M, Dar AA. MicroRNA-mediated regulation of melanoma. Br J Dermatol. 2014;171(2):234-41. doi: 10.1111/bjd.12989. [PubMed: 24665835].

  • 21.

    Noman MZ, Buart S, Romero P, Ketari S, Janji B, Mari B, et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res. 2012;72(18):4629-41. doi: 10.1158/0008-5472.CAN-12-1383. [PubMed: 22962263].

  • 22.

    Gaziel-Sovran A, Segura MF, Di Micco R, Collins MK, Hanniford D, Vega-Saenz de Miera E, et al. miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell. 2011;20(1):104-18. doi: 10.1016/j.ccr.2011.05.027. [PubMed: 21741600].

  • 23.

    Luo C, Tetteh PW, Merz PR, Dickes E, Abukiwan A, Hotz Wagenblatt A, et al. miR-137 inhibits the invasion of melanoma cells through downregulation of multiple oncogenic target genes. J Invest Dermatol. 2013;133(3):768-75. doi: 10.1038/jid.2012.357. [PubMed: 23151846].

  • 24.

    Migliore C, Petrelli A, Ghiso E, Corso S, Capparuccia L, Eramo A, et al. MicroRNAs impair MET-mediated invasive growth. Cancer Res. 2008;68(24):10128-36. doi: 10.1158/0008-5472.CAN-08-2148. [PubMed: 19074879].

  • 25.

    Melis C, Rogiers A, Bechter O, van den Oord JJ. Molecular genetic and immunotherapeutic targets in metastatic melanoma. Virchows Arch. 2017. doi: 10.1007/s00428-017-2113-3. [PubMed: 28357489].

  • 26.

    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135-47. doi: 10.1056/NEJMoa050092. [PubMed: 16291983].

  • 27.

    Pencheva N, Tran H, Buss C, Huh D, Drobnjak M, Busam K, et al. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell. 2012;151(5):1068-82. doi: 10.1016/j.cell.2012.10.028. [PubMed: 23142051].

  • 28.

    Segura MF, Greenwald HS, Hanniford D, Osman I, Hernando E. MicroRNA and cutaneous melanoma: from discovery to prognosis and therapy. Carcinogenesis. 2012;33(10):1823-32. doi: 10.1093/carcin/bgs205. [PubMed: 22693259].

  • 29.

    Boyle GM, Woods SL, Bonazzi VF, Stark MS, Hacker E, Aoude LG, et al. Melanoma cell invasiveness is regulated by miR-211 suppression of the BRN2 transcription factor. Pigment Cell Melanoma Res. 2011;24(3):525-37. doi: 10.1111/j.1755-148X.2011.00849.x. [PubMed: 21435193].

  • 30.

    Levy C, Khaled M, Iliopoulos D, Janas MM, Schubert S, Pinner S, et al. Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma. Mol Cell. 2010;40(5):841-9. doi: 10.1016/j.molcel.2010.11.020. [PubMed: 21109473].

  • 31.

    Pinto R, Strippoli S, De Summa S, Albano A, Azzariti A, Guida G, et al. MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors. Expert Opin Ther Targets. 2015;19(8):1027-35. doi: 10.1517/14728222.2015.1065818. [PubMed: 26156293].

  • 32.

    Sun M, Wang X, Tu C, Wang S, Qu J, Xiao S. microRNA-216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo. Cell Biol Int. 2017;41(12):1272-82. doi: 10.1002/cbin.10754. [PubMed: 28225180].

  • 33.

    Long J, Menggen Q, Wuren Q, Shi Q, Pi X. MiR-219-5p Inhibits the Growth and Metastasis of Malignant Melanoma by Targeting BCL-2. Biomed Res Int. 2017;2017:9032502. doi: 10.1155/2017/9032502. [PubMed: 28884131].

  • 34.

    Fang W, Fan Y, Fa Z, Xu J, Yu H, Li P, et al. microRNA-625 inhibits tumorigenicity by suppressing proliferation, migration and invasion in malignant melanoma. Oncotarget. 2017;8(8):13253-63. doi: 10.18632/oncotarget.14710. [PubMed: 28129648].

  • 35.

    Greenberg E, Hershkovitz L, Itzhaki O, Hajdu S, Nemlich Y, Ortenberg R, et al. Regulation of cancer aggressive features in melanoma cells by microRNAs. PLoS One. 2011;6(4):18936. doi: 10.1371/journal.pone.0018936. [PubMed: 21541354].

  • 36.

    Leibowitz-Amit R, Sidi Y, Avni D. Aberrations in the micro-RNA biogenesis machinery and the emerging roles of micro-RNAs in the pathogenesis of cutaneous malignant melanoma. Pigment Cell Melanoma Res. 2012;25(6):740-57. doi: 10.1111/pcmr.12018. [PubMed: 22958787].

  • 37.

    Fu TY, Chang CC, Lin CT, Lai CH, Peng SY, Ko YJ, et al. Let-7b-mediated suppression of basigin expression and metastasis in mouse melanoma cells. Exp Cell Res. 2011;317(4):445-51. doi: 10.1016/j.yexcr.2010.11.004. [PubMed: 21087605].

  • 38.

    Zhang K, Wong P, Duan J, Jacobs B, Borden EC, Bedogni B. An ERBB3/ERBB2 oncogenic unit plays a key role in NRG1 signaling and melanoma cell growth and survival. Pigment Cell Melanoma Res. 2013;26(3):408-14. doi: 10.1111/pcmr.12089. [PubMed: 23480537].

  • 39.

    Noguchi S, Mori T, Hoshino Y, Yamada N, Nakagawa T, Sasaki N, et al. Comparative study of anti-oncogenic microRNA-145 in canine and human malignant melanoma. J Vet Med Sci. 2012;74(1):1-8. [PubMed: 21836381].

  • 40.

    Georgantas R3, Streicher K, Luo X, Greenlees L, Zhu W, Liu Z, et al. MicroRNA-206 induces G1 arrest in melanoma by inhibition of CDK4 and Cyclin D. Pigment Cell Melanoma Res. 2014;27(2):275-86. doi: 10.1111/pcmr.12200. [PubMed: 24289491].

  • 41.

    Roberts JD. E2F1 amplication and genetic heterogeneity in melanoma. Cancer Biol Ther. 2006;5(6):691-2. doi: 10.4161/cbt.5.6.2926.

  • 42.

    Limon J, Dal Cin P, Sait SNJ, Karakousis C, Sandberg AA. Chromosome changes in metastatic human melanoma. Cancer Genet Cytogenet. 1988;30(2):201-11. doi: 10.1016/0165-4608(88)90186-0.

  • 43.

    Dar AA, Majid S, de Semir D, Nosrati M, Bezrookove V, Kashani-Sabet M. miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem. 2011;286(19):16606-14. doi: 10.1074/jbc.M111.227611. [PubMed: 21454583].

  • 44.

    Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995;14(9):1878-91. [PubMed: 7743995].

  • 45.

    Mazar J, Khaitan D, DeBlasio D, Zhong C, Govindarajan SS, Kopanathi S, et al. Epigenetic regulation of microRNA genes and the role of miR-34b in cell invasion and motility in human melanoma. PLoS One. 2011;6(9):24922. doi: 10.1371/journal.pone.0024922. [PubMed: 21949788].

  • 46.

    Asangani IA, Harms PW, Dodson L, Pandhi M, Kunju LP, Maher CA, et al. Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget. 2012;3(9):1011-25. doi: 10.18632/oncotarget.622. [PubMed: 22948084].

  • 47.

    Cruz J, Reis-Filho JS, Silva P, Lopes JM. Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas. Oncology. 2003;65(1):72-82. doi: 10.1159/000071207. [PubMed: 12837985].

  • 48.

    Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, et al. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res. 1998;58(22):5157-67. [PubMed: 9823327].

  • 49.

    Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med. 2015;373(20):1926-36. doi: 10.1056/NEJMoa1502583. [PubMed: 26559571].

  • 50.

    Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-84. doi: 10.1016/S1470-2045(15)70076-8. [PubMed: 25795410].

  • 51.

    De Unamuno Bustos B, Murria Estal R, Perez Simo G, de Juan Jimenez I, Escutia Munoz B, Rodriguez Serna M, et al. Towards personalized medicine in melanoma: Implementation of a clinical next-generation sequencing panel. Sci Rep. 2017;7(1):495. doi: 10.1038/s41598-017-00606-w. [PubMed: 28356599].

  • 52.

    Martorell-Calatayud A, Nagore E, Botella-Estrada R, Scherer D, Requena C, Serra-Guillen C, et al. Defining fast-growing melanomas: reappraisal of epidemiological, clinical, and histological features. Melanoma Res. 2011;21(2):131-8. doi: 10.1097/CMR.0b013e328342f312. [PubMed: 21183860].

  • 53.

    Huynh C, Segura MF, Gaziel-Sovran A, Menendez S, Darvishian F, Chiriboga L, et al. Efficient in vivo microRNA targeting of liver metastasis. Oncogene. 2011;30(12):1481-8. doi: 10.1038/onc.2010.523. [PubMed: 21102518].

  • 54.

    Koetz Ploch L, Hanniford D, Dolgalev I, Sokolova E, Zhong J, Diaz Martinez M, et al. MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway. Pigment Cell Melanoma Res. 2017;30(3):328-38. doi: 10.1111/pcmr.12578. [PubMed: 28140520].

Copyright © 2016, Journal of Skin and Stem Cell. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited