Kazunori Yamaguchi - Academia.edu (original) (raw)

Papers by Kazunori Yamaguchi

Journal of Biological Chemistry, 2000

Progress in molecular biology and translational science, 2018

Sialidases are glycosidases responsible for the removal of α-glycosidically linked sialic acid re... more Sialidases are glycosidases responsible for the removal of α-glycosidically linked sialic acid residues from carbohydrate portions of glycoproteins and glycolipids, this process being the initial step in the degradation of such glycoconjugates. Sialic acids are considered to play important roles in various biological processes largely in two ways, one related to their hydrophilic and acidic properties exerting physicochemical effects on the glycoconjugates to which they are attached, and the other as recognition sites or in an opposing fashion as masking sites. The removal of sialic acids catalyzed by a sialidase, therefore greatly influences many biological processes through changing the conformation of glycoproteins and through recognition and masking of biological sites of functional molecules. Sialidases are found widely distributed in metazoan animals, from echinoderms to mammals, and are also present in viruses and other microorganisms, including fungi, protozoa, and bacteria ...

PLoS ONE, 2012

Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and chan... more Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and change their conformation, intermolecular interactions, and/or half-life. Thus, sialidases are believed to modulate the function of sialoglycoconjugates by desialylation. We previously reported that the membrane-associated mammalian sialidase NEU3, which preferentially acts on gangliosides, is involved in cell differentiation, motility, and tumorigenesis. The NEU3 gene expression is aberrantly elevated in several human cancers, including colon, renal, prostate, and ovarian cancers. The small interfering RNA-mediated knock-down of NEU3 in cancer cell lines, but not in normal cell-derived primary cultures, downregulates EGFR signaling and induces apoptosis. Here, to investigate the physiological role of NEU3 in tumorigenesis, we established Neu3-deficient mice and then subjected them to carcinogen-induced tumorigenesis, using a sporadic and a colitis-associated colon cancer models. The Neu3-deficient mice showed no conspicuous accumulation of gangliosides in the brain or colon mucosa, or overt abnormalities in their growth, development, behavior, or fertility. In dimethylhydrazine-induced colon carcinogenesis, there were no differences in the incidence or growth of tumors between the Neu3-deficient and wild-type mice. On the other hand, the Neu3-deficient mice were less susceptible than wild-type mice to the colitis-associated colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. These results suggest that NEU3 plays an important role in inflammation-dependent tumor development.

Oncotarget, Jan 13, 2018

Inflammatory bowel diseases, which are multifactorial autoimmune colitis diseases, are occurring ... more Inflammatory bowel diseases, which are multifactorial autoimmune colitis diseases, are occurring with increasing prevalence. One of the most serious complications of these diseases is colorectal cancer. Here we investigated the role of periostin (Postn), a matricellular protein that interacts with various integrin molecules on the cell surface, in colitis-induced colorectal cancer. Immunohistochemistry of mouse and human colorectal cancer samples revealed that Postn was expressed in the stroma and was upregulated in close proximity to the cancer cells. The colonic tumorigenesis in an inflammation-related colon carcinogenesis mouse model was increased in Postn knock-out (Postn) mice compared to Postn mice. Although no difference was found in the degree of colitis between Postn and Postn mice, Postn inhibited tumor growth and induced the apoptosis of mouse rectal cancer cells . Furthermore, fewer apoptotic colorectal cancer cells were observed in Postn than in Postn mice. These data s...

Oncotarget

Periostin is a matricellular protein that is secreted by fibroblasts and interacts with various c... more Periostin is a matricellular protein that is secreted by fibroblasts and interacts with various cell-surface integrin molecules. Although periostin is known to support tumor development in human malignancies, little is known about its effect on lungcancer progression. We here demonstrate that periostin is a negative prognostic factor that increases tumor proliferation through ERK signaling in non-small cell lung carcinoma. We classified 189 clinical specimens from patients with non-small cell lung-cancer according to high or low periostin expression, and found a better prognosis for patients with low rather than high periostin, even in cases of advancedstage cancer. In a syngenic implantation model, murine Ex3LL lung-cancer cells formed smaller tumor nodules in periostin −/− mice than in periostin +/+ mice, both at the primary site and at metastatic lung sites. An in vitro proliferation assay showed that stimulation with recombinant periostin increased Ex3LL-cell proliferation. We also found that periostin promotes ERK phosphorylation, but not Akt or FAK activation. These findings suggest that periostin represents a potential target in lung-cancer tumor progression.

Cancer cell, Jan 12, 2018

Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways,... more Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Oncology letters, 2018

Accumulating evidence demonstrated that Hox antisense intergenic RNA (HOTAIR) serves essential ro... more Accumulating evidence demonstrated that Hox antisense intergenic RNA (HOTAIR) serves essential roles in the development and metastasis of several types of cancer. In hepatocellular carcinoma (HCC), high expression of HOTAIR is associated with poor prognosis, and HOTAIR regulates cell migration and proliferation. However, the downstream molecular targets of HOTAIR depend on the cancer cell types, and little is known about the precise molecular mechanisms of HOTAIR involved in cancer development. The present study investigated the role of HOTAIR in HCC cell lines. Notably, the overexpression of HOTAIR in HCC cell lines did not affect cell migration and proliferation capability. In the microarray analysis, C-C motif chemokine ligand (CCL)2 was identified to be differentially expressed in HOTAIR-overexpressing cells, and it was confirmed that HOTAIR promotes the secretion of CCL2. Furthermore, it was revealed that the proportion of macrophages and myeloid-derived suppressor cells (MDSCs...

International journal of oncology, 2018

The majority of cancer cells maintain a high glycolytic activity and an increased lactate product... more The majority of cancer cells maintain a high glycolytic activity and an increased lactate production, even in a well oxygenated environment. This phenomenon is known as the Warburg effect. Previous studies have revealed that various types of cancer selectively express the pyruvate kinase M2 isoform (PKM2), and that PKM2 plays a pivotal role in the Warburg effect. Although elevated PKM2 levels have been observed in pancreatic cancer and other types of cancer, little is known about the biological function of PKM2. In this study, in order to examine the expression and role of PKM2 in pancreatic ductal adenocarcinoma (PDAC), we knocked down PKM2 in PDAC cells by introducing small interfering and short hairpin RNAs, and examined the gene expression profiles in the cells by microarray analysis. We analyzed the energy-producing pathways in the cells by XFe Extracellular Flux Analyzers, and detected intracellular metabolites by capillary electrophoresis time-of-flight mass spectrometry. We ...

Experimental neurology, 2018

Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene th... more Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal β-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexamice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by β-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The HexaNeu3mice were healthy at birth, but died at 1.5 to 4.5months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of HexaNeu3mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistoch...

Biochimica et biophysica acta, Nov 1, 2017

Glioblastoma multiforme is one of the most malignant tumors of the human central nervous system c... more Glioblastoma multiforme is one of the most malignant tumors of the human central nervous system characterized by high degree of invasiveness. Focusing on this invasive nature, we investigated whether ganglioside-specific sialidase NEU3 might be involved, because gangliosides are major components of brain tissues, and cell surface sialic acids, as target residues of sialidase catalysis, are thought to be closely related to cell invasion. NEU3 mRNA levels of human glioblastoma specimens were evaluated by quantitative RT-PCR. Human glioblastoma cell lines, U251, A172, and T98G were used for cell invasion and migration by transwell and cell scratching assay. The molecules involved in the signaling cascade were investigated by western blot and immunofluorescent microscopy. NEU3 expression was down-regulated in human glioblastoma specimens. In the human glioblastoma cell lines, NEU3 overexpression reduced invasion and migration by promoting the assembly of focal adhesions through reduced ...

Scientific Reports

Renal cell carcinoma (RCC) is one of the most lethal urologic cancers. About one-third of RCC pat... more Renal cell carcinoma (RCC) is one of the most lethal urologic cancers. About one-third of RCC patients already have distal metastasis at the time of diagnosis. There is growing evidence that Hox antisense intergenic RNA (HOTAIR) plays essential roles in metastasis in several types of cancers. However, the precise mechanism by which HOTAIR enhances malignancy remains unclear, especially in RCC. Here, we demonstrated that HOTAIR enhances RCC-cell migration by regulating the insulin growth factorbinding protein 2 (IGFBP2) expression. HOTAIR expression in tumors was significantly correlated with nuclear grade, lymph-node metastasis, and lung metastasis. High HOTAIR expression was associated with a poor prognosis in both our dataset and The Cancer Genome Atlas dataset. Migratory capacity was enhanced in RCC cell lines in a HOTAIR-dependent manner. HOTAIR overexpression accelerated tumorigenicity and lung metastasis in immunodeficient mice. Microarray analysis revealed that IGFBP2 expression was upregulated in HOTAIR-overexpressing cells compared with control cells. The enhanced migration activity of HOTAIR-overexpressing cells was attenuated by IGFBP2 knockdown. IGFBP2 and HOTAIR were co-expressed in clinical RCC samples. Our findings suggest that the HOTAIR-IGFBP2 axis plays critical roles in RCC metastasis and may serve as a novel therapeutic target for advanced RCC. Renal cell carcinoma (RCC), which accounts for about 3% of all cancers in adults, is the most lethal of all urological malignancies 1. One-third of RCC patients already have metastases at the time of diagnosis, and 20-30% of patients treated by radical nephrectomy will suffer metastasis or recurrence 2. The prognosis of metastatic RCC is poor: the median survival is about 13 months 3. Although recent developments in targeted therapy have improved survival rates for metastatic RCC, most patients still succumb to the disease. Therefore, new therapeutic approaches and prognostic factors are needed to treat advanced RCC. Although numerous lncRNAs (non-coding RNAs longer than 200 nucleotides) 4 have been identified as factors in cancer progression and the development and spread of metastases 5 , lncRNAs also regulate a wide variety of cell functions in normal tissue. Since many lncRNAs are differentially expressed in specific organs, tissues, or cancer types, lncRNAs are potential prognostic markers 4. Hox antisense intergenic RNA (HOTAIR), a lncRNA that acts as an oncogenic molecule in various types of cancer, is localized to the HOXC gene cluster. HOTAIR interacts with PRC2 (polycomb repressive complex 2) to enhance H3K27 trimethylation, and thereby decreases the expression of a large number of genes 6. Several groups, including our laboratory, have reported that high HOTAIR expression is correlated with a poor prognosis

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Aug 25, 2017

Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition... more Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro Double-knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Furthermore, neuraminidase 3 deficiency drastically increased s...

Cancer science, Jan 24, 2017

Recent studies have indicated that an increased expression of the M2 isoform of pyruvate kinase (... more Recent studies have indicated that an increased expression of the M2 isoform of pyruvate kinase (PKM2) is involved in glycolysis and in tumor development. However, little is known about the role of PKM2 in gastric cancer (GC). Therefore, we examined the expression and function of PKM2 in human GC. We evaluated PKM1 and PKM2 expression by quantitative RT-PCR in gastric tissues from 10 patients who underwent gastric endoscopic submucosal dissection (ESD), 80 patients who underwent gastrectomy, and 7 healthy volunteers, and analyzed the correlation with clinicopathological variables. To assess the function of PKM2, we generated PKM2-knockdown GC cells, and investigated the phenotypic changes. Furthermore, we examined the induction of PKM2 expression by CagA, a pathogenic factor of Helicobacter pylori, using CagA-inducible GC cells. PKM2 was predominantly expressed not only in GC lesions but also in the normal gastric regions of GC patients and in the gastric mucosa of healthy volunteer...

Scientific Reports, 2016

CD271 (p75 neurotrophin receptor) plays both positive and negative roles in cancer development, d... more CD271 (p75 neurotrophin receptor) plays both positive and negative roles in cancer development, depending on the cell type. We previously reported that CD271 is a marker for tumor initiation and is correlated with a poor prognosis in human hypopharyngeal cancer (HPC). To clarify the role of CD271 in HPC, we established HPC cell lines and knocked down the CD271 expression using siRNA. We found that CD271-knockdown completely suppressed the cells' tumor-forming capability both in vivo and in vitro. CD271-knockdown also induced cell-cycle arrest in G 0 and suppressed ERK phosphorylation. While treatment with an ERK inhibitor only partially inhibited cell growth, CDKN1C, which is required for maintenance of quiescence, was strongly upregulated in CD271-depleted HPC cells, and the double knockdown of CD271 and CDKN1C partially rescued the cells from G 0 arrest. In addition, either CD271 depletion or the inhibition of CD271-RhoA signaling by TAT-Pep5 diminished the in vitro migration capability of the HPC cells. Collectively, CD271 initiates tumor formation by increasing the cell proliferation capacity through CDKN1C suppression and ERK-signaling activation, and by accelerating the migration signaling pathway in HPC. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, worldwide. HNSCC is a general classification given to various independent cancers, including those of the oral cavity, nasopharynx, oropharynx, and hypopharynx 1. Hypopharyngeal cancer (HPC) accounts for approximately 10% of all HNSCCs. Unfortunately, approximately 80% of the HPC patients diagnosed are in the advanced stages of the disease and frequently develop delayed regional lymph node metastases or distant metastases during the course of the disease 2. Thus, the prognosis for HPC patients remains poor, indicating the need for innovative treatment strategies. CD271, also known as the p75 neurotrophin receptor, is a member of the tumor necrosis factor receptor (TNFR) superfamily, which binds to several ligands including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophine-3 (NT3), and neurotrohine-4 (NT4). Like other members of the TNFR superfamily, CD271 plays opposing roles in the development of several cancers. CD271 accelerates cell proliferation in oral cancer 3 , melanoma 4 , breast cancer 5,6 , brain tumors 7 , and normal myoblasts 8. In contrast, the same receptor acts to suppress tumor growth or induce apoptosis in prostate cancer 9 , gastric cancer 10 , bladder tumors 11 , and medulloblastoma 12. Moreover, CD271 is a negative prognostic factor in melanoma 4 , breast cancer 5,6 , and HPC 13 , but is a positive prognostic factor in gastric cancer 10. In glioma cells, CD271 plays a critical role in actin fiber formation via a RhoA-dependent pathway 14. These findings suggest that CD271-mediated downstream pathways vary in different cell types and tissues, and may also vary in response to different ligands. Consistent

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Tanpakushitsu Kakusan Koso Protein Nucleic Acid Enzyme, Sep 1, 2008

Glycoconjugate J, 2003

Aberrant sialylation in cancer cells is thought to be a characteristic feature associated with ma... more Aberrant sialylation in cancer cells is thought to be a characteristic feature associated with malignant properties including invasiveness and metastatic potential. Sialidase which catalyzes the removal of sialic acid residues from glycoproteins and glycolipids, has been suggested to play important roles in many biological processes through regulation of cellular sialic acid contents. The altered expression of sialidase observed in cancer would, therefore, suggest its involvement in the malignant process. In mammalian cells, three types of sialidase cloned and characterized to date were found to behave in different manners during carcinogenesis. Recent progress in molecular cloning of these sialidases has facilitated elucidation of the molecular mechanisms and significance of these alterations. Herein we briefly describe our own studies on sialidase changes associated with malignant transformation and summarize the topic from both a retrospective and a prospective viewpoint. Sialidases are indeed closely related to malignancy and are thus potential targets for cancer diagnosis and therapy.

Cancer Science, 2014

ABSTRACT No abstract is available for this article.

Neurochemical research, 2002

Plasma membrane-associated sialidase (Neu 3), which specifically hydrolyzes gangliosides, is rela... more Plasma membrane-associated sialidase (Neu 3), which specifically hydrolyzes gangliosides, is relatively abundantly present in the nervous system. To understand the role of Neu 3 in neuronal differentiation, we studied the relationship between neurite outgrowth and Neu 3 expression in human neuroblastoma NB-1 cells. The expression of Neu 3 in NB-1 cells increased when neurite outgrowth in these cells was induced by dibutyryl cAMP. While treatment with dibutyryl cAMP alone enhanced the outgrowth of dendrite-like processes, transfection of the Neu 3 gave rise to a more prominent outgrowth of neurites with axon-like characteristics, even in the absence of dibutyryl cAMP. Neu 3 induction by dibutyryl cAMP is probably attributable, in part, to transactivation of the Neu 3 gene through cAMP responsive elements in the 5'-upstream region, as revealed by the promotor activity assay using Neu 3 promotor expression plasmid. These results indicate that Neu 3 regulates neurite formation in NB...

Antisense research and development, 1995

We have developed a transient expression assay for selection of effective antisense RNAs using ep... more We have developed a transient expression assay for selection of effective antisense RNAs using episomal replication of plasmids in COS-7 cells, an African green monkey kidney-derived cell line expressing SV40 large T antigen. The transient expression assay was enabled by a liposome-mediated DNA transfection method, by which about 70% of the cells were reproducibly transfected with exogenous DNAs. Plasmids expressing antisense RNAs for the retinoblastoma gene (Rb-1) mRNA and harboring SV40 ori were constructed and introduced into COS-7 cells to examine their inhibitory effect on the accumulation of endogenous Rb protein (pRb). Only the antisense RNA complementary to the 3'-untranslated region (UTR) in Rb-1 mRNA was expressed stably at high levels for 3 days after the transfection. This antisense RNA reduced by 73% the content of endogenous pRb 70 h after transfection. A similar inhibition was detected in mouse mammary carcinoma cells (FM3A) that were stably transfected with the a...