title: Constitutive RAC activation is not sufficient to initiate melanocyte neoplasia but accelerates malignant progression.
abstract: Deregulated Ras signaling initiates and maintains melanocyte neoplasia. The Rho-like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras/Raf/mitogen-activated protein kinase signaling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Furthermore, we did not detect an additive effect when combined with V600EBRAF, nor could V12RAC1 substitute for suppressed Pi3k signaling to restore melanoma progression. However, coexpression of V12RAC1 and oncogenic RAS accelerated tumor nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 (T-cell lymphoma invasion and metastasis 1) is overexpressed in melanoma tumor nodules in both zebrafish and humans. Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations.
authors: Cancer Research UK Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors: Lucy E
authors: LE
authors: Dalton
authors: Jivko
authors: J
authors: Kamarashev
authors: Irene
authors: I
authors: Barinaga-Rementeria Ramirez
authors: Gavin
authors: G
authors: White
authors: Angeliki
authors: A
authors: Malliri
authors: Adam
authors: A
authors: Hurlstone
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D018450:Disease Progression; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008544:Melanocytes / Q000473:pathology* / Q000502:physiology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D029961:Zebrafish Proteins; C582243:rac1a protein, zebrafish; D020830:rac1 GTP-Binding Protein