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Biomedical subjects

Ken Omura

Publications and source records attributed to Ken Omura.

At least 19 recordsLinked to original sources
PubMed2006

Hypoxia-inducible factor-1 mediates the expression of DNA polymerase iota in human tumor cells.

Hypoxia generated in tumors has been shown to contribute to mutations and genetic instability. However, the molecular mechanisms remain incompletely defined. Since reactive oxygen species (ROS) are overproduced immediately after reoxygenation of hypoxic cells and generate oxidized guanine, we assumed that the mechanisms might involve translesion DNA polymerases that can bypass oxidized guanine. We report here that hypoxia as well as hypoxia mimetics, desferrioxamine, and CoCl(2), enhanced the expression of DNA polymerase iota (pol iota) in human tumor cell lines. Searching the consensus sequence of hypoxia response element to which HIF-1 binds revealed that it locates in the intron 1 of the pol iota gene. These results suggest that HIF-1-mediated pol iota gene expression may be involved in the generation of translesion mutations during DNA replication after hypoxia followed by reoxygenation, thereby contributing to the accumulation of genetic changes in tumor cells.

Cell Hypoxia↗
PubMed2006

Multipotency of CD11bhighGr-1+ immature myeloid cells accumulating in oral squamous cell carcinoma-bearing mice.

We demonstrated the accumulation of CD11b(high)Gr-1(+) cells in a murine model of squamous cell carcinoma (SCC). Inoculation of NR-S1K cells derived from oral SCC induced a rapid and clear accumulation of CD11b(high)Gr-1(+) cells in secondary lymphoid organs as well as in peripheral blood. Phenotypic and morphological analyses revealed that these CD11b(high)Gr-1(+) cells were not lymphoid lineage cells, mature dendritic cells, macrophages, or granulocytes. Although the freshly isolated CD11b(high) cells lacked antigen-presenting capacity, they acquired a potent antigen-presenting capacity that included the induction of MHC class II after culture with GM-CSF and IL-4 in vitro. These results suggest that CD11b(high) cells that accumulate in tumor-bearing hosts are immature myeloid cells, but have considerable potential to differentiate into potent antigen-presenting cells under appropriate culture conditions. The use of in vitro differentiated CD11b(high) cells may be a potential strategy for obtaining patient-matched dendritic cells for tumor immunotherapy.

Animals↗
PubMed2006

A new evaluation method for neurosensory disturbance in the chin of patients undergoing mandibular sagittal split ramus osteotomy: an application of the heat flux technique.

OBJECTIVE: To examine neurosensory changes in the chin following bilateral sagittal split ramus osteotomy (BSSRO) using the heat flux technique. STUDY DESIGN: Twelve healthy adults (C-group) and 23 patients undergoing BSSRO (P-group) were examined. The warm sense threshold (WHF) and cold sense threshold (CHF) in the chin of these patients were measured by the heat flux technique. In the P-group, touch sensation also was measured with a visual analog scale (VAS) and the Semmes-Weinstein monofilament test (SW test). RESULTS: Both WHF and CHF were significantly larger in the P-group than in the C-group (P = .024). Touch sensation (VAS and SW test) were damaged in some patients of the P-group. However, no correlation was revealed between thermal sensation (WHF and CHF) and touch sensation (VAS and SW test) in the P-group. CONCLUSIONS: These results suggest that the thermal sensation in the chin was damaged after BSSRO. The heat flux technique appears to be one of the useful methods for the examination of neurosensory disturbance in the chin.

Adult↗
PubMed2006

Long-term maxillomandibular skeletal and dental changes in children with cleft lip and palate after maxillary distraction.

Long-term skeletal and dental changes were examined in 8 children with cleft lip and palate who underwent maxillary distraction to allow the maxilla to catch up to their mandibular growth at the treatment point. Changes in the overjet (OJ), overbite (OB), and positions of the anterior nasal spine (ANS), upper incisors (U1), pogonion (Pog), and lower incisors (L1) were measured on preoperative to 36 months postoperative lateral-cephalograms. In most of the children, the long-term changes after the maxillary distraction resulted in an inferior growth of the maxilla and anteroinferior growth of the mandible. This seems to suggest that maxillary distraction performed during childhood needs considerable overcorrection. However, if the maxilla is distracted to an adult position during childhood, the masticatory functions of the children will markedly deteriorate until their jaws grow. Therefore, we believe that one goal of maxillary distraction during childhood can be to allow the maxilla to catch up to the mandibular growth of the children at the treatment point.

Adolescent↗
PubMed2006

Orthognathic surgery for a patient with trichorhinophalangeal syndrome type I: a case report.

Trichorhinophalangeal syndrome (TRPS) type I is characterized by slowly progressing systemic osseous dysplasia, exhibiting craniofacial and other skeletal deformities. However, there have been few reports describing this syndrome after undergoing orthognathic surgery. In this report, we present a patient with TRPS I who successfully underwent orthognathic surgery. In addition, we examined the skeletal stability of the patient for 2 years after the surgery.

Abnormalities, Multiple↗
PubMed2006

Genetic or epigenetic silencing of low density lipoprotein receptor-related protein 1B expression in oral squamous cell carcinoma.

Previously, we have reported frequent silencing of the expression of LRP1B by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma. As the same events might be involved in the development/progression of OSCC, we examined intragenic homozygous deletions, expression levels, and methylation status in the CpG island of this gene. Homozygous deletion was detected in only 1 of 18 (5.6%) OSCC lines, whereas the expression of LRP1B mRNA was silenced in 8 of 17 (47.1%) OSCC lines without homozygous deletion. An inverse correlation between mRNA expression and methylation status of the LRP1B CpG island was clearly observed in OSCC lines, and LRP1B mRNA expression was restored by treatment with 5-aza-dCyd. Frequent methylation of the LRP1B promoter was also observed in primary OSCC. Taken together, the results suggested that frequent inactivation of LRP1B mainly occurs by means of epigenetic mechanisms in OSCC, which might play an important role in oral tumorigenesis.

Carcinoma, Squamous Cell↗
PubMed2006

PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma.

Phosphatidylinositol 3-kinases (PI3K) are a group of heterodimeric lipid kinases that regulate many cellular processes. Gene amplification and somatic mutations mainly within the helical (exon 9) and kinase (exon 20) domains of PIK3CA, which encode the 110-kDa catalytic subunit of PI3K and are mapped to 3q26, have been reported in various human cancers. Herein, 14 human oral squamous cell carcinoma (OSCC) cell lines and 108 primary OSCC tumors were investigated for activating mutations at exons 9 and 20 as well as amplifications in PIK3CA. PIK3CA missense mutations in exons 9 and 20 were identified in 21.4% (3/14) of OSCC cell lines and 7.4% (8/108) of OSCC tumors by genomic DNA sequencing. An increase in the copy number of PIK3CA, although small, was detected in 57.1% (8/14) of OSCC lines and 16.7% (18/108) of OSCC tumors using quantitative real-time PCR. A significant correlation between somatic mutations of PIK3CA and disease stage was observed: the frequency of mutations was higher in stage IV (16.1%, 5/31) than in a subset of early stages (stages I-III) (3.9%, 3/77; P = 0.042, Fisher's extract test). In contrast, the amplification of PIK3CA was observed at a similar frequency among all stages. AKT was highly phosphorylated in OSCC cell lines with PIK3CA mutations compared to those without mutations, despite the amplification. The results suggest that somatic mutations of the PIK3CA gene are likely to occur late in the development of OSCC, and play a crucial role through the PI3K-AKT signaling pathway in cancer progression.

Adult↗
PubMed2006

Gene expression analysis by cDNA microarray in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is common type of human cancer, but little is known about the molecular mechanisms deciding on this malignancy. Comprehensive gene expression profiling is essential for understanding OSCC. METHODS: cDNA microarray was used to analyze expression patterns of 16 617 genes in nine OSCC patients. RESULTS: Forty-seven genes with altered expression among all cases were extracted. The ontology of these 47 genes was classified into 10 categories. To validate the microarray data, the expression of genes, including TGFBI, FADD and DUSP1 was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). By hierarchical clustering analysis, the nine cases were divided into two clusters. CONCLUSIONS: The 47 genes are suggested as having a functional significance in oral squamous cell carcinogenesis. It is also suggested that the gene expression patterns by hierarchical clustering analysis can represent degrees of differentiation. The postoperative recovery was uneventful and patients free from tumor after surgery. In the future, on the occasion when the time comes that the number of cases accumulated for microarray increases and each case is observed more over a long-term, these data of 5-year survival rate will be added. Thereby, it will become possible to represent the malignancy of OSCC by these gene expression patterns.

Adult↗
PubMed2006

Role of caspase 8 as a determinant in chemosensitivity of p53-mutated head and neck squamous cell carcinoma cell lines.

We studied factors that control chemoresistance to 6 head and neck squamous cell carcinoma cell lines carrying p53 mutations. Cell lines were chosen, based on the presence of EGFR amplifications, the presence of H-ras mutations, and the absence of either. WST-1 viability assays showed that, in response to etoposide, Ca922 was most sensitive, HOC313 most resistant, and HSC6 and the others moderately sensitive. A similar tendency was shown by further analyses with cisplatin, 5-fluorouracil, LY294002, and combined treatment with LY294002 and TNF-related apoptosis-inducing ligand (TRAIL). Although both Ca922 and HOC313 had activating mutations upstream of Akt signaling, the constitutive phosphorylation of Akt at S473 was observed in chemosensitive Ca922, but not in chemoresistant HOC313, suggesting that constitutive Akt phosphorylation was not the primary determinant for chemoresistance in these cell lines. Further, by the combined treatment with LY294002 and TRAIL, apoptosis was induced in Ca922 and HSC6 but not in HOC313. Interestingly, caspase 8 was not detected in HOC313, while it was cleaved in the other 2 cell lines. Further, in Ca922 and HSC6 but not in HOC313, caspase 8 inhibitor restored loss of viability induced either with LY294002 and TRAIL or even with etoposide alone. These findings suggest that caspase 8 played an important role in chemoresistance against genotoxic drugs.

Antineoplastic Agents↗
PubMed2006

Teeth contacting habit as a contributing factor to chronic pain in patients with temporomandibular disorders.

Many different factors are known to cause and perpetuate the symptoms of temporomandibular disorders (TMD). However, the roles of parafunctional factors have not been clearly elucidated. We found one of these habits in the clinical setting. This parafunctional habit involves daily light touching of the upper and lower teeth, when the mouth is closed. We named this habit Teeth Contacting Habit (TCH). [OBJECTIVES] To investigate the following hypotheses: 1) TCH is associated with perpetuation of chronic pain of TMD patients; 2) TCH is associated with other behavioral factors. [METHODS] Two hundred and twenty-nine TMD outpatients with chronic pain were analyzed with multivariate logistic regression models. [RESULTS] TCH was found in 52.4% of patients. Patients with TCH and pain lasting for more than four months were less likely to experience improvements in pain at the first visit (OR = 1.944, p = 0.043). Other factors associated with TCH were as follows: unilateral chewing (OR = 2.802) and involvement in a precision job (OR = 2.195). [CONCLUSION] TCH can prolong TMD pain and is associated with other behavioral factors.

Adult↗
PubMed2005

Parp-1 deficiency does not increase the frequency of tumors in the oral cavity and esophagus of ICR/129Sv mice by 4-nitroquinoline 1-oxide, a carcinogen producing bulky adducts.

The impact of poly(ADP-ribose) polymerase-1 (Parp-1)-deficiency on 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis was studied in mice with an ICR/129Sv mixed genetic background. Parp-1(+/+), Parp-1(+/-) and Parp-1(-/-) animals given 4NQO for thirty-two weeks at 0.001% in their drinking water developed papillomas and squamous cell carcinomas of the tongue, palate and esophagus, but with no statistically significant variation with the Parp-1 genotype. Thus Parp-1 deficiency does not elevate susceptibility to carcinogenesis induced by a carcinogen which gives rise to bulky DNA lesions. This study also indicated that the ICR/129Sv mixed genetic background is associated with high yield induction of esophageal tumors by 4NQO.

4-Nitroquinoline-1-oxide↗
PubMed2005

Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma.

We examined cell surface expression of five B7 costimulatory molecules (B7-H1, B7-DC, B7h, CD80 and CD86) in human oral squamous cell carcinoma (SCC) lines. Most human SCC cell lines expressed various levels of B7-H1 and B7-DC. Their expression was further upregulated by interferon (IFN)-gamma stimulation. Immunohistochemical staining revealed substantial and predominant expression of B7-H1 on human primary oral SCC. A murine SCC line, NR-S1, neither expressed B7-H1 nor B7-DC, but induced B7-H1 by IFN-gamma stimulation in culture and the inoculation in vivo. Although NR-S1 tumors grew progressively in immunocompetent syngeneic mice, the administration of blocking anti-B7-Hl or anti-PD-1 mAb significantly inhibited the tumor growth, suggesting the negative regulation of host immune responses by the PD-1:B7-H1 pathway. Our results demonstrate that B7-H1 is predominantly induced on oral SCC within the B7 family molecules. A successful inhibition of tumor growth by blockade of the PD-1:B7-H1 pathway may implicate a new approach for immunotherapy of oral SCC.

Animals↗
PubMed2005

Long-term skeletal and dental changes in patients with cleft lip and palate after maxillary distraction: a report of three cases treated with a rigid external distraction device.

We examined long-term skeletal and dental changes in three patients with cleft lip and palate who underwent maxillary distraction using a rigid external distraction device. Two were children, and one was an adult. Changes in the overjet (OJ), overbite (OB), and positions of the anterior nasal spine (ANS), upper incisors (U1), pogonion (Pog), and lower incisors (L1) were measured on preoperative to 36 months postoperative lateral-cephalograms. In the adult, the positions of all examination points were relatively stable from 6 to 36 months postoperatively, and the OJ and OB were maintained at over 2 mm at 36 months. In the children, the positions of ANS and U1 changed inferiorly, Pog and L1 changed anteroinferiorly, and OJ and OB tended to decrease from 6 to 36 months postoperatively. Long-term skeletal and dental stability following maxillary distraction was relatively well maintained in the adult patient. In the children, the maxillomandibular growth was observed after maxillary distraction, but the mandibular overgrowth might have been inhibited by the correction of class III dentoskeletal deformity resulting from the maxillary distraction.

Adult↗
PubMed2005

A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation.

The EGFR/Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and differentiation. Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported. In this study, we present evidence for a mutation in an oral squamous cell carcinoma cell line, HSC6. PCR-amplification of cDNA, cloning and sequencing resulted in the identification of glutamic acid to lysine substitution at codon 322 (E322K) that occurred in the common docking (CD) domain of ERK2. The mutant protein contributed towards faster-migration in SDS-PAGE, and constitutive phosphorylation in a MEK-dependent manner. The transient transfection of the mutant ERK2 in 293T cells resulted in the expression of the same faster-migrating band in SDS-PAGE as was detected in HSC6 cells, which was preferentially phosphorylated relative to endogenous wild-type ERK2. The present study is the first to report ERK2 substitution mutation in a human cancer cell line which resulted in constitutive phosphorylation.

Amino Acid Sequence↗
PubMed2004

The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role.

PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-gamma. The T-cell proliferative responses and IFN-gamma production that were induced by IFN-gamma-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin.

Adult↗
PubMed2004

The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD).

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.

Amino Acid Sequence↗
PubMed2004

Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells.

Cyclooxygenase (COX)-2 is generally known as an inducible enzyme, and it produces arachidonic acid to prostaglandin E2 (PGE2), which modulates bone metabolism. Here, we investigated the expression and role of COX isomers in human mesenchymal stem cells. Human mesenchymal stem cells constitutively expressed COX-2 as well as COX-1, and secretion of PGE2 was completely inhibited by NS-398, a specific inhibitor of COX-2. Levels of secreted PGE2 were strikingly higher in human mesenchymal stem cells than in osteoblastic cells differentiated from the mesenchymal cells. This higher production of PGE2 in mesenchymal stem cells was due to higher expression of membrane-associated PGE synthase (mPGES) regulated by early growth response factor-1 (Egr-1). Treatment of human mesenchymal stem cells with NS-398 suppressed expression of bone morphogenetic protein-2 (BMP-2). The suppression of BMP-2 by NS-398 was abrogated by an EP4 receptor agonist as well as by PGE2. Moreover, BMP-2 expression was suppressed by an EP4 receptor antagonist. These data indicate that PGE2 produced by COX-2 increases BMP-2 expression via binding the EP4 receptor.

Bone Morphogenetic Protein 2↗