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signaling","Organ: skin","CellType: cancer cell","PMID: 19708915","PMID: 20067521","Notes: Headnote: Melanoma is the most aggressive form of skin cancer caused by malignant transformation of melanocytes. It accounts for only 4-7% of all skin malignancies; yet, it is responsible for about 80% of all skin tumor deaths. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The exposure to ultraviolet radiation is one of the primary triggers of melanoma.    Signaling description: A family history of the disease is identified in 10% of all cases and associated with CDKN2A and CDK4 mutations. In addition, important genetic risk factors may be polymorphisms of the MC1R gene. Germline mutations of MC1R are found in 80% of individuals with red hair color, fair skin, and poor tanning. The highest risk of melanoma incidence is in populations with fair skin types with low melanin production. Melanin is an important chromophore in the skin and is able to absorb ultraviolet (UV) radiation and visible light; it is also able to scavenge molecular oxygen and hydroxyl radicals thereby protecting DNA from UV damage. UV induces malignant changes in the skin through direct DNA damage, impairing cutaneous immune response, inducing local growth factors, and giving rise to reactive oxygen species which cause DNA damage. UV radiation stimulates skin keratinocytes to release POMC, which binds to the melanocyte receptor MC1R resulting in the expression of MITF, a master regulator of melanocyte function which also serves as an oncogene in melanoma cells. WNT3A/CTNNB1 signaling also induces MITF expression. MITF regulates the expression of genes such as TYR, TYRP1, DCT, MLANA, PMEL, RAB27A, and others and is responsible for melanin production and transportation to keratinocytes. In melanoma, the synthesis of melanin is continued but transportation of melanin to keratinocytes is disrupted due to the loss of normal melanocyte-keratinocyte junctions. Several hypotheses point to the pro-oncogenic effect of melanin in melanoma cells, but the exact mechanism is unknown. MITF plays both cancer-promoting and cancer-inhibiting roles in melanoma. MITF has the ability to upregulate transcription of melanoma-promoting genes (CCND1, BCL2, and MET) and also melanoma-repressing genes (CDKN2A, CDKN1A, and DIAPH1). Many melanocytic signaling pathways are initiated via activation of KIT receptor that triggers MAPK and PI3K pathway activation. KIT aberrations are found in 28-39% of melanoma cases. The mutagenic activation of the MAPK pathway is observed in up to 90% of melanoma cases and is most commonly achieved via mutations in NRAS or BRAF. In addition, PTEN is mutated in up to 10-30% of melanoma cases. 43-50% of melanoma cases have activated AKT3 due to mutation or gene amplification. CCND1, CDKN2B, TP53, and MDM2 may also be mutated. Furthermore, constant MAPK activation drives cell cycle progression and antiapoptotic signaling. BCL2, MCL1, BCL2L1, BCL2L11, and BIRC7 are found to be constantly activated. BAX and APAF1 are repressed. Metastatic progression is associated with the loss of E-cadherin (CDH1) and increased expression of N-cadherin (CDH2), vitronectin receptor (integrin), and matrix metalloproteinases (MMPs). The activation of NODAL plays a role in melanocyte dedifferentiation and is regulated by NOTCH4 signaling. POU5F1, driven by EPAS1, also plays a role in dedifferentiation. WNT5A is overexpressed in melanoma and downregulates CDH1; while, the metastasis suppressor KISS1 upregulates VIM and CD44 which is a tumor homing and metastasis antigen. Additionally, autocrine/paracrine signaling and intercellular interactions are important in melanoma progression, including IGF1/IGF1R, HGF/MET, VEGFA /FLT1, VEGFA/KDR, PGF/FLT1, PGF/KDR, EFNA1/EPHA2, EDN3/EDNRB, EGF/EGFR, FGF1/FGFR1, IL8/CXCR1/CXCR2, CXCL12/CXCR4, and PLAU/PLAUR interactions.    Outcome effects: Following exposure to UV radiation multiple molecular alterations in signaling pathways lead to block of apoptosis, a","PMID: 20079807","PMID: 19571822","PMID: 18927540","NodeType: Pathway","CellType: melanocyte","Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin","Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-c6cbe021-c7d0-473c-9421-fd293590cccc","PMID: 22046555","Organ_System: integumentary system","PMID: 12778131","Description: Melanoma is the most aggressive form of skin cancer. Pathway is built manually using published studies.","PMID: 16822996","PMID: 18083379","PMID: 19056669","Source: 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