METTL14 Gene Polymorphisms Confer Neuroblastoma Susceptibility: An Eight-Center Case-Control Study

Zhang, Zhuo; Lu, Hongting; Zhu, Jinhong; Hua, Rui‐Xi; Li, Yong; Yang, Zhonghua; Zhang, Jiao; Cheng, Jiwen; Zhou, Haixia; Li, Suhong; Li, Li; Xia, Huimin; He, Jing

doi:10.1016/j.omtn.2020.08.009

Cited by 47 publications

(47 citation statements)

References 54 publications

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“…The present and previous results (21) indicate that C282Y HFE impacts neuroblastoma characteristics such as therapy resistance and cell proliferation. Several studies reported that single nucleotide polymorphisms (SNPs) in genes [e.g., ATP binding cassette subfamily C member 1 (ABCC1); caspase 8 (CASP8); ERCC excision repair 1, endonuclease non-catalytic subunit/ERCC excision repair 4, endonuclease non-catalytic subunit (ERCC1/XPF or ERCC1/ERCC4); poly(ADP-ribose) polymerase 1 (PARP1); base excision repair (BER); methyltransferase like 14 (METTL14)] are risk factors for neuroblastoma development and patient survival (40)(41)(42)(43)(44)(45). Our data indicate that the frequency of the C282Y HFE SNP in neuroblastoma patients should also be determined in future clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas

et al. 2021

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Background/Aim: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma. Materials and Methods: The biological activity of CC-I on drug-resistant neuroblastomas [e.g., HFE gene variant C282Y stably transfected human neuroblastoma SH-SY5Y cells (C282Y HFE/SH-SY5Y), SK-N-AS] was characterized using cell culture models and in vivo mouse tumor models. Results: CC-I had potent cytotoxicity on therapy-resistant neuroblastoma cells and limited cytotoxicity on human primary dermal fibroblast cells. In addition, CC-I showed a robust anti-tumor effect on therapyresistant human neuroblastoma C282Y HFE/SH-SY5Y cells but not on SK-N-AS cells in a subcutaneous tumor model. CC-I induced phosphorylation of heat shock protein 27 (HSP27), protein kinase B (Akt), and c-Jun N-terminal kinase (JNK) in C282Y HFE/SH-SY5Y neuroblastoma cells. Conclusion: CC-I may be an effective therapeutic option for therapy-resistant neuroblastomas, especially if they express the C282Y HFE gene variant. Its anti-tumor effects are possibly through HSP27-Akt-JNK activation. Neuroblastoma is the second most common solid tumor discovered in children (1). It begins in the nerve cells outside of the brain, most often in the adrenal glands located on top of both kidneys. Nearly 90% of neuroblastomas are diagnosed by age 10 (2). In the United States, neuroblastoma occurs in about 800 children (age up to 14) each year, which accounts for 6% of all childhood cancers (3). The International Neuroblastoma Risk Group Staging System was developed by the International Neuroblastoma Risk Group for the standardization of neuroblastoma risk classification and for clinical trials (4). Risk factors for neuroblastoma include age at diagnosis, disease stage, tumor histology, and N-myc proto-oncogene protein (MYCN) amplification status (5). Although the 5-year survival rate for low-risk neuroblastoma is 95%, the 5-year survival rate for high-risk neuroblastoma is only 40-50% (3). About half of the neuroblastomas are metastatic at diagnosis, and advanced disease remains difficult to treat successfully despite the aggressive multimodality therapy. Treatment for neuroblastoma usually involves a variety of approaches such as chemotherapy, radiation, surgery, stem cell transplantation, biological agents, and immunotherapy (6, 7). The majority of patients with high-risk neuroblastoma will relapse despite receiving aggressive multimodal therapy, while an additional 10% to 20% will be refractory to induction therapy (8, 9). Because of disease heterogeneity among highrisk cases, subsequent management with salvage chemotherapy can be very challenging. Therefore, developing new treatment agents against neuroblastoma, especially therapy-resistant neuroblastoma, is urgently needed. We previously reported the identification of compound CC-I, a thiobarbituric acid derivative, from the screening of the ChemBridge small molecule library compounds, as an effective agent against drug-resistant glioblasto...

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Section: Discussionmentioning

confidence: 99%

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas

et al. 2021

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“…Odds ratios (ORs) and 95% confidence interval (CI) adjusted age were calculated, and haplotype frequencies were estimated using PLINK software. False-positive report probability (FPRP) analysis was used to evaluate the noteworthy associations of the significant findings ( 18 , 19 ). We set 0.2 as the FPRP threshold and assigned a prior probability of 0.1 for an association with genotypes under investigation.…”

Section: Methodsmentioning

confidence: 99%

LRRC3B Polymorphisms Contributed to Breast Cancer Susceptibility in Chinese Han Population

Wang

2021

Front. Oncol.

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PurposeLRRC3B gene, as a tumor suppressor gene was involved in the development and progress of breast cancer (BC). However, the effect of LRRC3B polymorphisms on BC has rarely been reported. In the study, we aimed to evaluate the relation between LRRC3B variants and BC risk.MethodsAmong 563 BC patients and 552 healthy controls, ten single-nucleotide polymorphisms (SNPs) in LRRC3B were genotyped by Agena MassARRAY. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using logistic regression model.ResultsOur study demonstrated that rs1907168 polymorphism (heterozygous: OR = 0.71, p = 0.017) was related to the reduced risk of BC in the overall. In stratified analyses by age, rs1907168 was associated with the decreased (heterozygous: OR = 0.53, p = 0.002) while rs78205284 (homozygote: OR = 2.83, p = 0.034) increased BC susceptibility among the population at age ≤51 years. Rs6551122 (recessive: OR = 0.51, p = 0.028) and rs12635768 (homozygote, OR = 0.36, p = 0.023) polymorphisms were related to the smaller BC tumor size (<2 cm). In addition, rs112276562 (heterozygote OR = 0.56, p = 0.002), rs6551122 (heterozygote OR = 0.63, p = 0.016), and rs73150416 (heterozygote OR = 0.57, p = 0.005) variants contributed to the lower incidence of PR-positive BC. Moreover, rs6788033 was associated with a lower expression level of Ki-67 (log-additive: OR = 0.68, p = 0.024). Furthermore, we found an association of ‘GATT’ haplotype with an increased risk for BC. In addition, LRRC3B gene was down-regulated in BC tumor and had a poor prognosis in BC in in silico analysis.ConclusionOur study firstly found LRRC3B SNPs contributed to the risk of BC, suggesting LRRC3B variants might help to predict BC progression.

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“…M 6 A RNA modification has also been associated with other brain cancers such as neuroblastoma. Zhuo et al identified several SNPs in the gene encoding METTL14 , which may be associated with a predisposition to neuroblastoma development in a Chinese population ( Zhuo et al, 2020 ). Moreover, m 6 A and associated proteins may also represent potential biomarkers of various brain cancers including neuroblastoma.…”

Section: A In Brain Disordersmentioning

confidence: 99%

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

Mathoux¹,

Henshall²,

Brennan³

2021

Front. Cell. Neurosci.

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RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

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METTL14 Gene Polymorphisms Confer Neuroblastoma Susceptibility: An Eight-Center Case-Control Study

Cited by 47 publications

References 54 publications

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas

LRRC3B Polymorphisms Contributed to Breast Cancer Susceptibility in Chinese Han Population

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

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