MicroRNA 218 Acts as a Tumor Suppressor by Targeting Multiple Cancer Phenotype-associated Genes in Medulloblastoma

Venkataraman, Sujatha; Birks, Diane K.; Balakrishnan, Ilango; Alimova, Irina; Harris, Peter; Patel, Purvi; Handler, Michael H.; Dubuc, Adrian M.; Taylor, Michael D.; Foreman, Nicholas K.; Vibhakar, Rajeev

doi:10.1074/jbc.m112.396762

Cited by 101 publications

(71 citation statements)

References 43 publications

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“…The precise role of DICER1 in medulloblastoma is less clear. For example, subsets of miRNAs have been shown as either growth-inhibitory (Ferretti et al 2008;Li et al 2009;Venkataraman et al 2013;Jin et al 2014;Hemmesi et al 2015) or oncogenic (Grunder et al 2011;Weeraratne et al 2012;Li et al 2015). In particular, the miR-1792 cluster has been shown as both necessary and sufficient to initiate medulloblastoma (Zindy et al 2014), which suggests an oncogenic role for Dicer1 on the basis of miR-1792 alone.…”

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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“…It has been shown that miR-218 expression is downregulated in many tumors including ESCC (15)(16)(17)(18)(19)(20) and is involved in cancer initiation and development (15)(16)(17)(18)(19)(20)(21)(22) SOT (38), Rob1 receptor (39) as well as LAmb3 (40), which are involved in several different signaling pathways, suggesting that miR-218 is a tumor suppressor miRNA and plays a crucial role in the initiation, development and metastasis of tumors. Therefore, we reasonably speculated that miR-218 suppresses the tumor growth of ESCC in vitro and in vivo by regulating multiple target genes.…”

Section: Discussionmentioning

confidence: 99%

“…microRNA-218 (miR-218) is a recently discovered miRNA and is downregulated in several types of cancer, such as gastric cancer (15,16), cervical squamous cell carcinoma (17), medulloblastoma (18), lung cancer (19) and glioblastoma (20). Accumulating evidence demonstrates that miR-218 acts as a tumor suppressor and confers an inhibitory effect on cancer cell proliferation, migration and invasion by targeting genes (15)(16)(17)(18)(19)(20)(21)(22). In particular, recently studies have demonstrated that overexpression of miR-218 increased chemosensitivity to cisplatin (CDDP) in cervical cancer cells (23).…”

Section: Introductionmentioning

confidence: 99%

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

et al. 2014

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Abstract.A growing body of evidence suggests that microRNA-218 (miR-218) acts as a tumor suppressor and is involved in tumor progression, development and metastasis and confers sensitivity to certain chemotherapeutic drugs in several types of cancer. However, our knowledge concerning the exact roles played by miR-218 in esophageal squamous cell carcinoma (ESCC) and the underlying molecular mechanisms remain relatively unclear. Thus, the aims of this study were to detect the expression of miR-218 in human ESCC tissues and explore its effects on the biological features and chemosensitivity to cisplatin (CDDP) in an ESCC cell line (Eca109), so as to provide new insights for ESCC treatment. Here, we found increased expression of miR-218 in the ESCC tissues compared with that in the matched non-tumor tissues, and its expression level was correlated with key pathological characteristics including clinical stage, tumor depth and metastasis. We also found that enforced expression of miR-218 significantly decreased cell proliferation, colony formation, migration and invasion, induced cell apoptosis and arrested the cell cycle in the G0/G1 phase, as well as suppressed tumor growth in a nude mouse model. In addition, our results showed that miR-218 mimics increased the sensitivity to the antitumor effect of CDDP in the human Eca109 cells. Importantly, this study also showed that miR-218 regulated the expression of phosphorylated PI3K, AKT and mTOR, which may contribute to suppressed tumor growth of ESCC and enhanced sensitivity of ESCC cells. These findings suggest that miR-218 is a potential therapeutic agent for the treatment of ESCC.

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“…Documented evidence has shown that the altered expression of specific miRNA genes contributes to the initiation and progression of cancer [2]. For instance, miR-218 [5], miR-10a [6] and miR-181b [7] acts as tumor suppressors in medulloblastoma, hepatoma cells and gastric adenocarcinomas, respectively. Studies on the function and mechanism of miRNAs can be especially useful in improving cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

et al. 2013

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Edited by Tamas DalmayKeywords: microRNA microRNA-7 X-linked inhibitor of apoptosis protein Cell apoptosis Cervical cancer a b s t r a c t Our study demonstrated the functions of microRNA-7 (miR-7) in cervical cancer. The overexpression of miR-7 in the cervical cancer cell lines HeLa and C-33A suppressed cell viability and promoted cell apoptosis, whereas the inhibition of miR-7 had opposite effects. Furthermore, an oncogene, Xlinked inhibitor of apoptosis protein (XIAP), was identified as a new target of miR-7, and the ectopic expression of XIAP rescued the effects induced by miR-7 in HeLa and C-33A cells. These results indicate that miR-7 targeted and downregulated the oncogene XIAP to regulate the effect of miR-7 on apoptosis and malignant behaviors of HeLa and C-33A cells.

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MicroRNA 218 Acts as a Tumor Suppressor by Targeting Multiple Cancer Phenotype-associated Genes in Medulloblastoma

Cited by 101 publications

References 43 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

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

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