MicroRNA‐137 promoter methylation is associated with poorer overall survival in patients with squamous cell carcinoma of the head and neck

Langevin, Scott M.; Stone, Roslyn A.; Bunker, Clareann H.; Lyons‐Weiler, Maureen A.; LaFramboise, William A.; Kelly, Lori A.; Seethala, Raja R.; Grandis, Jennifer R.; Sobol, Robert W.; Taioli, Emanuela

doi:10.1002/cncr.25689

Cited by 101 publications

(88 citation statements)

References 57 publications

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“…Previous studies have confirmed that the aberrant methylation of the miR-137 promoter contributes to miR-137 silencing (Langevin et al 2010(Langevin et al , 2011Dang et al 2013). In the present study, we speculated that the continuous downregulation of miR-137 might reflect an increasing level of methylation, forming a feedback loop that increases AjBHMT levels and decreases in miR-137 levels to further increase the concentration of AjBHMT.…”

Section: Discussionsupporting

confidence: 65%

The Roles of Two miRNAs in Regulating the Immune Response of Sea Cucumber

Zhang

et al. 2015

Genetics

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MicroRNAs (miRNAs) have emerged as key regulators in many pathological processes by suppressing the transcriptional and post-transcriptional expression of target genes. MiR-2008 was previously found to be significantly up-regulated in diseased sea cucumber Apostichopus japonicus by high-through sequencing, whereas the reads of miR-137, a well-documented tumor repressor, displayed no significant change. In the present study, we found that miR-137 expression was slightly attenuated and miR-2008 was significantly enhanced after Vibrio splendidus infection or Lipopolysaccharides application. Further target screening and dual-luciferase reporter assay revealed that the two important miRNAs shared a common target gene of betaine-homocysteine S-methyltransferase (AjBHMT), which exhibited noncorrelated messenger RNA and protein expression patterns after bacterial challenge. In order to fully understand their regulatory mechanisms, we conducted the functional experiments in vitro and in vivo. The overexpression of miR-137 in sea cucumber or primary coelomocytes significantly decreased, whereas the inhibition of miR-137 increased the mRNA and protein expression levels of AjBHMT. In contrast, miR-2008 overexpression and inhibition showed no effect on AjBHMT mRNA levels, but the concentration of AjBHMT protein displayed significant changes both in vitro and in vivo. Consistently, the homocysteine (Hcy) contents were also accordingly altered in the aberrant expression analysis of both miRNAs, consistent with the results of the AjBHMT silencing assay in vitro and in vivo. More importantly, small interfering RNA mediated AjBHMT knockdown and Hcy exposure analyses both significantly increased reactive oxygen species (ROS) production and decreased the number of surviving invasive pathogen in sea cucumber coelomocytes. Taken together, these findings confirmed the differential roles of sea cucumber miR-137 and miR-2008 in regulating the common target AjBHMT to promote ROS production and the clearance of pathogenic microorganisms through Hcy accumulation.KEYWORDS Apostichopus japonicus; miR-137; miR-2008; betaine-homocysteine S-methyltransferase; homocysteine; ROS, genetics of immunity M ICRORNAS (miRNAs) are a class of endogenous small noncoding RNAs of $22 nucleotides, which typically function as repressors of target genes, resulting in direct messenger RNA (mRNA) degradation or translation inhibition (Bartel 2004). These RNAs play crucial roles in many cellular processes, such as proliferation, differentiation, apoptosis, and survival (Lai 2002;He and Hannon 2004;Miska 2005). The expression of up to 60% of all protein-coding genes is estimated to be under the control of miRNAs (Friedman 2009), and combinatorial regulation has been identified as a prominent feature of miRNA regulation. Thus, a given miR-NA might have multiple different mRNA targets, and a given mRNA might similarly be targeted by multiple miRNAs (Krek et al. 2005;Rajewsky 2006). Consistent with the crucial roles of miRNA in the normal functioning of euka...

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Section: Discussionsupporting

confidence: 65%

The Roles of Two miRNAs in Regulating the Immune Response of Sea Cucumber

Zhang

et al. 2015

Genetics

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“…Mammalian miRNAs appear to target a wide variety of cellular functions using these posttranscriptional control mechanisms, including cellular proliferation and differentiation (Fazi et al, 2007;Lowenberg, 2008;Langevin et al, 2011). In the last few years, it has become evident that miRNA expression is deregulated in human cancer, resulting in specific oncogenic events, reviewed in Calin and Croce (Garzon et al, 2006) and Esquela-Kerscher and Slack (Esquela-Kerscher and Slack, 2006).…”

mentioning

confidence: 99%

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Dou

Zheng

et al. 2011

Oncogene

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Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3 0 untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL.

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“…Apart from the microRNA itself, the methylation status of miR-137 promoter has potential clinical value. Methylated miR-137 is a potential prognostic marker in HNSCC and is associated with survival (Langevin et al, 2011).…”

Section: Mir-137 [Mature Sequence: 59 -Uuauugcuuaagaauacgcguag -81 (Mmentioning

confidence: 99%