title: Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma.
abstract: Misexpression of stem cell-related genes may occur in some cancer cells, influencing patient's prognosis. This is the case of medulloblastoma, a common and clinically challenging malignant tumor of the central nervous system, where expression of the pluripotency factor, OCT4, is correlated with poor survival. A downstream target of OCT4, L1TD1 (LINE-1 type transposase domain-containing protein 1 family member), encodes a novel embryonic stem cell (ESC)-related protein involved in pluripotency and self-renewal of ESCs. L1TD1 is still poorly characterized and its expression pattern and function in cancer cells are virtually unknown. Although normally restricted to non-neoplastic undifferentiated cells and germ cells, we found that high L1TD1 expression also occurs in medulloblastoma cells, reaching levels similar to those found in ESCs, and is correlated with poor prognosis. Conversely to what is reported during normal cell differentiation, when differentiated cells remain healthy, despite L1TD1 downregulation, depletion of L1TD1 protein levels by targeted gene silencing significantly reduced medulloblastoma cell viability, inhibiting cell proliferation and inducing apoptosis. More strikingly, L1TD1 depletion downregulated expression of the neural stem cell markers, CD133 and Nestin, inhibited neurosphere generation capability, and sensitized medulloblastoma cells to temozolomide and cisplatin, two chemotherapeutic agents of clinical relevance in medulloblastoma treatment. Our findings provide insights about the contribution of pluripotency-related genes to a more aggressive tumor phenotype through their involvement in the acquisition of stem-like properties by cancer cells and point out L1TD1 as a potential therapeutic target in malignant brain tumors.
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: Márcia Cristina Teixeira
authors.initials: MC
authors.lastname: Santos
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: Patrícia Benites Gonçalves
authors.initials: PB
authors.lastname: Silva
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: Carolina Oliveira
authors.initials: CO
authors.lastname: Rodini
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: Gabriela
authors.initials: G
authors.lastname: Furukawa
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: David Santos
authors.initials: DS
authors.lastname: Marco Antonio
authors.affiliation: 2 Department of Biochemistry, Oxidative Stress Research Center, Federal University of Rio Grande do Sul , Porto Alegre, Brazil .
authors.forename: Alfeu
authors.initials: A
authors.lastname: Zanotto-Filho
authors.affiliation: 2 Department of Biochemistry, Oxidative Stress Research Center, Federal University of Rio Grande do Sul , Porto Alegre, Brazil .
authors.forename: José C F
authors.initials: JC
authors.lastname: Moreira
authors.affiliation: 1 Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil .
authors.forename: Oswaldo Keith
authors.initials: OK
authors.lastname: Okamoto
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C562346:L1TD1 protein, human; D064231:Nestin; C000606023:PROM1 protein, human; D010455:Peptides; D011506:Proteins; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide