title: eIF4E is an adverse prognostic marker of melanoma patient survival by increasing melanoma cell invasion.
abstract: Human cutaneous melanoma is a devastating skin cancer because of its invasive nature and high metastatic potential. We used tissue microarray to study the role of human eukaryotic translation initiation factor 4E (eIF4E) in melanoma progression in 448 melanocytic lesions and found that high eIF4E expression was significantly increased in primary melanomas compared with dysplastic nevi (P<0.001), and further increased in metastatic melanomas (P<0.001). High eIF4E expression was associated with melanoma thickness (P=0.046), and poor overall and disease-specific 5-year survival of all, and primary melanoma patients, especially those with tumors ≥1 mm thick. Multivariate Cox regression analysis revealed that eIF4E is an independent prognostic marker. eIF4E knockdown (KD) in melanoma cells resulted in a significant increase in apoptosis (sub-G1 populations) and decrease in cell proliferation, and also resulted in downregulation of mesenchymal markers and upregulation of E-cadherin. In addition, eIF4E KD led to a decrease in melanoma cell invasion, matrix metalloproteinase-2 expression and activity, c-myc and BCL2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Taken together, our data suggest that the eIF4E may promote melanoma cell invasion and metastasis, and may also serve as a promising prognostic marker and a potential therapeutic target for melanoma.
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Department of Surgery, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: shahramk1@yahoo.com.
authors.forename: Shahram
authors.initials: S
authors.lastname: Khosravi
authors.affiliation: Department of Surgery, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tam
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Gholamreza S
authors.initials: GS
authors.lastname: Ardekani
authors.affiliation: Department of Pathology, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Martinka
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McElwee
authors.affiliation: Department of Surgery, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D012044:Regression Analysis; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D039561:Eukaryotic Initiation Factor-4E