title: Prognostic significance of Fbw7 in human melanoma and its role in cell migration.
abstract: The E3 ubiquitin ligase Fbw7 (F-box and WD repeat domain-containing 7) is broadly considered as a tumor suppressor because of its role in the turnover of several well-known oncoproteins. However, the role of Fbw7 in melanomagenesis is not clear. To investigate the expression profile and biological functions of Fbw7 in melanoma, we examined Fbw7 expression level using melanoma tissue microarray and immunohistochemistry. Our data showed that Fbw7 expression is significantly reduced in primary melanoma compared with dysplastic nevi (P=0.020) and further reduced in metastatic melanoma compared with primary melanoma (P=0.011). Furthermore, we observed a strong correlation between negative Fbw7 expression and a worse 5-year survival of melanoma patients (P=0.015). We also found that both Fbw7 protein and mRNA expression was significantly reduced in nine melanoma cell lines compared with normal melanocytes. Moreover, our in vitro studies showed a remarkable increase of cell migration and stress fiber formation in Fbw7 knockdown cells, and treatment of selective MEK (MAPK/ERK kinase) inhibitor abrogated Fbw7α knockdown-induced melanoma cell migration. Taken together, our findings indicate that Fbw7 has an important role in melanoma progression, and it inhibits melanoma cell migration through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and may serve as a prognostic marker.
authors: Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Yabin
authors: Y
authors: Cheng
authors: Guangdi
authors: G
authors: Chen
authors: Magdalena
authors: M
authors: Martinka
authors: Vincent
authors: V
authors: Ho
authors: Gang
authors: G
authors: Li
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004416:Dysplastic Nevus Syndrome / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases; D020929:Mitogen-Activated Protein Kinase Kinases