The human homologue of Dictyostelium discoideum phg1A is expressed by human metastatic melanoma cells.
Tumour cannibalism is a characteristic of malignancy and metastatic behaviour. This atypical phagocytic activity is a crucial survival option for tumours in conditions of low nutrient supply, and has some similarities to the phagocytic activity of unicellular microorganisms. In fact, Dictyostelium discoideum has been used widely as a model to study phagocytosis. Recently, phg1A has been described as a protein that is primarily involved in the phagocytic process of this microorganism. The closest human homologue to phg1A is transmembrane 9 superfamily protein member 4 (TM9SF4). Here, we report that TM9SF4 is highly expressed in human malignant melanoma cells deriving from metastatic lesions, whereas it is undetectable in healthy human tissues and cells. TM9SF4 is predominantly expressed in acidic vesicles of melanoma cells, in which it co-localizes with the early endosome antigens Rab5 and early endosome antigen 1. TM9SF4 silencing induced marked inhibition of cannibal activity, which is consistent with a derangement of intracellular pH gradients, with alkalinization of acidic vesicles and acidification of the cell cytosol. We propose TM9SF4 as a new marker of malignancy, representing a potential new target for anti-tumour strategies with a specific role in tumour cannibalism and in the establishment of a metastatic phenotype.
Lozupone
Francesco
F
Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. francesco.lozupone@iss.it
Perdicchio
Maurizio
M
Brambilla
Daria
D
Borghi
Martina
M
Meschini
Stefania
S
Barca
Stefano
S
Marino
Maria Lucia
ML
Logozzi
Mariantonia
M
Federici
Cristina
C
Iessi
Elisabetta
E
de Milito
Angelo
A
Fais
Stefano
S
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004023:Dictyostelium / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics; D017385:Sequence Homology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C416668:Phg1 protein, Dictyostelium discoideum; D020033:Protein Isoforms; C547837:TM9SF4 protein, human