TY - JOUR
T1 - Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor
T2 - New insight to the pathophysiology of an aggressive brain tumor
AU - Suzuki, Mario
AU - Kondo, Akihide
AU - Ogino, Ikuko
AU - Arai, Hajime
AU - Tomita, Tadanori
AU - Sredni, Simone Treiger
N1 - Funding Information:
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.
Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
KW - AT/RT
KW - Hippo pathway
KW - TEAD4
KW - YAP1
KW - atypical teratoid/rhabdoid tumor
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UR - http://www.scopus.com/inward/citedby.url?scp=85007190436&partnerID=8YFLogxK
U2 - 10.1002/pbc.26398
DO - 10.1002/pbc.26398
M3 - Article
C2 - 27966820
AN - SCOPUS:85007190436
VL - 64
JO - Medical and Pediatric Oncology
JF - Medical and Pediatric Oncology
SN - 1545-5009
IS - 7
M1 - e26398
ER -
