Abstract
Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown. Procedure: We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells. Results: TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4’s co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells. Conclusions: We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.
| Original language | English (US) |
|---|---|
| Article number | e26398 |
| Journal | Pediatric Blood and Cancer |
| Volume | 64 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2017 |
Funding
This work was supported by Graduate School Research Program from Juntendo University, Juntendo University Research Institute for Disease of Old Ages, and the Rally Foundation for Childhood Cancer Research in memory of Hailey Trainer. We thank Miyuki Kunichika, Naira Margarian DVM, PhD, Lin Li MD, MSc, and Dorina Veliceasa, PhD, for technical assistance, and Jessica Jacubowski, BSc, for editorial support. We also thank all the patients, their families, and the people who work for our patients. The authors declare that there is no conflict of interest.
Keywords
- AT/RT
- Hippo pathway
- TEAD4
- YAP1
- atypical teratoid/rhabdoid tumor
ASJC Scopus subject areas
- Hematology
- Oncology
- Pediatrics, Perinatology, and Child Health
