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| 1 | Association of Fusobacterium nucleatum with immunity andmolecular alterations in colorectal cancer显示文摘The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer. | Katsuhiko Nosho Yasutaka Sukawa Yasushi Adachi Miki Ito Kei Mitsuhashi Hiroyoshi Kurihara Shinichi Kanno Itaru Yamamoto Keisuke Ishigami Hisayoshi Igarashi Reo Maruyama Kohzoh Imai Hiroyuki Yamamoto Yasuhisa Shinomura | 2016 | World Journal of Gastroenterology2016，22，2： | 44 |
| 2 | Association of glypican-3 expression with growth signaling molecules in hepatocellular carcinoma显示文摘AIM:To clarify the association of glypican-3(GPC3)expression with Wnt and other growth signaling molecules in hepatocellular carcinoma(HCC). METHODS:Expression of GPC3,Wnt,matrix metalloproteinases(MMPs),sulfatase(SULF)1,SULF2,and other growth signaling molecules was analyzed in HCC cell lines and tissue samples by real-time reverse transcriptionpolymerase chain reaction,immunoblotting,and/or immunostaining.Expression of various genes in GPC3 siRNA-transfected HCC cells was analyzed. RESULTS:GPC3 was overexpressed in most HCCs at mRNA and protein levels and its serum levels weresignificantly higher in patients with HCC than in non- HCC subjects(P<0.05).Altered expressions of various MMPs and growth signaling molecules,some of which were correlated with GPC3 expression,were observed in HCCs.Down-regulation of GPC3 expression by siRNA in GPC3-overexpressing HCC cell lines resulted in a significant decrease in expressions of MMP2,MMP14,fibroblast growth factor receptor 1,insulin-like growth factor 1 receptor.GPC3 expression was significantly correlated with nuclear/cytoplasmic localization ofβ-catenin. CONCLUSION:These results suggest that GPC3,in conjunction with MMPs and growth signaling molecules, might play an important role in the progression of HCC. | Noriyuki Akutsu Hiroyuki Yamamoto Shigeru Sasaki Hiroaki Taniguchi Yoshiaki Arimura Kohzoh Imai Yasuhisa Shinomura | 2010 | World Journal of Gastroenterology2010，16，28： | 20 |
| 3 | Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer显示文摘AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis. | Yasutaka Sukawa Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Kunimoto Hiromu Suzuki Yasushi Adachi Mayumi Nakazawa Takayuki Nobuoka Mariko Kawayama Masashi Mikami Takashi Matsuno Tadashi Hasegawa Koichi Hirata Kohzoh Imai Yasuhisa Shinomura | 2012 | World Journal of Gastroenterology2012，18，45： | 19 |
| 4 | A candidate targeting molecule of insulin-like growth factor-Ⅰ receptor for gastrointestinal cancers显示文摘Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage.One new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) carcinomas.The concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new drugs.Type I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human malignancies.In this review,we focus on this promising therapeutic target,IGF-IR.The IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI cancers.Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments.These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and pancreas.We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences.Several mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single agents.We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug combinations.Thus,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas. | Yasushi Adachi Hiroyuki Yamamoto Hirokazu Ohashi Takao Endo David P Carbone Kohzoh Imai Yasuhisa Shinomura | 2010 | World Journal of Gastroenterology2010，16，46： | 14 |
| 5 | Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer显示文摘There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2 , less frequently MSH6 , and rarely PMS2 . MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2 , but also miRNA processing machinery genes, including TARBP2 and XPO5 , were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets. | Hiroyuki Yamamoto Yasushi Adachi Hiroaki Taniguchi Hiroaki Kunimoto Katsuhiko Nosho Hiromu Suzuki Yasuhisa Shinomura | 2012 | World Journal of Gastroenterology2012，18，22： | 14 |
| 6 | An updated review of gastric cancer in the next-generation sequencing era:Insights from bench to bedside and vice versa显示文摘Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets. | Hiroyuki Yamamoto Yoshiyuki Watanabe Tadateru Maehata Ryo Morita Yoshihito Yoshida Ritsuko Oikawa Shinya Ishigooka Shun-ichiro Ozawa Yasumasa Matsuo Kosuke Hosoya Masaki Yamashita Hiroaki Taniguchi Katsuhiko Nosho Hiromu Suzuki Hiroshi Yasuda Yasuhisa Shinomura Fumio Itoh | 2014 | World Journal of Gastroenterology2014，20，14： | 12 |
| 7 | Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers显示文摘AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed. RESULTS: Overexpression of EphA4 mRNA expres-sion was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Over-expression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. CONCLUSION: Our results suggest that overexpres-sion of EphA4 plays a role in gastric cancer. | Mariko Oki Hiroyuki Yamamoto Hiroaki Taniguchi Yasushi Adachi Kohzoh Imai Yasuhisa Shinomura | 2008 | World Journal of Gastroenterology2008，14，37： | 11 |
| 8 | MicroRNA-31 expression in colorectal serrated pathway progression显示文摘MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers(CRC).We have recently observed that microRNA-31(miR-31)expression is associated with BRAF mutation and prognosis in CRC.Moreover,high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps(HPs).These results suggest that miR-31 may contribute to the progression of serrated lesions.At a follow-up colonoscopy,we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features.Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component.Higher miR-31 expression was observed in the carcinoma component(57-fold increase)and the HP component(8-fold increase)compared with the paired normal mucosa,suggesting that miR-31 may be one of the key molecules in serrated pathway progression. | Hironori Aoki Katsuhiko Nosho Hisayoshi Igarashi Miki Ito Kei Mitsuhashi Takafumi Naito Eiichiro Yamamoto Tokuma Tanuma Masafumi Nomura Hiroyuki Maguchi Toshiya Shinohara Hiromu Suzuki Hiroyuki Yamamoto Yasuhisa Shinomura | 2014 | World Journal of Gastroenterology2014，20，34： | 5 |
| 9 | Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen显示文摘AIM:To clarify the significance of JC virus(JCV)T-antigen (T-Ag)expression in human gastric cancer. METHODS:We investigated the relationship between T-Ag detected by immunohistochemistry and Epstein- Barr virus(EBV)infection,microsatellite instability (MSI),and genetic and epigenetic alterations in gastric cancers.Mutations in the p53,β-catenin,KRAS,BRAF, PIK3CA genes were analyzed by polymerase chain reaction(PCR)-single strand conformation polymorphism and DNA sequencing.Allelic losses were determined by PCR at 7 microsatellite loci.Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS:JCV T-Ag protein expression was found in 49%of 90 gastric cancer tissues.T-Ag positivity was not correlated with clinicopathological characteristics. T-Ag expression was detected in a similar percentage of EBV positive cancers(4 of 9,44%)and EBV negativecancers(35 of 73,48%).T-Ag expression was detected in a significantly lower percentage of MSI-H cancers (14%)than in non MSI-H cancers(55%,P=0.005). T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of catenin(15 of 21,71%)than in cancers without(42%,P=0.018).p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers(32%)than in T-Ag negative cancers(57%,P= 0.018).T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers(P=0.008 and P=0.003). CONCLUSION:The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations. | Satoshi Yamaoka Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Taniguchi Yasushi Adachi Shigeru Sasaki Yoshiaki Arimura Kohzoh Imai Yasuhisa Shinomura | 2009 | World Journal of Gastroenterology2009，15，44： | 3 |
| 10 | Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids显示文摘AIM:To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers.METHODS:DNA was extracted from undiluted pancreatic and biliary fluids.As a surrogate for a genomewide hypomethylation assay,levels of long interspersed nuclear element-1(LINE-1) methylation were analyzed using bisulfite pyrosequencing.CpG island hypermethylation of 10 tumor-associated genes,aryl-hydrocarbon receptor repressor,adenomatous polyposis coli,calcium channel,voltage dependent,T type α1G subunit,insulin-like growth factor 2,O-6-methyl-guanine-DNA methyltransferase,neurogenin 1,CDKN2A,runt-related transcription factor 3(RUNX3),secreted frizzled-related protein 1,and ubiquitin carboxyl-terminal esterase L1(UCHL1),was analyzed using MethyLight.To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1,human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 μmol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h.After the treatment,UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction.RESULTS:Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease(58.7% ± 4.3% vs 61.7% ± 2.2%,P = 0.027;53.8% ± 6.6% vs 57.5% ± 1.7%,P = 0.007);however,LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids(45.4% ± 5.5% vs 58.7% ± 4.3%,P < 0.001).CpG island hypermethylation of tumor-associated genes was detected at various frequencies,but it was not correlated with LINE-1 hypomethylation.Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic(67%) or biliary(70%) fluids from patients with pancreatobiliary cancer.As a single marker,hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers,respectively(100% specificity).Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic(87% sensitivity and 100% specificity) and pancreatobiliary(97% sensitivity and 100% specificity) cancers.Treatment with a demethylating agent,5-AZA-2'-deoxycytidine,restored UCHL1 expression in pancreatobiliary cancer cell lines.CONCLUSION:Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers. | Norihiro Kato Hiroyuki Yamamoto Yasushi Adachi Hirokazu Ohashi Hiroaki Taniguchi Hiromu Suzuki Mayumi Nakazawa Hiroyuki Kaneto Shigeru Sasaki Kohzoh Imai Yasuhisa Shinomura | 2013 | World Journal of Gastroenterology2013，19，11： | 3 |
| 11 | A Rice Phytochrome A in Arabidopsis: The Role of the N-terminus under red and far-red light显示文摘phytochrome (phy ) A 和 phyB 光敏电阻器调停在植物的三个 photobiological 反应模式;而 phyA 能调停, very-low-fluence 反应(VLFR ) ,对某程度的高发光的反应(HIR ) 并且,,低 fluence 反应(LFR ) , phyB 和另外的类型 II phytochromes 仅仅调停 LFR。为了调查到铺平米饭 phyA 的,能为 Arabidopsis phyA 或 phyB 功能并且到补充在 phyA 的N终点的开始的 20 氨基酸评估丝氨酸残余的角色,我们检验了 VLFR , LFR ,并且在 phyB 和 phyAphyB 异种植物的 HIR 回答与开始的 10 丝氨酸残余在被变异到丙氨酸( phyA SA )的米饭 PHYA cDNA 或变异的米饭 PHYA cDNA 转变了。没有内长的 phyB,利用异种允许米饭 phyA 察觉到的 red-light-derived 回答的评估。在摘要, WT 米饭 phyA 能在 FR 或连续 R 光的脉搏下面补充象胚轴延伸的抑制那样的 VLFR 和 LFR 回答, flowering 和叶扩大感应,而 phyA SA 为 HIR 回答是更特定的(例如胚轴的抑制,在连续 far-red 下面的延伸和 anthocyanin 累积点亮)。因为 N 终端丝氨酸能不再是在 phyA SA 异种的 phosphorylated,这为在不同 phyA 依赖的回答之间区别的 phosphorylation 建议一个角色。在 Arabidopsis 表示的米饭 phyA 的功效依赖于分析的植物并且在生理的反应上的发展年龄,下游地建议一个阶段依赖者 phytochrome 发信号的调整。 | Julia Kneissl Tomoko Shinomura Masaki Furuya Cordelia Bolle | 2008 | Molecular Plant2008，1，1： | 3 |
| 12 | Endoscopic submucosal dissection is superior to conventional endoscopic resection as a curative treatment for early squamous cell carcinoma of the esophagus (with video)显示文摘 | Hiroaki Takahashi Yoshiaki Arimura Hosokawa Masao Satoshi Okahara Tokuma Tanuma Junichi Kodaira Hidetoshi Kagaya Yuichi Shimizu Kaku Hokari Hiroyuki Tsukagoshi Yasuhisa Shinomura Masahiro Fujita | 2010 | Gastrointestinal Endoscopy2010，，2： | 2 |
| 13 | Overexpression of β3/γ2 chains of laminin-5 and MMP7 in biliary cancer显示文摘AIM:To clarify the clinicopathological significance of laminin-5 γ2 (LNγ2) and β3 (LNβ3) chains and MMP7 expression in biliary tract cancer.METHODS: We analyzed the association between immunohistochemically detected LNγ2, LNβ3, and MMP7 expression in biliary tract cancer and clinicopathological characteristics. Activity of MMP7 was analyzed by casein zymography. An in vitro invasion assay after treatment with MMP7-specific siRNA was performed.RESULTS: LNγ2 expression was predominantly observed in carcinoma cells at the invasive front. LNγ2 expression was seen in 57% of patients with biliary tract cancer, and was associated with depth of invasion, histologic type, and advanced stage. The expression pattern of LNβ3 was classified into two types: invasive front dominant type (38%) and diffuse type (28%).The invasive front dominant type was associated with histologic type and advanced stage. MMP7 positivity was correlated with LNγ2 or LNβ3 expression but not with clinicopathological characteristics. Active MMP7 detected by casein zymography was correlated with depth of invasion and advanced stage. Downregulation of MMP7 expression by siRNA resulted in a significant decrease in biliary tract cancer cell invasion in vitro.CONCLUSION: Our results suggest that LNγ2 and LNβ3, in conjunction with MMP7, play a key role in the progression of biliary tract cancer. | Toshikuni Oka Hiroyuki Yamamoto Shigeru Sasaki Masanori Ii Keiichi Hizaki Hiroaki Taniguchi Yasushi Adachi Kohzoh Imai Yasuhisa Shinomura | 2009 | World Journal of Gastroenterology2009，15，31： | 2 |
| 14 | Peroxisome proliferatoractivated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells显示文摘 | Kitamura S Miyazaki Y Shinomura Y | 1999 | Jpn J Cancer Res1999，90，： | 2 |
| 15 | Molecular cloning of the mouse osteoglycin-encoding gene显示文摘 | Ujita M Shinomura T Kimata K | 1995 | Gene1995，158，2： | 1 |
| 16 | The tetraspanin CD9 modulates epidermal growth factor receptor signaling in cancer cells显示文摘 | Murayama Y Shinomura Y Orltani K | 2008 | J Cell Physiol2008，216，1： | 1 |
| 17 | Phytochrome-me-diated inhibition of coleoptile growth in rice:Age-depend-ency and action spectra显示文摘 | Xie X Shinomura T Inagaki N | | 0，，： | 1 |
| 18 | A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease显示文摘 | Motohisa Yamamoto Hiroki Takahashi Mikiko Ohara Chisako Suzuki Yasuyoshi Naishiro Hiroyuki Yamamoto Yasuhisa Shinomura Kohzoh Imai | 2006 | Modern Rheumatology2006，，6： | 1 |
| 19 | DNA methylation and cancer pathways in gastrointestinal tumors显示文摘 | Suzuki H Tokino T Shinomura Y | 2008 | Pharmaeogenomics2008，9，12： | 1 |
| 20 | Isolation and characterization of rice phytochrome A mutants显示文摘 | Takano M Kanegae H Shinomura T | | 0，，： | 1 |
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