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Yukako Hinohara,
Mariko Naito,
Rieko Okada,
Guan Yin,
Takahiro Higashibata,
Takashi Tamura,
Sayo Kawai,
Emi Morita,
Kenji Wakai, Hirotaka Matsuo,
Atsuyoshi Mori,
Nobuyuki Hamajima
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ABSTRACT: Several genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNPs) of ABCG2 and SLC22A12 were strongly associated with serum uric acid (SUA), but those of methylene tetrahydrofolate reductase (MTHFR) were not. However, there were several studies indicating the association with MTHFR C677T polymorphism. This study examined the association with the polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Subjects were 5,028 health checkup examinees of Seirei Preventive Health Care Center (3,416 males and 1,612 females) aged 35 to 69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Hyperuricemia was defined as SUA equal to 7 mg/dL or over. The genotype frequency was 35.9% for CC, 48.1% for CT, and 16.0% for TT, being in Hardy-Weinberg equilibrium (p=0.90). Among 4,425 participants with ABCG2 126QQ and SLC22A12 258WW who were not under medication for hyperuricemia, the mean SUA was 5.6 mg/dL, 5.6 mg/dL, and 5.7 mg/dL, respectively. When 114 participants with ABCG2 126QQ and SLC22A12 258WW under medication for hyperuricemia were included in hyperuricemia cases, the sex-age adjusted odds ratio (OR) of hyperuricemia was not significant; OR=1.00 (95% confidence interval, 0.89-1.24) for CT genotype and OR=0.98 (0.84-1.32) for TT genotype, relative to CC genotype. The present study indicated no association between SUA and MTHFR C677T genotype, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed.
Nagoya journal of medical science 02/2013; 75(1-2):93-100.
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Satoru Takeuchi,
Kojiro Wada,
Terushige Toyooka,
Nariyoshi Shinomiya,
Hideyuki Shimazaki,
Kuniaki Nakanishi,
Kimihiro Nagatani,
Naoki Otani,
Hideo Osada,
Yoichi Uozumi, Hirotaka Matsuo,
Hiroshi Nawashiro
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ABSTRACT: BACKGROUND:: xCT is a light chain of the cystine/glutamate antiporter system xc. Glutamate that is released by system xc plays an important role in the infiltration of glioblastoma (GBM) cells. Furthermore, increased glutathione synthesis by system xc may protect tumor cells from oxidative stress induced by radiotherapy and chemotherapy. OBJECTIVE:: To investigate whether the levels of xCT expression correlated with infiltrative imaging phenotypes on magnetic resonance imaging (MRI) and outcomes in patients with GBMs. METHODS:: Forty patients with histologically confirmed primary GBM were included in the present study. Patient charts were retrospectively reviewed for age, sex, Karnofsky performance status (KPS), mini-mental state examination scores, MRI features, xCT expression, isocitrate dehydrogenase 1 (IDH1) R132H expression, O6-methylguanine-DNA methyltransferase promoter methylation status, type of surgery, progression-free survival (PFS), and overall survival (OS). RESULTS:: In invasive margins, xCT expression was weak in 20 patients and strong in 20 patients. A Cox regression model revealed that (1) KPS < 60 (hazard ratio [HR], 4.525; P = .013), partial removal (HR, 2.839; P = .030), and strong xCT expression (HR, 4.134; P < .001) were significantly associated with shorter PFS, and that (2) partial removal (HR, 2.865; P = .033), weak IDH1 R132H expression (HR, 15.729; P = .012), and strong xCT expression (HR, 2.863; P = .040) were significantly associated with shorter OS. CONCLUSION:: These findings suggest that xCT is an independent predictive factor in GBM.
Neurosurgery 10/2012; · 2.79 Impact Factor
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Nobuyuki Hamajima,
Mariko Naito,
Rieko Okada,
Sayo Kawai,
Guang Yin,
Emi Morita,
Takahiro Higashibata,
Takashi Tamura,
Hiroko Nakagawa, Hirotaka Matsuo,
Atsuyoshi Mori,
Kenji Wakai
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ABSTRACT: A genome-wide association study identified that LRP2 rs2544390 in intron 1 was associated with serum uric acid (SUA) levels among Japanese, as well as polymorphisms of SLC22A12, ABCG2, and SLC2A9. This study aimed to confirm the association of rs2544390 C/T with SUA, as well as another LRP2 polymorphism (rs3755166 G/A) in the promoter. Subjects were 5016 health checkup examinees (3409 males and 1607 females) aged 35 to 69years with creatinine<2.0mg/dL. The subjects with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele (2546 males and 1199 females) were selected for analysis. Mean SUA was 6.03mg/dL for CC, 6.18mg/dL for CT, and 6.19mg/dL for TT among males (p=0.012), and 4.49mg/dL, 4.45mg/dL, and 4.42mg/dL among females (not significant), respectively. No association was observed for rs3755166. The association with rs2544390 was stronger among male drinkers. The odds ratio of drinking ≥5/week relative to no drinking for hyperuricemia (SUA≥7mg/dL and/or under medication for hyperuricemia) was 1.11 (95% confidence interval, 0.67-1.84) among CC males, 1.75 (1.22-2.51) among CT males, and 3.13 (1.80-5.43) among TT males. The interaction terms with drinking ≥5/week were 1.56 (p=0.156) for CT and 2.87 (p=0.005) for TT. This was the first report on the interaction between LRP2 genotype and alcohol drinking for SUA. Since the low density lipoprotein-related protein 2 (megalin) encoded by LRP2 is a multi-ligand endocytic receptor expressed in many tissues including the kidney proximal tubules, the association/interaction remained to be confirmed both epidemiologically and biologically.
Gene 04/2012; 503(1):131-6. · 2.34 Impact Factor
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Kimiyoshi Ichida, Hirotaka Matsuo,
Tappei Takada,
Akiyoshi Nakayama,
Keizo Murakami,
Toru Shimizu,
Yoshihide Yamanashi,
Hiroshi Kasuga,
Hiroshi Nakashima,
Takahiro Nakamura, [......],
Yoshitaka Utsumi,
Yuki Ikebuchi,
Kousei Ito,
Makiko Nakamura,
Yoshihiko Shinohara,
Makoto Hosoyamada,
Yutaka Sakurai,
Nariyoshi Shinomiya,
Tatsuo Hosoya,
Hiroshi Suzuki
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ABSTRACT: ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.
Nature Communications 01/2012; 3:764. · 7.40 Impact Factor
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Akiyoshi Nakayama, Hirotaka Matsuo,
Tappei Takada,
Kimiyoshi Ichida,
Takahiro Nakamura,
Yuki Ikebuchi,
Kousei Ito,
Tatsuo Hosoya,
Yoshikatsu Kanai,
Hiroshi Suzuki,
Nariyoshi Shinomiya
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ABSTRACT: The ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) gene encodes a well-known transporter, which exports various substrates including nucleotide analogs such as 3'-azido-3'-deoxythymidine (AZT). ABCG2 is also located in a gout-susceptibility locus (MIM 138900) on chromosome 4q, and has recently been identified by genome-wide association studies to relate to serum uric acid (SUA) and gout. Becuase urate is structurally similar to nucleotide analogs, we hypothesized that ABCG2 might be a urate exporter. To demonstrate our hypothesis, transport assays were performed with membrane vesicles prepared from ABCG2-overexpressing cells. Transport of estrone-3-sulfate (ES), a typical substrate of ABCG2, is inhibited by urate as well as AZT and ES. ATP-dependent transport of urate was then detected in ABCG2-expressing vesicles but not in control vesicles. Kinetic analysis revealed that ABCG2 is a high-capacity urate transporter that maintained its function even under high-urate concentration. The calculated parameters of ABCG2-mediated transport of urate were a Km of 8.24 ± 1.44 mM and a Vmax of 6.96 ± 0.89 nmol/min per mg of protein. Moreover, the quantitative trait locus (QTL) analysis performed in 739 Japanese individuals revealed that a dysfunctional variant of ABCG2 increased SUA as the number of minor alleles of the variant increased (p = 6.60 × 10(-5)). Because ABCG2 is expressed on the apical membrane in several tissues, including kidney, intestine, and liver, these findings indicate that ABCG2, a high-capacity urate exporter, has a physiological role of urate homeostasis in the human body through both renal and extrarenal urate excretion.
Nucleosides Nucleotides & Nucleic Acids 12/2011; 30(12):1091-7. · 0.90 Impact Factor
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ABSTRACT: Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 ± 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 × 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with ≤1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 × 10(-21)). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population.
Nucleosides Nucleotides & Nucleic Acids 12/2011; 30(12):1117-28. · 0.90 Impact Factor
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Seikagaku. The Journal of Japanese Biochemical Society 12/2011; 83(12):1131-5. · 0.04 Impact Factor
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ABSTRACT: Glioma is the most common type of brain tumor, and has the worst prognosis in human malignancy. Experimental evidence suggests that the use of high concentrations of various amino acids may perturb neoplastic cell growth. Thus, the aim of this study was to investigate whether essential amino acids can alter the growth and proliferation of glioma cells. Studies were performed using C6 rat glioma cell lines. High concentration of L-leucine induced growth arrest of glioma cell lines. Terminal transferase uridyl nick end labeling assay and cell cycle analysis showed that the effect of L-leucine on glioma cells growth was not cytotoxic, but rather cytostatic. Additionally, the extracellular signal-regulated protein kinase was activated in L-leucine-treated glioma cells, and inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK) enhanced the effect of L-leucine on glioma cell growth. These data suggest that high concentration L-leucine combined with inhibition of MEK is a potential strategy for glioma cell growth arrest.
Amino Acids 10/2011; 43(2):717-24. · 3.25 Impact Factor
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ABSTRACT: Previously, we reported that rhizome powder of Kaempferia parviflora Wall. Ex. Baker prevented obesity and a range of metabolic diseases. In this study, to clarify which molecular mechanisms and active ingredients of K. parviflora have an anti-obesity effect, we investigated the effect of ethyl acetate extract of K. parviflora (KPE) on TSOD mice, a spontaneously obese Type II diabetes model, and on pancreatic lipase. In the TSOD groups, KPE showed a suppressive effect on body weight increase and visceral fat accumulation and also showed preventive effects on symptoms related to insulin resistance, hypertension and fatty liver. In addition, KPE also suppressed body weight increase and food intake in TSNO mice groups, which served as reference animals, at an early stage of administration. Searching for the ingredients in KPE revealed that KPE contains at least 12 kinds of polymethoxyflavonoid (PMF). Furthermore, KPE and its component PMFs showed an inhibitory effect on pancreatic lipase. The above results suggest that KPE has a preventive effect on obesity and various metabolic diseases. The mechanisms of action probably involve inhibition of pancreatic lipase by the PMFs in KPE.
Fitoterapia 09/2011; 82(8):1272-8. · 1.85 Impact Factor
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Nobuyuki Hamajima,
Rieko Okada,
Sayo Kawai,
Asahi Hishida,
Emi Morita,
Guang Yin,
Kenji Wakai, Hirotaka Matsuo,
Hiroki Inoue,
Yuzo Takada,
Yatami Asai,
Atsuyoshi Mori,
Mariko Naito
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ABSTRACT: Genome-wide association studies identified that SLC2A9 (GLUT9) gene polymorphisms were associated with serum uric acid (SUA) levels. Among the Japanese, a C/T polymorphism in intron 8 (rs11722228) was reported to be highly significant, though the function and strength of association were unknown. This study aimed to confirm the association, estimating the means of SUA according to the genotype, as well as OR of the genotype. Subjects were 5024 health checkup examinees (3413 males and 1611 females) aged 35 to 69 years with creatinine <2.0 mg/dL. Since SLC22A12 258X allele and ABCG2 126X allele are known to influence SUA levels strongly, the subjects with SLC22A12 258WW and ABCG2 126QQ (3082 males and 1453 females, in total 4535 subjects) were selected. The genotype frequency of SLC2A9 rs11722228 was 2184 for CC, 1947 for CT, and 404 for TT, being in Hardy-Weinberg equilibrium (p=0.312). Mean SUA was 6.10 mg/dL for CC, 6.25 mg/dL for CT, and 6.45 mg/dL for TT among males (p=1.5E-6), and 4.34 mg/dL, 4.59 mg/dL, and 4.87 mg/dL among females (p=4.6E-11), respectively. Males with SUA less than 5.0 mg/dL were 14.7% for CC, 10.6% for CT, and 7.8% for TT (p=2.3E-4), and females with SUA less than 4.0 mg/dL were 34.1%, 25.5%, and 15.4% (p=3.7E-6), respectively. This study was the first report to estimate the impact of SLC2A9 rs11722228 on SUA levels. Since the allele frequency of rs11722228 is similar among different ethnic groups, the impact remains to be examined in other ethnic groups.
Molecular Genetics and Metabolism 04/2011; 103(4):378-82. · 3.19 Impact Factor
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ABSTRACT: The neurotoxicity of carbon monoxide (CO) poisoning is a significant clinical problem, but its mechanisms remain unclear. Previous studies of CO-exposed rats showed spatial memory disturbances and degradation of myelin basic protein (MBP) in the brain; however, regional localization of the degradation was not analyzed. In the present study, we histologically determined the foci of CO effects in the hippocampus. Wistar rats were exposed to CO for 60min (1000ppm for 40min+3000ppm for 20min) and returned into room air. For histological evaluation, the animals were sacrificed 90min, 1, 7 and 14 days after CO exposure and the brain tissue was analyzed with hematoxylin-eosin (HE), Nissl and Gallyas myelin staining as well as immunohistochemistry for MBP and phosphorylated or nonphosphorylated neurofilament. No histological changes were observed on HE, Nissl or Gallyas staining. In contrast, we detected MBP reduction at 90min after CO exposure in the dentate gyrus and CA3, and the recovery of MBP was observed after 14 days. The immunoreactivity of neurofilament also changed after CO exposure. Nevertheless, water maze test showed no significant effects of CO exposure on spatial memory. Our findings demonstrate that CO poisoning causes transient degradation of MBP and axonal injury in the hippocampus even though the animals showed no neurological disturbances.
Neuroscience Research 11/2010; 68(3):232-40. · 2.25 Impact Factor
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Hirotaka Matsuo,
Tappei Takada,
Kimiyoshi Ichida,
Takahiro Nakamura,
Akiyoshi Nakayama,
Yuki Ikebuchi,
Kousei Ito,
Yasuyoshi Kusanagi,
Toshinori Chiba,
Shin Tadokoro, [......],
Yatami Asai,
Kazuki Niwa,
Keiko Kamakura,
Shigeaki Nonoyama,
Yutaka Sakurai,
Tatsuo Hosoya,
Yoshikatsu Kanai,
Hiroshi Suzuki,
Nobuyuki Hamajima,
Nariyoshi Shinomiya
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ABSTRACT: Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.
Science translational medicine 11/2009; 1(5):5ra11. · 7.80 Impact Factor
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ABSTRACT: System l-amino acid transport mediates the uptake of aromatic neutral amino acids and nutritionally essential amino acids from extracellular fluids. Little is known about the role of l-amino acid transporter 1 (LAT1), a member of the system l-amino acid transporter family, in non-small-cell lung carcinomas (NSCLCs).
We examined (i) LAT1 mRNA levels in 40 normal lung tissues (NLTs) and 237 NSCLCs using semiquantitative RT-PCR, (ii) LAT1 protein expression in 295 NSCLCs using immunohistochemistry, and (iii) whether LAT1 mRNA and protein expressions were related to clinicopathologic findings and outcome.
The LAT1 mRNA level was significantly higher in all NSCLCs (6.81+/-1.13) than in NLT (1.00+/-0.18). The LAT1 mRNA level showed no association with clinicopathologic findings or outcome. LAT1 protein was detected with a diffuse or granular appearance within the cytoplasm and/or on the plasma membrane of tumor cells. When tumors were graded as positive if staining indicating a plasma membrane expression of LAT1 protein made up more than 10% of the tumor, the frequency of this membrane expression was found to be associated with tumor histology, differentiation grade, pathologic stage, T classification, pleural invasion, lymph-vessel invasion, and overall survival rate.
Detection of a plasma membrane expression of LAT1 protein would appear to be of value in informing the prognosis in NSCLC cases.
Lung cancer (Amsterdam, Netherlands) 07/2009; 68(1):58-65. · 3.14 Impact Factor
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Hirotaka Matsuo,
Toshinori Chiba,
Shushi Nagamori,
Akiyoshi Nakayama,
Hideharu Domoto,
Kanokporn Phetdee,
Pattama Wiriyasermkul,
Yuichi Kikuchi,
Takashi Oda,
Junichiro Nishiyama,
Takahiro Nakamura,
Yuji Morimoto,
Keiko Kamakura,
Yutaka Sakurai,
Shigeaki Nonoyama,
Yoshikatsu Kanai,
Nariyoshi Shinomiya
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ABSTRACT: Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.
The American Journal of Human Genetics 12/2008; 83(6):744-51. · 10.60 Impact Factor
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ABSTRACT: L-type amino acid transporter 1 (LAT1) is proposed to be a major nutrient transporter at the blood brain barrier. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for functional expression.
We investigated the expression of this heterodimeric transporter after traumatic spinal cord injury in rat by using immunohistochemical and western blot analyses.
LAT1 immunoreactivities were up-regulated in the capillary endothelia in close to the injury epicenter 24 hours after injury. It reached a peak at 48 hours after injury, and thereafter decreased. 4F2hc was abundant and unchanged all through the time course after SCI. Western blot analysis under reductive and non-reductive conditions showed that LAT1 and 4F2hc were conjugated as a heterodimeric transporter and the functional regulation was dependent on the light chain, LAT1.
We suggest that LAT1 may be transiently upregulated as part of the tissue-repair process after traumatic contusion injury in the spinal cord.
Acta neurochirurgica. Supplement 02/2008; 102:385-8.
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ABSTRACT: L-type amino acid transporter 1 (LAT1), a neutral amino acid transporter, requires covalent association with the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional form. We investigated the importance of LAT1 and 4F2hc expressions to progression in upper urinary tract cancer. We examined their expressions and their relationships to clinicopathologic parameters and clinical outcome in 124 cases. Positive expressions of LAT1 (protein and messenger ribonucleic acid) and 4F2hc (protein) were recognized in 79.8, 89.5, and 87.9% of tumor samples, respectively. In tumor cells, LAT1 protein was detected either as nodular granules within the cytoplasm or diffusely within the cytoplasm and/or on plasma membrane. In the normal urothelium, its expression was detected as nodular granules within the cytoplasm. A correlation with stage was shown for LAT1 protein expression and for a cooperative expression of LAT1 protein with 4F2hc protein (active form of LAT1 protein). Further, in all tumors, a cooperative expression of LAT1 protein and 4F2hc protein was significantly correlated with both overall and disease-free survival rates in the univariate analysis but not in the multivariate analysis. In conclusion, the detection of the active form of LAT1 protein would appear to be of value in informing the risk of progression in transitional cell carcinoma of the upper urinary tract.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2007; 451(3):681-90. · 2.49 Impact Factor
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Shinya Kohyama,
Yuji Morimoto,
Kanji Nakai,
Tatsumi Kaji,
Aya Tokumaru,
Hiroshi Nawashiro,
Katsuji Shima,
Yasushi Satoh,
Kunio Takishima,
Makoto Kikuchi, Hirotaka Matsuo
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ABSTRACT: Narrow-band ultraviolet-B light (NBUVB) (313 nm) is known to have anti-proliferative effects, implying a potential treatment for intimal hyperplasia, but it remains to be ascertained. We assessed the effects of NBUVB irradiation for prevention of intimal hyperplasia.
The rat carotid arteries were irradiated with NBUVB after balloon injury (BI), and the degree of intimal hyperplasia was histopathologically assessed. The anti-proliferative effects using cultured human smooth muscle cells were evaluated by flow cytometry and immunoblot analysis.
NBUVB (0.3-4.5 J/cm(2)) irradiation immediately after BI reduced the degree of intimal hyperplasia at 14 and 28 days after BI (P<0.001) without any obvious complications. Neither an increase in the number of medial cells nor upregulation of proliferating cell nuclear antigen was observed in the irradiated arteries. NBUVB irradiation at 2 or 14 days after BI significantly suppressed further intimal hyperplasia (P<0.01). NBUVB-irradiated cultured cells showed inhibited proliferation involved with G(1) and G(2)/M arrests. Increased expression of p53 and inhibition of retinoblastoma protein (pRB) phosphorylation were also seen in the NBUVB-irradiated cells.
These data suggest that NBUVB irradiation is an effective method for preventing intimal hyperplasia. The anti-proliferative effect is partly due to the cell cycle arrest caused by p53 expression and inhibited pRB phosphorylation.
Lasers in Surgery and Medicine 10/2007; 39(8):659-66. · 2.75 Impact Factor
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ABSTRACT: The expression of amino acid transporter (AT) mRNAs including A system (ATA1/SNAT1/SLC38A1, ATA2/SNAT2/SLC38A2 and ATA3/SNAT3/SLC38A4), L system (LAT1/SLC7A5 and LAT2/SLC7A8), and y+ (CAT2/SLC7A2) genes, were compared among hepatocellular carcinoma (HCC) and non-cancerous liver cells. Among them the ATA1 mRNA expression was significantly elevated in all HCC cell lines (HepG2, HLF, HuH7 and JHH4) examined compared with normal liver tissue. We further discovered that the expression of ATA1 mRNA was significantly activated in HCC tissues and also elevated in pre-malignant cirrhotic livers from HCC patients, compared with normal livers from non-HCC patients. The ATA1 protein was extensively accumulated in the cytoplasm of pre-malignant liver and most HCCs, while being weak or undetectably low in normal liver tissues. SiRNA-mediated suppression of endogenous ATA1 lowered the viability of HepG2 cells. Thus, the activation of ATA1 confers growth and survival advantages in pre-malignant and malignant liver lesions.
International Journal of Oncology 08/2007; 31(1):81-7. · 2.40 Impact Factor
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ABSTRACT: L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p<0.0001) and for those with glioblastoma multiforme in particular (p=0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner. Kaplan-Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy.
International Journal of Cancer 09/2006; 119(3):484-92. · 5.44 Impact Factor
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Kuniaki Nakanishi, Hirotaka Matsuo,
Yoshikatsu Kanai,
Hitoshi Endou,
Sadayuki Hiroi,
Susumu Tominaga,
Makio Mukai,
Eiji Ikeda,
Yuichi Ozeki,
Shinsuke Aida,
Toshiaki Kawai
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ABSTRACT: No previous study has investigated neutral large amino acid transporter type 1 (LAT1) in normal lung cells, or in atypical adenomatous hyperplasia(s) (AAH) and nonmucinous bronchioloalveolar carcinoma(s) (NMBAC) of the lung. The authors examined: (1) the levels of LAT1 mRNA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 41 normal lung tissues and 34 NMBAC using semiquantitative reverse transcription-polymerase chain reaction; (2) LAT1 mRNA and protein expressions in 35 normal lung tissues, 34 AAH (11 lesions were interpreted as low-grade AAH and 23 as high-grade AAH), and 43 NMBAC using in situ hybridization and immunohistochemistry; and (2) the association of the incidences of LAT1 mRNA and protein expressions with cell proliferation in these lesions. The level of LAT1 mRNA/GAPDH mRNA (1) tended to be higher in NMBAC (12.0+/-8.1) than in normal lung tissues (1.0+/-0.2), and (2) covered a much wider range (from 0 to 276) in NMBAC than in normal lung tissues (from 0 to 5.8), with six NMBAC having values higher than 7.0, while 5.8 was the highest value detected in normal lung tissues. In peripheral normal lung tissues, LAT1 mRNA and protein were detected in bronchial surface epithelial cells and alveolar macrophages (but not in nonciliated bronchiolar epithelial cells, or in alveolar type I or type II cells). In bronchial surface epithelial cells, LAT1 protein appeared to be of a nodular type, which was considered to be a nonfunctional protein pattern. The incidences of positive expressions for LAT1 mRNA and protein were 54.5 and 27.3% in low-grade AAH, 65.2 and 52.2% in high-grade AAH, and 65.1 and 79.1% in NMBAC, respectively. In the case of LAT1 protein expression, significant differences could be shown between total (low-grade plus high-grade) AAH and NMBAC, and between low-grade AAH and NMBAC. Thus, in terms of the incidence of LAT1 protein expression, high-grade AAH appeared intermediate between low-grade AAH and NMBAC. The Ki-67 labeling index (a cell proliferation score) was significantly higher in those AAH and NMBAC that were LTA1-protein-positive than in their LAT1-protein-negative counterparts. In conclusion, LAT1 expression may increase with the upregulation of metabolic activity and cell proliferation in high-grade AAH and NMBAC.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2006; 448(2):142-50. · 2.49 Impact Factor
