Pleiotropic function of ezrin in human metastatic melanomas.
The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors.
Federici
Cristina
C
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Brambilla
Daria
D
Lozupone
Francesco
F
Matarrese
Paola
P
de Milito
Angelo
A
Lugini
Luana
L
Iessi
Elisabetta
E
Cecchetti
Serena
S
Marino
Marialucia
M
Perdicchio
Maurizio
M
Logozzi
Mariantonia
M
Spada
Massimo
M
Malorni
Walter
W
Fais
Stefano
S
D000818:Animals; D015153:Blotting, Western; D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D025581:Neurofibromin 2 / Q000378:metabolism; D010587:Phagocytosis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000099149:Ezrin; D052118:Lysosomal-Associated Membrane Protein 1
D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D051907:Lysosomal Membrane Proteins; D025581:Neurofibromin 2; D000099149:Ezrin; C497483:CD44 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1