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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

Relative expression of mRNAs and miRNAs in cortical dysplasia (CD), medulloblastoma (MB) and AT/RT clinical samples. The relative expression of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, CDKN1C and MYC was detected using RT-qPCR. The levels of Lin28B and CCND1were upregulated, while the levels ofpri-let-7g, and CDKN1C were significantly down-regulated in AT/RT. The expression of LIN28B, rather than LIN28A, is more represented in AT/RT compared with CD and MB. *P < 0.05; **P < 0.01. Error bars represent ±SD
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Fig1: Relative expression of mRNAs and miRNAs in cortical dysplasia (CD), medulloblastoma (MB) and AT/RT clinical samples. The relative expression of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, CDKN1C and MYC was detected using RT-qPCR. The levels of Lin28B and CCND1were upregulated, while the levels ofpri-let-7g, and CDKN1C were significantly down-regulated in AT/RT. The expression of LIN28B, rather than LIN28A, is more represented in AT/RT compared with CD and MB. *P < 0.05; **P < 0.01. Error bars represent ±SD

Mentions: We investigated the relative levels of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, and CDKN1C expression using RT-qPCR. The relative expression of LIN28A (3.8–156.9-fold; p = 0.009), LIN28B (4.1–76.9-fold; p = 0.012) and CCND1 (5.7–126.0-fold; p = 0.009) were higher in AT/RT tissues, compared with cortical dysplasia tissues, (Fig. 1; Table 2). The expression of pri-let-7g (0.4–1.9-fold; p = 0.517), mature let-7g (0.0–0.3-fold; p = 1.000) and CDKN1C(0.2–9.1-fold; p = 0.864) were similar in AT/RT tissues. The expression of LIN28B (p = 0.008), CCND1 (p = 0.013), pri-let-7g (p = 0.007), and CDKN1C (p = 0.036) were significantly higher in AT/RT tissues than in MB tissues. This difference was not observed for LIN28A (p = 0.441) and mature-let-7g (p = 0.075). We next examined protein expression using immunochemistry and western blot analysis. The results of immunohistochemistry showed that LIN28B protein expression was predominantly detected in AT/RT in MB tissues compared with LIN28A (Fig. 2a). The CCND1 and CDKN1C expression patterns were mutually exclusive in AT/RT and MB tissues. To further confirm these findings, we performed western blot analysis. The expression patterns of LIN28A, LIN28B, CCND1 and CDKN1C were remarkably similar to the RT-qPCR and immunochemistry results (Fig. 2b). Taken together, these data show that the expression of LIN28B is more specific than LIN28A in AT/RT.Fig. 1


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)

Relative expression of mRNAs and miRNAs in cortical dysplasia (CD), medulloblastoma (MB) and AT/RT clinical samples. The relative expression of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, CDKN1C and MYC was detected using RT-qPCR. The levels of Lin28B and CCND1were upregulated, while the levels ofpri-let-7g, and CDKN1C were significantly down-regulated in AT/RT. The expression of LIN28B, rather than LIN28A, is more represented in AT/RT compared with CD and MB. *P < 0.05; **P < 0.01. Error bars represent ±SD
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Related In: Results  -  Collection

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Fig1: Relative expression of mRNAs and miRNAs in cortical dysplasia (CD), medulloblastoma (MB) and AT/RT clinical samples. The relative expression of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, CDKN1C and MYC was detected using RT-qPCR. The levels of Lin28B and CCND1were upregulated, while the levels ofpri-let-7g, and CDKN1C were significantly down-regulated in AT/RT. The expression of LIN28B, rather than LIN28A, is more represented in AT/RT compared with CD and MB. *P < 0.05; **P < 0.01. Error bars represent ±SD
Mentions: We investigated the relative levels of LIN28A, LIN28B, pri-let-7g, mature let-7g, CCND1, and CDKN1C expression using RT-qPCR. The relative expression of LIN28A (3.8–156.9-fold; p = 0.009), LIN28B (4.1–76.9-fold; p = 0.012) and CCND1 (5.7–126.0-fold; p = 0.009) were higher in AT/RT tissues, compared with cortical dysplasia tissues, (Fig. 1; Table 2). The expression of pri-let-7g (0.4–1.9-fold; p = 0.517), mature let-7g (0.0–0.3-fold; p = 1.000) and CDKN1C(0.2–9.1-fold; p = 0.864) were similar in AT/RT tissues. The expression of LIN28B (p = 0.008), CCND1 (p = 0.013), pri-let-7g (p = 0.007), and CDKN1C (p = 0.036) were significantly higher in AT/RT tissues than in MB tissues. This difference was not observed for LIN28A (p = 0.441) and mature-let-7g (p = 0.075). We next examined protein expression using immunochemistry and western blot analysis. The results of immunohistochemistry showed that LIN28B protein expression was predominantly detected in AT/RT in MB tissues compared with LIN28A (Fig. 2a). The CCND1 and CDKN1C expression patterns were mutually exclusive in AT/RT and MB tissues. To further confirm these findings, we performed western blot analysis. The expression patterns of LIN28A, LIN28B, CCND1 and CDKN1C were remarkably similar to the RT-qPCR and immunochemistry results (Fig. 2b). Taken together, these data show that the expression of LIN28B is more specific than LIN28A in AT/RT.Fig. 1

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