Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo

Abstract

Human tumors are characterized by widespread reduction in microRNA (miRNA) expression, although it is unclear how such changes come about and whether they have an etiological role in the disease. Importantly, miRNA knockdown has been shown to enhance the tumorigenic potential of human lung adenocarcinoma cells. A defect in miRNA processing is one possible mechanism for global downregulation. To explore this possibility in more detail in vivo, we have manipulated Dicer1 gene dosage in a mouse model of retinoblastoma. We show that although monoallelic loss of Dicer1 does not affect normal retinal development, it dramatically accelerates tumor formation on a retinoblastoma-sensitized background. Importantly, these tumors retain one wild-type Dicer1 allele and exhibit only a partial decrease in miRNA processing. Accordingly, in silico analysis of human cancer genome data reveals frequent hemizygous, but not homozygous, deletions of DICER1. Strikingly, complete loss of Dicer1 function in mice did not accelerate retinoblastoma formation. miRNA profiling of these tumors identified members of the let-7 and miR-34 families as candidate tumor suppressors in retinoblastoma. We conclude that Dicer1 functions as a haploinsufficient tumor suppressor. This finding has implications for cancer etiology and cancer therapy.

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…Further to this, monoallelic Dicer1 loss exerted an effect, which indicates that Dicer1 is also a haploinsufficient tumor suppressor gene. These findings are consistent with the role of Dicer1 in other tumor types (Arrate et al 2010;Lambertz et al 2010;Nittner et al 2012;Yoshikawa et al 2013;Zhang et al 2014).…”

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

“…30 Furthermore, hemizygous deletion of DICER1 occurs in 27% of the human cancers, 14 and recent studies have demonstrated that DICER1 is a haploinsufficent tumour suppressor in both lung cancer and retinoblastoma. 13,14 This is supported by a recent report, in which DICER was shown to be specifically targeted by the miR-103/107 family in breast cancer, where overexpression of miR-103/107 members induced epithelial-to-mesenchymal transition via reduced levels of miR-200b. 31 Therefore, direct regulation of DICER1 levels by miR-9 overexpression could contribute to transformation and invasiveness in HL.…”

“…Interestingly, although the function of DICER1 as a key enzyme in miRNA biogenesis is well characterized, recent reports have demonstrated that DICER acts as a haploinsufficent tumour suppressor in lung cancer and retinoblastoma. 13,14 On the other hand, HuR is a well-documented regulator of cytokine expression acting via direct binding to ARE sequence motifs. AREs are short AU-rich sequences in the 3 0 untranslated region (UTR) of several mRNAs, especially cytokines and growth-related genes that affect mRNA stability and translation.…”

Posttranscriptional regulation of miRNAs in the DNA damage response

“…and co-workers discovered that monoallelic loss of Dicer1 had no effect on the normal retinal development of mice, but remarkably accelerated retinoblastoma formation. 29 Frequent hemizygous deletions of DICER1 have been observed in human cancers as well. 29 In addition, Su et al reported that the tumor suppressor p63, a member of the p53 family, binds to the promoter region of the Dicer gene and activates its transcription.…”

“…29 Frequent hemizygous deletions of DICER1 have been observed in human cancers as well. 29 In addition, Su et al reported that the tumor suppressor p63, a member of the p53 family, binds to the promoter region of the Dicer gene and activates its transcription. Knockout of p63 dampens tumor metastasis in mice.…”