title: HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features.
abstract: Melanoma is a heterogeneous tumor in which phenotype-switching and CD133 marker have been associated with metastasis promotion and chemotherapy resistance. CD133 positive (CD133+) subpopulation has also been suggested as putative cancer stem cell (CSC) of melanoma tumor. Human endogenous retrovirus type K (HERV-K) has been described to be aberrantly activated during melanoma progression and implicated in the etiopathogenesis of disease. Earlier, we reported that stress-induced HERV-K activation promotes cell malignant transformation and reduces the immunogenicity of melanoma cells. Herein, we investigated the correlation between HERV-K and the CD133+ melanoma cells during microenvironmental modifications.
  
  
  
  TVM-A12 cell line, isolated in our laboratory from a primary human melanoma lesion, and other commercial melanoma cell lines (G-361, WM-115, WM-266-4 and A375) were grown and maintained in the standard and stem cell media. RNA interference, Real-time PCR, flow cytometry analysis, self-renewal and migration/invasion assays were performed to characterize cell behavior and HERV-K expression.
  
  
  
  Melanoma cells, exposed to stem cell media, undergo phenotype-switching and expansion of CD133+ melanoma cells, concomitantly promoted by HERV-K activation. Notably, the sorted CD133+ subpopulation showed stemness features, characterized by higher self-renewal ability, embryonic genes expression, migration and invasion capacities compared to the parental cell line. RNA interference-mediated downregulation experiments showed that HERV-K has a decisive role to expand and maintain the CD133+ melanoma subpopulation during microenvironmental modifications. Similarly, non nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine were effective to restrain the activation of HERV-K in melanoma cells, to antagonize CD133+ subpopulation expansion and to induce selective high level apoptosis in CD133+ cells.
  
  
  
  HERV-K activation promotes melanoma cells phenotype-switching and is strictly required to expand and maintain the CD133+ melanoma cells with stemness features in response to microenvironmental modifications.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Ayele
authors.initials: A
authors.lastname: Argaw-Denboba
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Balestrieri
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133, Rome, Italy.
authors.forename: Annalucia
authors.initials: A
authors.lastname: Serafino
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cipriani
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bucci
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sorrentino
authors.affiliation: S.B.G.S.A. Istituto Superiore di Sanità (Italian National Institute of Health), Viale Regina Elena 299, 00161, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sciamanna
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambacurta
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.|Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sinibaldi-Vallebona
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy. matteucci@med.uniroma2.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Matteucci
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D020077:Endogenous Retroviruses / Q000502:physiology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000821:virology*; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000821:virology; D059016:Tumor Microenvironment; D014775:Virus Activation
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human
keywords: CD133; Cancer stem cell; HERV-K; Melanoma; Microenvironment; Retroelements