Abstract 3107: The role of LIN28 in atypical teratoid rhabdoid tumor (ATRT) pathogenesis

Abstract

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant brain tumor developing almost exclusively in children. It belongs to the embryonal brain tumor group which consists of primitive tumors recapitulating early embryogenesis of nervous system. It is known that loss of INI protein expression is the hallmark of ATRT pathogenesis. LIN28 is a key gene in embryonic development and maintenance of pluripotency in stem cells. Considering the primitive nature and young age onset of ATRT, LIN28 may be an important co-player in ATRT pathogenesis. We explored the expression and functional role of LIN28 in ATRT. In tumor tissues, LIN28 is highly expressed in ATRT compared with medulloblastomas, another embroynal tumor, whereas primary let-7 microRNA is down-regulated in ATRT. ATRT also showed higher expression of CCND1 and MYC and lower expression of CDKN1C. Knockdown of LIN28 with siRNA in ATRT cell lines resulted decreased cell viability, proliferation, and migration capability. Suppression of CCND1 and MYC expression and enhanced expression of CDKN1C were also observed. Knockdown of LIN28 lead to decreased expression of other pulripotency genes (OCT4 and NANOG) and signature of mesenchymal-epithelial transition was observed after suppression of LIN28. We then introduced wild-type INI1 into ATRT cells by transfection. Restoration of INI in ATRT cell lines lead to decreased expression of LIN28 and CCND1. These results showed that LIN28 is regulated by INI1 and that loss of INI1 protein in ATRT results in unopposed expression of LIN28 and related oncogenes such as CCND1, leading to tumorigenesis. Therefore, the strategic role of LIN28 in ATRT may be utilized as an important therapeutic target. Citation Format: Ji Hoon Phi, Seung Ah Choi, Yong Hwy Kim, Young-Hoon Kim, Chul-Kee Park, Kyu-Chang Wang, Seung-Ki Kim. The role of LIN28 in atypical teratoid rhabdoid tumor (ATRT) pathogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2014-3107