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LIN28B is highly expressed in atypical teratoid/rhabdoid tumor (AT/RT) and suppressed through the restoration of SMARCB1.

Choi SA, Kim SK, Lee JY, Wang KC, Lee C, Phi JH - Cancer Cell Int. (2016)

Bottom Line: The knockdown of LIN28B decreased cell viability and proliferation, induced cell cycle arrest, and reduced migration in primary cultured AT/RT cells.The restoration of SMARCB1 in AT/RT cells decreased the expression of LIN28B and CCND1.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Regulation of pluripotent stem cell, differentiation and epithelial and mesenchymal cell-related gene expression through LIN28B knockdown. a After LIN28B knockdown, all pluripotent stem cell-related gene expression was reduced in SNU-AT/RT4, and SOX2 and NCAM was increased in SNU-AT/RT3. b The expression of GFAP, Tuj1 and O4 was variable in AT/RT cells. c The level of E-cadherin and ZO-1 was elevated and Vimentin was decreased in both AT/RT cell lines. Error bars represent ±SD
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Fig5: Regulation of pluripotent stem cell, differentiation and epithelial and mesenchymal cell-related gene expression through LIN28B knockdown. a After LIN28B knockdown, all pluripotent stem cell-related gene expression was reduced in SNU-AT/RT4, and SOX2 and NCAM was increased in SNU-AT/RT3. b The expression of GFAP, Tuj1 and O4 was variable in AT/RT cells. c The level of E-cadherin and ZO-1 was elevated and Vimentin was decreased in both AT/RT cell lines. Error bars represent ±SD

Mentions: RT-qPCR analysis showed that expression of OCT4, MYC, NANOG, and KLF4 were decreased in SNU-AT/RT3and SNU-AT/RT4 (Fig. 5a). The pattern of SOX2 expression was variable, with an increase in SNU-AT/RT3 and a decrease in SNU-AT/RT4. In SNU-AT/RT3, the increased expression of SOX2 and NCAM were observed after LIN28 siRNA treatment. This increase likely reflects enhanced neuroglia differentiation, as SOX2 is also a marker of immature glia and NCAM is a marker of early neurogenesis. To determine whether the suppression of LIN28B and other pluripotency-related genes leads to cellular differentiation, we confirmed the mRNA expression of GFAP, TUJ1 and O4 after LIN28B suppression (Fig. 5b). Although the changes in expression did not convey a solid pattern, general increase in the expression of differentiation markers were observed.Fig. 5


LIN28B is highly expressed in atypical teratoid/rhabdoid tumor (AT/RT) and suppressed through the restoration of SMARCB1.

Choi SA, Kim SK, Lee JY, Wang KC, Lee C, Phi JH - Cancer Cell Int. (2016)

Regulation of pluripotent stem cell, differentiation and epithelial and mesenchymal cell-related gene expression through LIN28B knockdown. a After LIN28B knockdown, all pluripotent stem cell-related gene expression was reduced in SNU-AT/RT4, and SOX2 and NCAM was increased in SNU-AT/RT3. b The expression of GFAP, Tuj1 and O4 was variable in AT/RT cells. c The level of E-cadherin and ZO-1 was elevated and Vimentin was decreased in both AT/RT cell lines. Error bars represent ±SD
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4836086&req=5

Fig5: Regulation of pluripotent stem cell, differentiation and epithelial and mesenchymal cell-related gene expression through LIN28B knockdown. a After LIN28B knockdown, all pluripotent stem cell-related gene expression was reduced in SNU-AT/RT4, and SOX2 and NCAM was increased in SNU-AT/RT3. b The expression of GFAP, Tuj1 and O4 was variable in AT/RT cells. c The level of E-cadherin and ZO-1 was elevated and Vimentin was decreased in both AT/RT cell lines. Error bars represent ±SD
Mentions: RT-qPCR analysis showed that expression of OCT4, MYC, NANOG, and KLF4 were decreased in SNU-AT/RT3and SNU-AT/RT4 (Fig. 5a). The pattern of SOX2 expression was variable, with an increase in SNU-AT/RT3 and a decrease in SNU-AT/RT4. In SNU-AT/RT3, the increased expression of SOX2 and NCAM were observed after LIN28 siRNA treatment. This increase likely reflects enhanced neuroglia differentiation, as SOX2 is also a marker of immature glia and NCAM is a marker of early neurogenesis. To determine whether the suppression of LIN28B and other pluripotency-related genes leads to cellular differentiation, we confirmed the mRNA expression of GFAP, TUJ1 and O4 after LIN28B suppression (Fig. 5b). Although the changes in expression did not convey a solid pattern, general increase in the expression of differentiation markers were observed.Fig. 5

Bottom Line: The knockdown of LIN28B decreased cell viability and proliferation, induced cell cycle arrest, and reduced migration in primary cultured AT/RT cells.The restoration of SMARCB1 in AT/RT cells decreased the expression of LIN28B and CCND1.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, Seoul, 03080 Republic of Korea.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus