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.

L1TD1 - a prognostic marker for colon cancer

“…Expression of L1TD1 at high levels in colon cancer cells led us to hypothesize that high expression of L1TD1 in colon cancer might be associated with prognosis. Earlier reports have demonstrated the association of stem cell pluripotency factors with poor prognosis in different cancer types, including medulloblastoma [30] and seminoma [15]. Interestingly, our results were in contrast with previous studies, suggesting that in colon cancer, high expression of L1TD1 is linked to better prognosis.…”

“…This points to the potential participation of L1TD1 ’s interaction partners in the contrasting prognostic outcome. This was further supported by a recent study in medulloblastoma, showing an association of high L1TD1 expression with poor clinical outcome and significant co-expression between L1TD1 and its interaction partner OCT4 [30]. Together, these findings suggest that the co-expression of L1TD1 with its interaction partners might be required for manifesting an aggressive and detrimental phenotype.…”

“…Expression of L1TD1 has earlier been reported to be highly specific to embryonic stem cells [10], brain [29], and colon (Additional file 1: Figure S7). Besides these healthy tissues, L1TD1 expression has also been reported in seminoma [10], embryonic carcinomas [10], medulloblastoma [30], and colon adenocarcinoma (Additional file 1: Figures S3 and S7). Expression of L1TD1 at high levels in colon cancer cells led us to hypothesize that high expression of L1TD1 in colon cancer might be associated with prognosis.…”

SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers

“…It is highly expressed in medulloblastoma cells where it is associated with cell viability, chemotherapeutic drug resistance and stem cell-like properties [38]. …”

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

“…For this particular purpose, a better knowledge of the basic biology of this important embryonal CNS tumor is crucial. Previous independent studies have shown an intriguing abnormal expression of the pluripotency-related genes POU5F1 / OCT4 [7], LIN28B [8], SOX2 [9] and L1TD1 [10], in medulloblastoma. In all cases, an aberrant overexpression of either gene was significantly correlated with poor survival.…”