Abstract
LIN28B drives neuroblastoma through suppression of let-7, which elevates MYCN levels.
Major finding: LIN28B drives neuroblastoma through suppression of let-7, which elevates MYCN levels.
Concept: Expression of LIN28B in the neural crest leads to neuroblastoma formation in 25% of mice.
Impact: These findings provide formal proof that LIN28B is an oncogene.
Lin-28 homolog B (LIN28B) is an RNA binding protein that inhibits let-7 microRNA (miRNA) biogenesis. Given that LIN28B amplification or overexpression has been observed in several tumor types and that let-7 miRNAs have tumor suppressor activity, LIN28B has been presumed to be an oncogene, but a role for LIN28B in tumorigenesis has not been demonstrated in vivo. Molenaar and colleagues identified a chromosome 6q21 amplicon that contained LIN28B in 3 high-risk neuroblastomas and observed selective upregulation of LIN28B in multiple neuroblastoma tumor series compared with other tumor types. Together with the finding that high LIN28B expression was significantly associated with lower overall survival in patients with neuroblastoma, these data suggest that LIN28B overexpression contributes to neuroblastoma development. Indeed, knockdown of LIN28B in neuroblastoma cell lines resulted in decreased cell viability and changes in morphology and gene expression consistent with differentiation into a neuroendocrine lineage, indicating that neuroblastoma cells are dependent on LIN28B. Consistent with the known role of LIN28B, let-7 miRNA levels were significantly upregulated following LIN28B knockdown and were found to be inversely correlated with LIN28B expression in primary neuroblastomas. However, MYCN, a putative let-7a target and known driver of neuroblastoma, was downregulated after LIN28B knockdown. Let-7a mimics decreased MYCN protein levels but did not affect MYCN mRNA levels, indicating that let-7 inhibits MYCN translation. Notably, 25% of transgenic mice expressing Lin28b in the neural crest developed tumors with low let-7 and high MYCN levels that had similar histology and location to human neuroblastomas, formally demonstrating that LIN28B is an oncogene. Although how LIN28B is upregulated in tumors lacking 6q21 amplification remains to be shown, these findings establish that a LIN28B–let-7–MYCN signaling axis plays a key role in the development of neuroblastoma.
