Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer

Merritt, William M.; Lin, Yvonne G.; Han, Liz Y.; Kamat, Aparna A.; Spannuth, Whitney A.; Schmandt, Rosemarie; Urbauer, Diana L.; Pennacchio, Len A.; Cheng, Jan‐Fang; Nick, Alpa M.; Deavers, Michael T.; Mourad-Zeidan, Alexandra A.; Wang, Hua; Mueller, Peter P.; Lenburg, Marc E.; Gray, Joe W.; Mok, Samuel C.; Birrer, Michael J.; López-Berestein, Gabriel; Coleman, Robert L.; Bar‐Eli, Menashe; Sood, Anil K.

doi:10.1056/nejmoa0803785

Cited by 621 publications

(571 citation statements)

References 39 publications

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“…Dicer1 functions as a haploinsufficient tumor suppressor gene in Ptch1-induced medulloblastoma DICER1 has previously been reported to function as a haploinsufficient tumor suppressor gene in human tumors (Karube et al 2005;Chiosea et al 2007;Merritt et al 2008;Grelier et al 2009;Faggad et al 2010;Lin et al 2010;Khoshnaw et al 2012;Jafarnejad et al 2013) and genetically engineered mouse models (Kumar et al 2009;Lambertz et al 2010), with only a handful of exceptions (Arrate et al 2010;Sabbaghian et al 2012;Zhang et al 2013). The precise role of DICER1 in medulloblastoma is less clear.…”

Section: Discussionmentioning

confidence: 99%

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

Constantin

Wainwright

2016

Genetics

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The Dicer1, Dcr-1 homolog (Drosophila) gene encodes a type III ribonuclease required for the canonical maturation and functioning of microRNAs (miRNAs). Subsets of miRNAs are known to regulate normal cerebellar granule cell development, in addition to the growth and progression of medulloblastoma, a neoplasm that often originates from granule cell precursors. Multiple independent studies have also demonstrated that deregulation of Sonic Hedgehog (Shh)-Patched (Ptch) signaling, through miRNAs, is causative of granule cell pathologies. In the present study, we investigated the genetic interplay between miRNA biogenesis and Shh-Ptch signaling in granule cells of the cerebellum by way of the Cre/lox recombination system in genetically engineered models of Mus musculus (mouse). We demonstrate that, although the miRNA biogenesis and Shh-Ptch-signaling pathways, respectively, regulate the opposing growth processes of cerebellar hypoplasia and hyperplasia leading to medulloblastoma, their concurrent deregulation was nonadditive and did not bring the growth phenotypes toward an expected equilibrium. Instead, mice developed either hypoplasia or medulloblastoma, but of a greater severity. Furthermore, some genotypes were bistable, whereby subsets of mice developed hypoplasia or medulloblastoma. This implies that miRNAs and Shh-Ptch signaling regulate an important developmental transition in granule cells of the cerebellum. We also conclusively show that the Dicer1 gene encodes a haploinsufficient tumor suppressor gene for Ptch1-induced medulloblastoma, with the monoallielic loss of Dicer1 more severe than biallelic loss. These findings exemplify how genetic interplay between pathways may produce nonadditive effects with a substantial and unpredictable impact on biology. Furthermore, these findings suggest that the functional dosage of Dicer1 may nonadditively influence a wide range of Shh-Ptch-dependent pathologies.

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Section: Discussionmentioning

confidence: 99%

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

Constantin

Wainwright

2016

Genetics

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“…This would be in keeping with multiple other studies showing dysregulation of parts of the pathway in cancer cell lines and tissues. 37,38 It is likely that there is a complex interaction between microRNA processing machinery, already abnormal in cancer cells, 39 and microRNA induced in hypoxia. It may also reflect post-translational processes such as prolyl 4-hydroxylation: the same process that regulates von Hippel-Lindau gene, and in turn HIFm, regulates Argonaute 2 stability.…”

Section: Discussionmentioning

confidence: 99%

hsa‐miR‐210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer

Gee

Camps

Buffa

et al. 2010

Cancer

224

157

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BACKGROUND:Hypoxia is an important mechanism of treatment resistance in head and neck squamous cell carcinoma (HNSCC). MicroRNAs are short noncoding RNAs that regulate multiple mRNAs and are frequently dysregulated in cancer. The authors have investigated the role of 3 microRNAs, including the hypoxia-induced hsa-miR-210, as potential markers of hypoxia or prognosis. METHODS: Three hypoxia-related microRNAs, hsa-miR-210, hsa-miR-21, and hsa-miR-10b, were measured in 46 samples from patients with HNSCC. Expression levels were correlated with clinicopathological variables and other markers of hypoxia: a published 99-gene hypoxia metagene, individual hypoxia-related genes such as TWIST1, and immunohistochemical expression of hypoxia-inducible factor 1 and its target gene carbonic anhydrase 9. We then performed survival analyses to investigate the prognostic significance of these microRNAs. RESULTS: Only the level of hsa-miR-210 was significantly correlated with other markers of hypoxia, including the 99-gene hypoxia metagene (rho ¼ 0.67, P < .001). We found no association between hsa-miR-210, hsamiR-21, or hsa-miR-10b and clinicopathological variables such as tumor size, differentiation, and stage. However, high levels of hsa-miR-210 were associated with locoregional disease recurrence (P ¼ .001) and short overall survival (P ¼ .008). hsa-miR-21 and hsa-miR-10b had no prognostic significance. CONCLUSIONS: Expression of hsa-miR-210 in head and neck cancer correlates with other approaches for assessing hypoxia and is associated with prognosis. This warrants further study as a classification marker of patients for therapies involving modulation of hypoxia.

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“…Downregulation of DGCR8 expression using RNA interference globally represses miRNA maturation and enhances cellular transformation and tumorigenesis, 20 consistent with clinical observations linking expression levels of miRNA processing factors and outcomes of cancers in patients. 21 DGCR8 is among the $30 genes that are heterozygously deleted in patients with DiGeorge syndrome. 22 Haploinsufficiency of DGCR8 in mice causes abnormal miRNA processing and induces behavioral and neuronal deficits similar to a subset of symptoms observed in DiGeorge syndrome.…”

mentioning

confidence: 99%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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Maturation of microRNAs (miRNAs,~22nt) from long primary transcripts [primary miRNAs (pri-miRNAs)] is regulated during development and is altered in diseases such as cancer. The first processing step is a cleavage mediated by the Microprocessor complex containing the Drosha nuclease and the RNA-binding protein DiGeorge critical region 8 (DGCR8). We previously reported that dimeric DGCR8 binds heme and that the heme-bound DGCR8 is more active than the heme-free form. Here, we identified a conserved dimerization domain in DGCR8. Our crystal structure of this domain (residues 298-352) at 1.7 Å resolution demonstrates a previously unknown use of a WW motif as a platform for extensive dimerization interactions. The dimerization domain of DGCR8 is embedded in an independently folded heme-binding domain and directly contributes to association with heme. Heme-binding-deficient DGCR8 mutants have reduced pri-miRNA processing activity in vitro. Our study provides structural and biochemical bases for understanding how dimerization and heme binding of DGCR8 may contribute to regulation of miRNA biogenesis.

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Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer

Abstract: Background-We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer.

Cited by 621 publications

References 39 publications

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

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

hsa‐miR‐210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer

Structure of the dimerization domain of DiGeorge Critical Region 8

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