Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Author(s)

Teixeira Santos, Marcia Cristina ^[1] ; Goncalves Silva, Patricia Benites ^[1] ; Rodini, Carolina Oliveira ^[1] ; Furukawa, Gabriela ^[1] ; Marco Antonio, David Santos ^[1] ; Zanotto-Filho, Alfeu ^[2] ; Moreira, Jose C. F. ^[2] ; Okamoto, Oswaldo Keith ^[1]

Affiliation

^[1] Univ Sao Paulo, Biosci Inst, Dept Genet & Evolutionary Biol, Human Genome & Stem Cell Res Ctr, BR-05508090 Sao Paulo - Brazil

^[2] Univ Fed Rio Grande do Sul, Oxidat Stress Res Ctr, Dept Biochem, Porto Alegre, RS - Brazil

• Document type: Journal article
• Source: STEM CELLS AND DEVELOPMENT; v. 24, n. 22, p. 2700-2708, NOV 15 2015.
• Web of Science Citations: 4

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. (AU)

• FAPESP's process: 11/10001-9 - Contribution of mesenchymal stem cells to tumor development
• Grantee: Carolina de Oliveira Rodini
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/17566-7 - Pluripotency factor OCT4A and aggressiveness of human medulloblastoma
• Grantee: Patrícia Benites Gonçalves da Silva
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 10/52686-5 - E2F2 transcription factor and expression of proto-oncogenes in human embryonic stem cells
• Grantee: Oswaldo Keith Okamoto
• Support type: Regular Research Grants
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/51588-2 - Functional characterization of the LIN28 protein in tumorigenesis of the central nervous system
• Grantee: Márcia Cristina Teixeira dos Santos
• Support type: Scholarships in Brazil - Post-Doctorate