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

Seung Ah Choi,Chanhee Lee,Ji Hoon Phi,Kyu-Chang Wang,Seung-Ki Kim,Ji Yeoun Lee

doi:10.1186/s12935-016-0307-4

Abstract

BackgroundAtypical 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.MethodsWe 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.ResultsLIN28B 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0307-4) contains supplementary material, which is available to authorized users.

Highlights

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that almost exclusively develops in young children
As the loss of function of SMARCB1 is a genetic hallmark of AT/RT, we explored the relationship of SMARCB1 and LIN28B
The restoration of SMARCB1 expression in AT/RT cells suppressed LIN28B over expression and decreased cell proliferation. These results indicate that LIN28B/let-7g/CCND1 is a key factor in AT/RT tumorigenesis, and the loss of SMARCB1 leads to LIN28B overexpression

Summary

Introduction

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that almost exclusively develops in young children. Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that predominantly develops in children. Recent studies have demonstrated that LIN28A/B are highly expressed in AT/RT primary tumors and cell lines, and the knockdown of LIN28A suppresses AT/RT growth and tumorigenicity [4]. The activation of LIN28A/B occurs in several different primary human tumors and plays an important role in cancer progression and metastasis [5, 6], involving stemness [7] through the negative regulation of the maturation of let-7 microRNA (miRNA) family members [8]. We reported reciprocal expression between LIN28 and miRNA let-7g in AT/RT cells in a previous study [14]

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Results

Conclusion