Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

Shinmura, Kazuya; Kato, Hisami; Kawanishi, Yuichi; Igarashi, Hisaki; Goto, Masanori; Hong, Tao; Inoue, Yusuke; Nakamura, Shuichi; Misawa, Kiyoshi; Mineta, Hiroyuki; Sugimura, Haruhiko

doi:10.1155/2016/1546392

Cited by 41 publications

(57 citation statements)

References 33 publications

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“…Abnormal methylation of CpG island in the promoter region of genes usually leads to transcriptional silencing of specific genes and therefore results in dysregulation of normal cellular biological processes (48). Toyota (53). TML is associated with tumor grade in glioma, and high-grade gliomas demonstrate higher TML (54).…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

Zhao

Zhang

Liu

et al. 2020

Preprint

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DNA methylation has been widely reported to associate with the progression of glioma.DNA methylation at the 5 position of cytosine (5-methylcytosine, 5mC), which is regulated by 5mC regulators ("writers", "erasers" and "readers"), is the most critical modification pattern. However, a systematic study on the role of these regulators in glioma is still lacking. In this study, we collected gene expression profiles and corresponding clinical information of gliomas from three independent public datasets.Gene expression of 21 5mC regulators was analyzed and linked to clinicopathological features. A novel molecular classification of glioma was developed using consensus non-negative matrix factorization (CNMF) algorithm, and the tight association with molecular characteristics as well as tumor immune microenvironment was clarified.Sixteen prognostic factors were identified using univariate Cox regression analysis, and a 5mC regulator-based gene signature was further constructed via the least absolute shrinkage and selection operator (LASSO) cox analysis. This risk model was proved as an efficient predictor of overall survival for diffuse glioma, glioblastoma (GBM), and low-grade glioma (LGG) patients in three glioma cohorts. The significant correlation between risk score and intratumoral infiltrated immune cells, as well as immunosuppressive pathways, was found, which explained the difference in clinical outcomes between high and low-risk groups. Finally, a nomogram incorporating the gene signature and other clinicopathological risk factors was established, which might direct clinical decision making. In summary, our work highlights the potential clinical application value of 5mC regulators in prognostic stratification of glioma and their potentialities for developing novel treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

Zhao

Zhang

Liu

et al. 2020

Preprint

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“…The PCR primers for the amplification of the WDR62 transcript were 5′‐AGT AAC CCC CAG CTT CCA GAG‐3′ and 5′‐CTG CCC TGT AAC AGA CCA AGT G‐3′. The transcript of the control housekeeping gene GAPDH was also amplified using primers as shown previously . The relative amounts of WDR62 transcript were normalized to those of the GAPDH transcript.…”

Section: Methodsmentioning

confidence: 99%

“…The transcript of the control housekeeping gene GAPDH was also amplified using primers as shown previously. 13 The relative amounts of WDR62 transcript were normalized to those of the GAPDH transcript. The T/N ratios were calculated by dividing the normalized transcript amounts in the cancerous tissue by the amounts in the non-cancerous tissue.…”

Section: Qrt-pcrmentioning

confidence: 99%

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Shinmura

Kato

Kawanishi

et al. 2017

Molecular Carcinogenesis

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Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.

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“…They initiate the excision of lesions present in a single-stranded region, a replication fork, or transcription bubble mimic (23)(24)(25)(26)(27)(28). Reduced expression of NEIL1, NEIL2, and elevated expression of NEIL3 is involved in the progression of several types of cancer via their association with the somatic mutation load (29). NEIL2's decreased level or loss of its activity, to a less extent, NEIL1, is a risk factor for the progression of cancers such as lung cancer and squamous cell carcinoma in the oral cavity (30)(31)(32)(33), and poor survival in patients with estrogenreceptor-positive breast cancer (34).…”

Section: Introductionmentioning

confidence: 99%

DNA glycosylase NEIL2 prevents Fusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Sayed

Chakraborty

Ali

et al. 2020

Preprint

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Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80-85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stemcell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cytokines..Murine CRC model also showed downregulation of the NEIL2 transcript and accumulation of DNA damage. Importantly, analysis of publicly available transcriptomic data showed that the downregulation of NEIL2 is specific for MSS compared to MSI CRCs. We thus conclude that the pathogenic bacterial infection-induced downregulation of NEIL2, and consequent accumulation of DNA damage, play critical roles in the progression of CRC.

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Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

Cited by 41 publications

References 33 publications

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

Molecular and clinical characterization of 5mC regulators in glioma: results of a multicenter study

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

DNA glycosylase NEIL2 prevents Fusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

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