LIN28B is highly expressed in atypical teratoid/rhabdoid tumor (AT/RT) and suppressed through the restoration of SMARCB1.
BACKGROUND
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that almost exclusively develops in young children. AT/RT belongs to the embryonal brain tumor group, comprising primitive tumors recapitulating the early development of the central nervous system during embryogenesis. The loss of SMARCB1 protein expression is a hallmark of AT/RT pathogenesis. LIN28A/B is a key gene in embryonic development and for the maintenance of pluripotency in stem cells. LIN28B might be an important co-player in AT/RT pathogenesis, considering the primitive nature and young age onset of AT/RT.


METHODS
We explored the expression patterns of LIN28B in AT/RT and compared it with the expression in cortical dysplasia and medulloblastoma. The functional role of LIN28B was assessed using LIN28B-siRNAs in primary cultured AT/RT cells.


RESULTS
LIN28B is highly expressed in AT/RT compared with medulloblastoma and other embryonal tumors, whereas primary let-7g miRNA is down-regulated. AT/RT also showed higher expression of CCND1 and MYC, and lower expression of CDKN1C. The suppression of CCND1 expression and enhanced expression of CDKN1C were also observed. The knockdown of LIN28B decreased cell viability and proliferation, induced cell cycle arrest, and reduced migration in primary cultured AT/RT cells. Furthermore, we showed that the knockdown of LIN28B decreased the expression of other pluripotency-related genes (OCT4 and NANOG) and the mesenchymal-epithelial transition signature. We also transfected wild-type SMARCB1 into primary cultured AT/RT cells. The restoration of SMARCB1 in AT/RT cells decreased the expression of LIN28B and CCND1.


CONCLUSIONS
These results show that LIN28B might be regulated through SMARCB1; the loss of SMARCB1 protein in AT/RT results in the unopposed expression of LIN28B and related oncogenes such as CCND1, leading to tumorigenesis. Therefore, the strategic role of LIN28B in AT/RT might be utilized as an important therapeutic target.
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.
Seung Ah
SA
Choi
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.
Seung-Ki
SK
Kim
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea ; Department of Anatomy, Seoul National University College of Medicine, Seoul, 03080 Republic of Korea.
Ji Yeoun
JY
Lee
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.
Kyu-Chang
KC
Wang
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.
Chanhee
C
Lee
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.
Ji Hoon
JH
Phi
Atypical teratoid/rhabdoid tumor; LIN28B; SMARCB1