المؤلفون: Issei Imoto, Masako Saito, Kenichi Suga, Tomohiro Kohmoto, Masanobu Otsu, Keisuke Horiuchi, Hironao Nakayama, Shigeki Higashiyama, Mayumi Sugimoto, Ayumi Sasaki, Yukako Homma, Miki Shono, Ryuji Nakagawa, Yasunobu Hayabuchi, Shoichiro Tange, Shoji Kagami, Kiyoshi Masuda

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17 −/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/f54d298d87a549a0b4eef6bb10764fdcTest

المؤلفون: Mitsuhiro Tsuboi, Kazuya Kondo, Kiyoshi Masuda, Shoichiro Tange, Koichiro Kajiura, Tomohiro Kohmoto, Hiromitsu Takizawa, Issei Imoto, Akira Tangoku

المصدر: Cancer Medicine, Vol 8, Iss 9, Pp 4189-4199 (2019)

مصطلحات موضوعية: DNA methylation, expression, GAD1, lung adenocarcinoma, prognosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background and Objectives In a previous genome‐wide screening, we identified hypermethylated CpG islands around glutamate decarboxylase 1 (GAD1) in lung adenocarcinoma (LADC). In this study, we aimed to investigate the methylation and expression status of GAD1 and its prognostic value in patients with LADC. Methods GAD1 methylation and mRNA expression status were analyzed using 33 tumorous and paired non‐tumorous LADC samples and publicly available datasets. The prognostic value of GAD1 overexpression was investigated using publicly available datasets of mRNA levels and 162 cases of LADC by immunohistochemistry. Results The methylation and mRNA expression levels of GAD1, each having a positive correlation, were significantly higher in LADC tumors than in paired non‐tumorous tissues. LADC patients with higher GAD1 mRNA expression showed significantly poorer prognosis for overall survival in publicly available datasets. Higher immunoreactivity of GAD1 was significantly associated with the pathological stage, pleural invasion, lymph vessel invasion, and poorer prognosis for cancer‐specific and disease‐free survival. Multivariate analysis revealed that GAD1 protein overexpression is an independent prognosticator for disease‐free survival. Conclusions GAD1 mRNA and protein expression levels were significant prognostic factors in LADC, suggesting that they might be useful biomarkers to stratify patients with worse clinical outcomes after resection.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-7634Test

الوصول الحر: https://doaj.org/article/f58723ba16434be4a37ee564d1ecd278Test

المؤلفون: Katsutoshi Shoda, Yuki Kuwano, Daisuke Ichikawa, Kiyoshi Masuda

المصدر: Biomedicines, Vol 10, Iss 7, p 1643 (2022)

مصطلحات موضوعية: circRNA, esophageal cancer, biomarker, therapeutic target, Biology (General), QH301-705.5

الوصف: Circular RNAs (circRNAs) comprise a large class of endogenous non-coding RNA with covalently closed loops and have independent functions as linear transcripts transcribed from identical genes. circRNAs are generated by a “back-splicing” process regulated by regulatory elements in cis and associating proteins in trans. Many studies have shown that circRNAs play important roles in multiple processes, including splicing, transcription, chromatin modification, miRNA sponges, and protein decoys. circRNAs are highly stable because of their closed ring structure, which prevents them from degradation by exonucleases, and are more abundant in terminally differentiated cells, such as brains. Recently, it was demonstrated that numerous circRNAs are differentially expressed in cancer cells, and their dysfunction is involved in tumorigenesis and metastasis. However, the crucial functions of these circRNAs and the dysregulation of circRNAs in cancer are still unknown. In this review, we summarize the recent reports on the biogenesis and biology of circRNAs and then catalog the advances in using circRNAs as biomarkers and therapeutic targets for cancer therapy, particularly esophageal cancer.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2227-9059/10/7/1643Test; https://doaj.org/toc/2227-9059Test

الوصول الحر: https://doaj.org/article/9837c24c1ae7426f844b86f12b9d774dTest

المؤلفون: Tomohiro Kohmoto, Nana Okamoto, Takuya Naruto, Chie Murata, Yuya Ouchi, Naoko Fujita, Hidehito Inagaki, Shigeko Satomura, Nobuhiko Okamoto, Masako Saito, Kiyoshi Masuda, Hiroki Kurahashi, Issei Imoto

المصدر: Molecular Cytogenetics, Vol 10, Iss 1, Pp 1-8 (2017)

مصطلحات موضوعية: 1q, Complex genomic rearrangement, Uniparental isodisomy, DUP-TRP/INV-DUP structure, Microhomology-mediated break-induced replication model, Template switching, Genetics, QH426-470

الوصف: Abstract Background Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented. Case presentation Here, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs + isoUPD implicated in chromosomal disorders. Conclusions To the best of our knowledge, this is the first case of CGRs + isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13039-017-0316-6Test; https://doaj.org/toc/1755-8166Test

الوصول الحر: https://doaj.org/article/407a5438f6fd40b9b765d03bdeb34368Test

المؤلفون: Daiju Fukuda, Sachiko Nishimoto, Kunduziayi Aini, Atsushi Tanaka, Tsuyoshi Nishiguchi, Joo‐ri Kim‐Kaneyama, Xiao‐Feng Lei, Kiyoshi Masuda, Takuya Naruto, Kimie Tanaka, Yasutomi Higashikuni, Yoichiro Hirata, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Issei Imoto, Takashi Akasaka, Michio Shimabukuro, Masataka Sata

المصدر: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 8, Iss 7 (2019)

مصطلحات موضوعية: atherosclerosis, inflammation, macrophage, Toll‐like receptor 9, vascular inflammation, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Background Toll‐like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient (Apoe−/−) mice. Methods and Results Tlr9‐deficient Apoe−/− (Tlr9−/−Apoe−/−) mice and Apoe−/− mice on a Western‐type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double‐stranded DNA, an endogenous ligand of TLR9, in these mice. Genetic deletion or pharmacologic blockade of TLR9 in angiotensin II–infused Apoe−/− mice attenuated atherogenesis in the aortic arch (P

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2047-9980Test

الوصول الحر: https://doaj.org/article/8f8f8329a3194984af6b247cbd40b84aTest

المؤلفون: Issei Imoto, Kazuhito Rokutan, Kensei Nishida, Kiyoshi Masuda, Yuki Kuwano

المصدر: International Journal of Molecular Sciences, Vol 14, Iss 8, Pp 17111-17121 (2013)

مصطلحات موضوعية: NF90, double-stranded RNA binding proteins, posttranscriptional regulation, microRNA biogenesis, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/1422-0067/14/8/17111Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/9bbf5c8ccdd6410ab0a9476f3609dc2aTest

المؤلفون: Kei-ichi Morita, Takuya Naruto, Kousuke Tanimoto, Chisato Yasukawa, Yu Oikawa, Kiyoshi Masuda, Issei Imoto, Johji Inazawa, Ken Omura, Hiroyuki Harada

المصدر: PLoS ONE, Vol 10, Iss 11, p e0140480 (2015)

مصطلحات موضوعية: Medicine, Science

الوصف: Gorlin syndrome (GS) is an autosomal dominant disorder that predisposes affected individuals to developmental defects and tumorigenesis, and caused mainly by heterozygous germline PTCH1 mutations. Despite exhaustive analysis, PTCH1 mutations are often unidentifiable in some patients; the failure to detect mutations is presumably because of mutations occurred in other causative genes or outside of analyzed regions of PTCH1, or copy number alterations (CNAs). In this study, we subjected a cohort of GS-affected individuals from six unrelated families to next-generation sequencing (NGS) analysis for the combined screening of causative alterations in Hedgehog signaling pathway-related genes. Specific single nucleotide variations (SNVs) of PTCH1 causing inferred amino acid changes were identified in four families (seven affected individuals), whereas CNAs within or around PTCH1 were found in two families in whom possible causative SNVs were not detected. Through a targeted resequencing of all coding exons, as well as simultaneous evaluation of copy number status using the alignment map files obtained via NGS, we found that GS phenotypes could be explained by PTCH1 mutations or deletions in all affected patients. Because it is advisable to evaluate CNAs of candidate causative genes in point mutation-negative cases, NGS methodology appears to be useful for improving molecular diagnosis through the simultaneous detection of both SNVs and CNAs in the targeted genes/regions.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC4636311?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/d8231e1ecccc401b8d8fe230d74edf6cTest

المؤلفون: Yuki Kuwano, Kensei Nishida, Yoko Akaike, Ken Kurokawa, Tatsuya Nishikawa, Kiyoshi Masuda, Kazuhito Rokutan

المصدر: International Journal of Molecular Sciences, Vol 17, Iss 10, p 1638 (2016)

مصطلحات موضوعية: DNA damage responses, HIPK2, HP1γ, cell cycle, apoptosis, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response (DDR) is triggered by DNA lesions or chromatin alterations. The DDR regulates DNA repair, cell cycle checkpoint activation, and apoptosis to restore genome integrity and cellular homeostasis. Maintenance of the DDR is essential to prevent development of diseases caused by genomic instability, including cancer, defects of development, and neurodegenerative disorders. Recent studies reveal a novel HIPK2-mediated pathway for DDR through interaction with chromatin remodeling factor homeodomain protein 1γ. In this review, we will highlight the molecular mechanisms of HIPK2 and show its functions as a crucial DDR regulator.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/1422-0067/17/10/1638Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/a1a266fa96ac4de58f46d8ba012d1753Test

المؤلفون: Manami Honda, Yuki Kuwano, Sakurako Katsuura-Kamano, Yoshiko Kamezaki, Kinuyo Fujita, Yoko Akaike, Shizuka Kano, Kensei Nishida, Kiyoshi Masuda, Kazuhito Rokutan

المصدر: PLoS ONE, Vol 8, Iss 10, p e75960 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: MicroRNAs (miRNAs) play key roles in regulation of cellular processes in response to changes in environment. In this study, we examined alterations in miRNA profiles in peripheral blood from 25 male medical students two months and two days before the National Examination for Medical Practitioners. Blood obtained one month after the examination were used as baseline controls. Levels of seven miRNAs (miR-16, -20b, -26b, -29a, -126, -144 and -144*) were significantly elevated during the pre-examination period in association with significant down-regulation of their target mRNAs (WNT4, CCM2, MAK, and FGFR1 mRNAs) two days before the examination. State anxiety assessed two months before the examination was positively and negatively correlated with miR-16 and its target WNT4 mRNA levels, respectively. Fold changes in miR-16 levels from two days before to one month after the examination were inversely correlated with those in WNT4 mRNA levels over the same time points. We also confirmed the interaction between miR-16 and WNT4 3'UTR in HEK293T cells overexpressing FLAG-tagged WNT4 3'UTR and miR-16. Thus, a distinct group of miRNAs in periheral blood may participate in the integrated response to chronic academic stress in healthy young men.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3794012?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/e43871082fa74864b1da13abbf0d2cbcTest

المؤلفون: Kiyoshi Masuda, Shigetada Teshima-Kondo, Mina Mukaijo, Naoko Yamagishi, Yoshiko Nishikawa, Kensei Nishida, Tomoko Kawai, Kazuhito Rokutan

المصدر: PLoS Medicine, Vol 5, Iss 5, p e94 (2008)

مصطلحات موضوعية: Medicine

الوصف: BackgroundVascular endothelial growth factor-A (VEGF) is one of the key regulators of tumor development, hence it is considered to be an important therapeutic target for cancer treatment. However, clinical trials have suggested that anti-VEGF monotherapy was less effective than standard chemotherapy. On the basis of the evidence, we hypothesized that vegf mRNA may have unrecognized function(s) in cancer cells.Methods and findingsKnockdown of VEGF with vegf-targeting small-interfering (si) RNAs increased susceptibility of human colon cancer cell line (HCT116) to apoptosis caused with 5-fluorouracil, etoposide, or doxorubicin. Recombinant human VEGF165 did not completely inhibit this apoptosis. Conversely, overexpression of VEGF165 increased resistance to anti-cancer drug-induced apoptosis, while an anti-VEGF165-neutralizing antibody did not completely block the resistance. We prepared plasmids encoding full-length vegf mRNA with mutation of signal sequence, vegf mRNAs lacking untranslated regions (UTRs), or mutated 5'UTRs. Using these plasmids, we revealed that the 5'UTR of vegf mRNA possessed anti-apoptotic activity. The 5'UTR-mediated activity was not affected by a protein synthesis inhibitor, cycloheximide. We established HCT116 clones stably expressing either the vegf 5'UTR or the mutated 5'UTR. The clones expressing the 5'UTR, but not the mutated one, showed increased anchorage-independent growth in vitro and formed progressive tumors when implanted in athymic nude mice. Microarray and quantitative real-time PCR analyses indicated that the vegf 5'UTR-expressing tumors had up-regulated anti-apoptotic genes, multidrug-resistant genes, and growth-promoting genes, while pro-apoptotic genes were down-regulated. Notably, expression of signal transducers and activators of transcription 1 (STAT1) was markedly repressed in the 5'UTR-expressing tumors, resulting in down-regulation of a STAT1-responsive cluster of genes (43 genes). As a result, the tumors did not respond to interferon (IFN)alpha therapy at all. We showed that stable silencing of endogenous vegf mRNA in HCT116 cells enhanced both STAT1 expression and IFNalpha responses.ConclusionsThese findings suggest that cancer cells have a survival system that is regulated by vegf mRNA and imply that both vegf mRNA and its protein may synergistically promote the malignancy of tumor cells. Therefore, combination of anti-vegf transcript strategies, such as siRNA-based gene silencing, with anti-VEGF antibody treatment may improve anti-cancer therapies that target VEGF.

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18494554/?tool=EBITest; https://doaj.org/toc/1549-1277Test; https://doaj.org/toc/1549-1676Test

الوصول الحر: https://doaj.org/article/2fb82b43a47c43e0b07742d512213682Test