Abstract
Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.
Highlights
Atypical teratoid rhabdoid tumor (AT/RT) is one of the most aggressive pediatric tumors of the central nervous system [1]
We investigated the mRNA expression of LIN28A and LIN28B in AT/RT tumors by qPCR, using pediatric pilocytic astrocytoma (PA) as a comparator
We found that primary AT/RT tumors expressed high level LIN28A and LIN28B mRNA (Figure 1B, p=0.002 for LIN28A and p=0.006 for LIN28B by Mann-Whitney test) compared to PA tumors
Summary
Atypical teratoid rhabdoid tumor (AT/RT) is one of the most aggressive pediatric tumors of the central nervous system [1]. Despite the use of intensive multimodality treatment, the overall survival rate is less than 50 percent www.impactjournals.com/oncotarget [2]. Due to its aggressive nature and resistance to existing treatment, there is a significant need for novel therapeutic targets in AT/RT. SMARCB1 is a component of the SWI/SNF chromatin remodeling complex, and loss of function of SMARCB1 can dysregulate thousands of genes across the genome [6]. While mutations at this locus are the defining genetic alteration of AT/RT, much of the biology contributing to the development and aggressiveness of AT/RT is poorly understood [7]
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