Oyokyo Kidney Research Institute

Hirosaki, Japan

Oyokyo Kidney Research Institute

Hirosaki, Japan
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Tsuboi S.,Oyokyo Kidney Research Institute | Tsuboi S.,Hirosaki University
Biological and Pharmaceutical Bulletin | Year: 2012

During the process of hematogenous tumor metastasis, tumor cells that dissociated from the primary site enter the blood vessels and are exposed to innate immune systems in host blood circulation. In the innate immune systems, natural killer (NK) cells play a major role in rejecting tumors and suppressing metastasis. To establish metastasis, tumor cells therefore need to defend themselves against tumor rejection by NK cells. It has been recently discovered that some tumor cells develop defense systems against NK cell attack using certain types of cell-surface carbohydrates. The types of carbohydrates attached to cell-surface glycoproteins through serine or threonine residues contain a branch consisting of β-1,6-linkage of N-acetylglucosamine and N-acetylgalactosamine and are designated as core2 O-glycans. Tumor cells expressing core2 O-glycans evade NK cell-mediated tumor rejection, thereby surviving longer in host circulation and acquiring high-metastatic phenotypes. This review explains two types of tumor defense systems against NK cell immunity using core2 O-glycans. © 2012 The Pharmaceutical Society of Japan.

PubMed | Oyokyo Kidney Research Institute and Hirosaki University
Type: | Journal: Neuropsychiatric disease and treatment | Year: 2016

Many studies have investigated insomnia and the factors associated with this condition in hemodialysis (HD) patients, although the influence of HD duration has not been thoroughly investigated. In the present study, we investigated the factors, especially the duration of HD, associated with insomnia in HD patients.A total of 138 patients undergoing HD were recruited, and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) was used to assess the quality of sleep. Subjects with a total PSQI score up to 4 and those with a score of at least 5 were identified as normal subjects and subjects with insomnia, respectively. Additionally, we assessed restless legs syndrome, depression using the Center for Epidemiologic Studies Depression Scale, and health-related quality of life (QOL) using the Short Form 8 Health Survey. We divided the subjects into two groups according to the median HD duration.The prevalence rate of insomnia was 54.3% among all the subjects. Twenty-one subjects (15.2%) had depression, 26 (18.8%) had restless legs syndrome, and 75 (54.3%) had insomnia. The median HD duration was 4 years. The scores of components 1 and 4 of the PSQI, subjective sleep quality and habitual sleep efficiency, did not show a significant difference between the normal and insomnia groups. The score of component 7, daytime dysfunction, showed a significant difference between the short and long HD duration groups. In multiple regression analysis, the score of the Short Form 8 Health Survey showed a significant association with the PSQI score in the long HD duration group, but no variable showed a significant association in the short HD duration group.Patients with a longer duration of HD indicated that insomnia has an influence on their daily activities, with a significant association between insomnia and QOL. Greater attention should be paid to poor QOL and troubles in daily activities caused by insomnia in patients with a longer HD duration.

Tsuboi S.,Oyokyo Kidney Research Institute | Tsuboi S.,Hirosaki University | Hatakeyama S.,Hirosaki University | Ohyama C.,Hirosaki University | Fukuda M.,Sanford Burnham Institute for Medical Research
Trends in Molecular Medicine | Year: 2012

Despite the high prevalence of metastatic cancers and the poor outcome for patients, the processes of tumor metastasis still remain poorly understood. It has been shown that cell-surface carbohydrates attached to proteins through the amino acids serine or threonine (O-glycans) are involved in tumor metastasis, with the roles of O-glycans varying depending on their structure. Core2 O-glycans allow tumor cells to evade natural killer (NK) cells of the immune system and survive longer in the circulatory system, thereby promoting tumor metastasis. Core3 O-glycans or O-mannosyl glycans suppress tumor formation and metastasis by modulating integrin-mediated signaling. Here, we highlight recent advances in our understanding of the detailed molecular mechanisms by which O-glycans promote or suppress tumor metastasis. © 2012 Elsevier Ltd.

Hatakeyama S.,Oyokyo Kidney Research Institute | Yamamoto H.,Oyokyo Kidney Research Institute | Ohyama C.,Hirosaki University
Methods in Enzymology | Year: 2010

Animal experiments are necessary to confirm and demonstrate the reliability of the results of in vitro assays and to reveal any unexpected effects in the living body. Tumor invasion and metastasis consist of multistep and complex cascades. Moreover, conflictive interactions between cancer cells and host immune system exist in the living body. Therefore, tumor formation assay is an essential technique in tumor biology. Methods used in tumor formation assay include injection and inoculation, and considerable skill is required to perform these basic techniques. Injections and inoculations are categorized according to the target site: intraperitoneal (IP), intravenous (IV), subcutaneous (SC), footpad (FP), and targeted organ inoculation. Tumor cell injections and inoculations are standard methods for the evaluation of the malignant potential of cancer cells. IP injection is a useful and uncomplicated method for drug administration, SC inoculation is used to evaluate tumor growth and size, FP inoculation to estimate lymph nodule metastasis, and IV injection into the tail vein to evaluate the metastatic potential for lung colonization. Using immune-deficiency mice, we can address possible roles of carbohydrate antigens against host immune system. In this chapter, we describe details of the materials and methods that can be used for injection (IP and IV) and inoculation (SC, FP, testis, and prostate) in mice. © 2010 Elsevier Inc.

Sutoh Yoneyama M.,Hirosaki University | Hatakeyama S.,Hirosaki University | Habuchi T.,Akita University | Inoue T.,Akita University | And 6 more authors.
European Journal of Cell Biology | Year: 2014

To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up-regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis. © 2014 Elsevier GmbH.

Tsuboi S.,Oyokyo Kidney Research Institute | Tsuboi S.,Hirosaki University | Sutoh M.,Oyokyo Kidney Research Institute | Hatakeyama S.,Hirosaki University | And 13 more authors.
EMBO Journal | Year: 2011

The O-glycan branching enzyme, core2 γ 2-1,6-N- acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis. © 2011 European Molecular Biology Organization.

Tsuboi S.,Oyokyo Kidney Research Institute | Tsuboi S.,Hirosaki University
Trends in Glycoscience and Glycotechnology | Year: 2013

The O-glycan branching enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms O-glycans containing a branch of β-1,6-linkage of N-acetylglucosamine and N-acetylgalctosamine (core2 O-glycans) on cell-surface glycoproteins. It was reported that expression of C2GnT, a key enzyme for core2 O-glycans expression, was closely correlated with high-metastatic phenotypes of numbers of cancers. Recently, it has been revealed that C2GnT-expressing cancer cells synthesize core2 O-glycans which have immunosuppressive functions against natural killer (NK) cell immunity by using their cell-surface core2 O-glycans, resulting in acquiring high-metastatic phenotypes. C2GnTexpressing cancer cells have two different types of immunosuppressive functions against NK cell immunity, molecular shield and tumor-ligand masking. Here, we highlight recent advances in our understanding of the detailed molecular mechanisms of those immunosuppressive functions of core2 O-glycans. © 2013 FCCA (Forum: Carbohydrates Coming of Age).

PubMed | Red Cross, Oyokyo Kidney Research Institute and Hirosaki University
Type: Comparative Study | Journal: Transplantation proceedings | Year: 2016

We evaluated the safety and feasibility of living kidney transplantation from marginal donors.Between June 2006 and March 2015, we performed 61 living related renal transplantations at two renal transplantation centers. Marginal donors were defined as those who were older than 70 years or who had hypertension, reduced renal function, body mass index greater than 30kg/m(2), or mildly impaired glucose tolerance. We retrospectively compared renal function and graft survival between marginal and standard living donor kidney transplantations. To evaluate renal function, creatinine clearance (CCr) was preoperatively used for donors, and estimated glomerular filtration rate (eGFR) was postoperatively used for donors and recipients.Among 61 donors, 14 (23%) met the marginal criteria, the major reason being hypertension (91%). The mean age tended to be higher in the marginal group. Preoperative eGFR was significantly lower in the marginal group, whereas postoperative renal function decline ratio at two years was not significantly different between the groups (67% vs 67%, P= .960). Five-year graft survival rates were not significantly different between the two groups. However, recipient eGFR 1 year after kidney transplantation was lower in the marginal group than in the standard group (44 8 vs 55 9 in eGFR, P= .003).No significant differences were observed between the groups regarding donor renal function. Careful marginal donor selection can be safe and feasible for donors and recipients of living kidney transplantation; however, it may have a negative impact on recipient renal function.

PubMed | Oyokyo Kidney Research Institute and Hirosaki University
Type: Journal Article | Journal: Molecular medicine reports | Year: 2014

Invasive cancer cells form the filamentous actinbased membrane protrusions known as invadopodia. Invadopodia are thought to play a critical role in cancer cell invasion and metastasis due to their ability to degrade the extracellular matrix. The present study assessed whether invadopodia formation is essential in extravasation of circulating bladder cancer cells and lung metastasis. To analyze the importance of invadopodia, bladder cancer cell lines with reduced invadopodia formation were established by silencing the expression of cortactin, an essential component of invadopodia, using cortactin short hairpin RNA. Bladder cancer cells with cortactin knockdown demonstrated a markedly decreased ability to form invadopodia, secrete matrix metalloproteinases and invade the extracellular matrix. In addition, the knockdown cells exhibited a reduced transendothelial invasion capacity and decreased formation of metastatic foci in the lungs. The present study demonstrated that bladder cancer cells with cortactin knockdown have a reduced capacity to extravasate into the lung from the circulation, due to the decreased invasive character of invadopodia. This suggests that invadopodia formation is a critical process for cancer cell extravasation.

PubMed | Oyokyo Kidney Research Institute
Type: | Journal: Journal of biochemistry | Year: 2016

Anti-tumor immunity by cytotoxic T-lymphocytes (CTLs) is essential to suppress tumor progression. Cancer cells that evade CTL immunity proliferate in the host, promoting metastasis, but mechanisms underlying this capacity remain unknown. Here we report that bladder cancer cells metastasized to lymph nodes evade CTL immunity by a new mechanism via altered glycosylation. CTLs normally recognize and kill cancer cells presenting antigenic peptides on human leukocyte antigen (HLA) class I. We show bladder cancer cells expressing the O-glycan processing enzyme, core2 -1,6-N-acetylglucosaminyltransferase (C2GnT) exhibit HLA class I O-glycan modified with poly-N-acetyllactosamine and are highly susceptible to CTL. In those cells, poly-N-acetyllactosamine on HLA class I O-glycan binds galectin-3 to form a cell-surface molecular lattice, enabling efficient cell-surface retention of HLA class I. By contrast, bladder cancer cells in which C2GnT is downregulated show decreased levels of poly-N-acetyllactosamine on HLA class I O-glycans, attenuating lattice formation and reducing the cell-surface half-life of HLA class I. These tumor cells present antigenic peptides less efficiently, thereby evading CTL lysis and facilitating metastasis.

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