Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Abstract

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.

Letting the breaks off MYCN

“…It has been shown previously in neuroblastoma that let-7 expression is repressed by the LIN28B protein, which can bind the pri-miR let-7 (among other microRNAs) and prevent their processing into mature, active forms. 3 As a starting point, Powers et al 2 have shown genetically that LIN28B is not required for repression of let-7 function in MYCN-amplified neuroblastoma cell lines. Instead, the abundant MYCN RNA is sufficient to soak up let-7 and still leave enough mRNA to be translated into elevated MYCN protein.…”

“…Furthermore, the selective pressure in favour of the often extraordinarily high copy number of MYCN genes in neuroblastoma has remained obscure. Now, Powers et al 2 have probably solved the puzzle. The amplification of MYCN copy number produces enough mRNA to effectively titrate down the amount of let-7.…”

“…One still cannot minimize the importance of MYCN transcriptional activity in neuroblastoma, and to be fair, Powers et al 2 do not dispute this. Transgenic mouse models of MYCN expression, that have been so important in advancing our understanding of this tumour, do not include the 3′UTR of MYCN, but still have a near 100% penetrance of a tumour that phenocopies human neuroblastoma very accurately.…”

“…Does this mechanism also operate in other MYCN-amplified tumours, such as some rhabdomyosarcomas, medulloblastomas and retinoblastomas? Further, although the data from Powers et al 2 clearly indicate that the two mechanisms, MYCN transcription and MYCN sponging, both contribute to the development of high-risk neuroblastoma, it would be fascinating to know if the 3′UTR of MYCN has an independent function to promote or accelerate the onset of neuroblastoma in transgenic animal models. This would provide powerful evidence that this mechanism is critical to the development of the disease.…”

“…6 However, the let-7 sites in MYCN 3′UTR are not conserved in c-MYC. It may be that the let-7 sponge function is the first truly distinctive difference between MYCN and c-MYC, and this is only now evident because Powers et al 2 had the insight to consider that the MYCN RNA had a biological function beyond the translation of MYCN protein.…”