Original ArticlesMethylation-mediated miR-155-FAM133A axis contributes to the attenuated invasion and migration of IDH mutant gliomas
Introduction
In the last decade, somatic mutations in isocitrate dehydrogenases (IDHMT) were found to be widespread in lower grade gliomas (LGG, WHO grade II and III) and secondary glioblastomas (GBM) [1], and were thought to be the earliest event in glioma development [2,3]. Meanwhile, IDHMT gliomas were found to be less aggressive than the WHO grade-matched wild-type counterparts [4]. The possible mechanisms include the attenuated invasion and migration [5], decreased proliferation [6], altered metabolic pathways [7,8] and sensitization to chemo-/radio-therapy [9,10]. Based on the profound influence of IDH mutation on gliomas, the current WHO classification of tumors of the central nervous system (2016) has placed IDH mutation as a standard prognostic molecular marker to help better define the specific entities of gliomas [11].
IDH mutations are located specifically within the enzymatically active sites at the amino acid residue arginine 132th (for IDH1) and 172th (for IDH2), with IDH1R132H and IDH2R172K substitutions being most common [12]. These mutations give IDH a neomorphic enzymatic activity catalyzing α-KG to a new metabolite (R)-enantiomer of 2-hydroxyglutarate (R-2HG), an onco-metabolite inhibiting α-KG-dependent enzymes, resulting in widespread genomic DNA hypermethylation [13]. The causal role of IDH mutation to the G-CIMP [14,15] had challenged researchers to find specific promoter methylation-mediated down-regulated gene signatures which may explain the tumor biology of IDHMT gliomas. Tumor suppressor genes such as RBP1 (retinol-binding protein 1) [16], miR-148a [17] and MTSS1 [18] have been found to be silenced by promoter CpG island methylation and can contribute to glioma formation, linking vital roles of IDH mutation in gliomagenesis. On the other hand, the role of silenced oncogenes or oncogenic miRNAs, which may play roles in the less malignant behaviors of IDHMT gliomas, has been largely under-investigated.
MicroRNAs (miRNAs) are small noncoding RNAs regulating gene expression by binding to the 3′-untranslated region (3′UTR) of target mRNAs, leading to mRNA cleavage and degradative repression [19]. It has been widely demonstrated that miRNAs play extremely important roles in regulating the malignant phenotypes of gliomas [20]. In this study, we identified a methylation-mediated miR-155-FAM133A axis in regulating the invasion/migration of IDHMT gliomas, which provides new insight into understanding the less aggressive malignant behaviors of IDHMT gliomas.
Section snippets
Glioma cohorts and clinical samples
A total of 41 LGG and 43 GBM tissues from our cohort (XQ cohort) with complete clinical follow-up information were recruited in this study. Another validation cohort from the Cancer Genome Atlas (TCGA) database was investigated in silico. Characteristics of patients are detailed in Supplementary Table 1.
Cell culture
Human anaplastic astrocytoma cell line SF268 (WHO grade III) [21] and GBM cell lines U251, SNB19, SF295 (WHO grade IV) [21] with less than 5 total passage times were directly selected from the
Oncogenic miR-155 is down-regulated in IDH-mutant gliomas
We initially isolated primary GBMs cells (IDHWT = 4 and IDHMT = 2) for miRNA-array analysis to determine miRNAs differentially expressed (DE-miRs) between IDHWT and IDHMT gliomas (Fig. 1A). To validate the list of candidates, we sought for clinical analysis either from publicly available database or from our own hospital. We first investigated an independent cohort of glioma patients from TCGA, including 121 cases of lower grade gliomas (LGG, IDHMT = 87) and early glioblastomas (eGBM, IDHWT
Discussion
Migration and invasion, key features of glioma aggressiveness, are largely responsible for difficulty of achieving surgical total resection and poor patients' prognosis [33]. Interestingly, it has been repeatedly reported that the migration and invasion are inhibited in IDHMT gliomas [5,10,34,35], this may in part explain the less aggressive behaviors of IDHMT gliomas. In this study, we provide new evidence that down-regulation of oncogenic miR-155 can contribute to the attenuated
Disclosure of potential conflicts of interest
The authors declare no potential conflicts of interest.
Acknowledgement
We thank Dr. Clive Da Costa (Francis Crick Institute, London, UK) for providing useful suggestions and carefully commenting on this manuscript. This work was supported by the National Natural Science Foundation of China (NSFC:81272783).
References (44)
- et al.
IDH mutations in cancer and progress toward development of targeted therapeutics
Ann. Oncol.
(2016) - et al.
Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis
Canc. Cell
(2016) - et al.
Genome-wide transcriptional analyses of Chinese patients reveal cell migration is attenuated in IDH1-mutant glioblastomas
Canc. Lett.
(2015) - et al.
IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status
Radiother. Oncol.
(2015) - et al.
The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation
Biochim. Biophys. Acta
(2014) - et al.
Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases
Canc. Cell
(2011) - et al.
MTSS1 is epigenetically regulated in glioma cells and inhibits glioma cell motility
Transl Oncol
(2017) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment
Exp. Cell Res.
(2016) - et al.
MiRNA-155 promotes proliferation by targeting caudal-type homeobox 1 (CDX1) in glioma cells
Biomed. Pharmacother.
(2017)
The emerging role of MMP14 in brain tumorigenesis and future therapeutics
Biochim. Biophys. Acta
R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/beta-catenin signaling
Int. J. Biochem. Cell Biol.
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts
Mol. Cell
Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin
J. Clin. Oncol.
Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas
J. Clin. Oncol.
IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo
Ann. Neurol.
IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma
Canc. Res.
Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1
Canc. Res.
IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma
Canc. Sci.
The 2016 world health organization classification of tumors of the central nervous system: a summary
Acta Neuropathol.
A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation
Genome Res.
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Nature
Cited by (21)
MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition
2023, Pathology Research and PracticeLower-Grade Gliomas: Predicting DNA Methylation Subtyping and its Consequences on Survival with MR Features
2021, Academic RadiologyCitation Excerpt :Hypermethylation mediated silencing of tumor suppressor genes and hypomethylation mediated increased expression of oncogenes are well known examples (11). Previous studies have identified alterations of DNA methylation in gliomas (12–14). It has been convincingly demonstrated that DNA methylation profiling is highly reproducible and robust even from poor quality material and small samples (15).
Short-chain fatty acids combined with intronic DNA methylation of HIF3A: Potential predictors for diabetic cardiomyopathy
2021, Clinical NutritionCitation Excerpt :DNA was extracted from blood leukocytes and stored at −30 °C until the subsequent pyrosequencing analysis. We conducted quantitative methylation analyses using the MassARRAY system (Sequenom, San Diego, CA) [24]. We used the Epidesigner online application (http://www.epidesigner.com/) to design PCR primers for the HIF3A gene.
Identification and characterization of a novel mutant isocitrate dehydrogenase 1 inhibitor for glioma treatment
2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Migration is a critical feature of glioma aggressiveness and one of the main reasons for unsuccessful surgical total resection and poor prognosis [22]. However, it is controversial about mutant IDH1 and cancer migration, either promotion [18], inhibition [23], or no effects [24] have been reported. It is noted that most of these studies were carried out in mutant IDH1 overexpressed cells.
Tanshinone prevents alveolar bone loss in ovariectomized osteoporosis rats by up-regulating phosphoglycerate dehydrogenase
2019, Toxicology and Applied PharmacologyCitation Excerpt :CpG islands and sites were predicted through the online software methprimer. Methylation of CpG sites was determined by BSP as described previously (Huang et al., 2018). Briefly, genomic DNA was isolated and treated with the Methyllamp DNA Modificaiton Kit (Epigenteck, USA) and was subjected to amplification using the EpiTaqHS kit (Takara, Japan).