Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Heparanase and vascular endothelial growth factor expression in the progression of oral mucosal melanoma International journal

Rosario S. Rivera, Hitoshi Nagatsuka, Chong Huat Siar, Mehmet Gunduz, Hidetsugu Tsujigiwa, Phuu Pwint Han, Naoki Katase, Ryo Tamamura, Kok Han Ng, Yoshio Naomoto, Motowo Nakajima, Noriyuki Nagai

Oncology Reports 19 ( 3 ) 657 - 661 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Oral mucosal melanoma is an aggressive neoplasm with poor prognosis. Heparanase is an endo-β-d-glucuronidase, which cleaves heparan sulphate chains. The vascular endothelial growth factor (VEGF) is the most potent angiogenic mitogen and interaction with its receptor (VEGFR) has been associated with angiogenesis. We investigated the expression of these molecules in the progression of oral mucosal melanoma. Immunohistochemistry was carried out in 15 oral melanotic macules and 19 oral melanomas using heparanase, VEGF, VEGFR-2, CD34 and Ki-67. Microvessel density was determined and subjected to statistical analysis. Heparanase and VEGFR-2 were not expressed in the oral melanotic macule. Atypical melanocytes and melanoma cells expressed heparanase, VEGF and VEGFR-2. An intense expression was noted in the early invasive phase, which marks the crucial transition from in situ to the invasive phase. In the invasive component, heparanase was intense but selective in the invasive fronts and at the periphery of nests unlike the extensive expression of VEGF and VEGFR-2. However, hot spots were only observed at the periphery of the nests. In conclusion, melanoma cells expressed heparanase, VEGF and VEGFR-2. The coexpression of these molecules in atypical melanocytes and melanoma cells suggests their function in cell migration and invasion. Moreover, the intense expression in the crucial transition from in situ to the invasive phase suggests their role in the progression of the tumor. The role of VEGF and VEGFR-2 in angiogenesis was evident only at the periphery of the nests in the invasive components.

DOI： 10.3892/or.19.3.657

Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer International journal

Mehmet Gunduz, Levent Bekir Beder, Esra Gunduz, Hitoshi Nagatsuka, Kunihiro Fukushima, Davut Pehlivan, Eren Cetin, Noboru Yamanaka, Kazunori Nishizaki, Kenji Shimizu, Noriyuki Nagai

Cancer Science 99 ( 3 ) 531 - 538 2008.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Although many clinical and pathological prognostic factors such as tumor stage and lymph-node involvement have been described, to date no reliable or clinically applicable marker or tumor aggressiveness has been identified for head and neck cancer. In an attempt to identify such a molecular prognostic marker, we analyzed the mRNA expression status of ING3 by quantitative reverse transcription-polymerase chain reaction. We also examined p53 mutation status and investigated its relationship with ING3, as well its clinicopathological characteristics. About half of the 71 tumor samples demonstrated downregulation of ING3 compared to their matched normal counterparts. Although most clinicopathological variables were not significantly related to ING3 downregulation or p53 mutation status, a significant relationship was detected in terms of overall survival between the cases with low and normal to high ING3 expression. At 5 years follow up, approximately 60% of the patients with normal to high ING3 expression survived, whereas this was 35% in the patients with low ING3 expression. Multivariate analysis also showed downregulation of ING3 as an independent prognostic factor for poor overall survival. These results reveal that ING3 would function as a potential tumor suppressor molecule and that low levels of ING3 may indicate an aggressive nature of head and neck cancer. © 2007 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2007.00708.x

Gene expression of Jagged2 in mandibular condylar cartilage development

T. Shimizu, H. Tsujigiwa, H. Nagatsuka, K. Nakano, N. Okafuji, S. Kurihara, N. Nagai, Toshiyuki Kawakami

European Journal of Medical Research 13 ( 1 ) 1 - 3 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：I HOLZAPFEL VERLAG GMBH

Expression pattern of Jagged2 gene in mandibular condylar cartilage was examined by means of in situ hybridization (ISH) technique. At E14, Jagged2 mRNA signals appeared in cytoplasm of proliferating chondrocytes. From E15 to E19, Jagged2 mRNA was detected throughout almost all cytoplasm in all layers. However, the distribution pattern was not uniform. These results suggest that Jagged2 plays an essential role for mandibular condylar cartilage morphogenesis and development. © I. Holzapfel Publishers 2008.

Cell differentiation of neoplastic cells originating in the oral and craniofacial regions

Toshiyuki Kawakami, Hitoshi Nagatsuka, Keisuke Nakano, Takako Shimizu, Hidetsugu Tsujigiwa, Hiromasa Hasegawa, Noriyuki Nagai

Cell Differentiation of Research Developments 1 - 30 2008.1

Publishing type：Part of collection (book)

Development of the oral and craniofacial region is a complex and fascinating set of processes which require a sequential integration of numerous biological steps. For medical and dental doctors, interest is particularly high in this region, because it is composed of three blastoderms - ectoderm, mesoderm, and endoderm - as well as neural crest cells. There are many different types of neoplasms in this region. In general, proliferation, development and cytological differentiation of the neoplastic cells reflect the normal physiological development of the outbreak mother cells and/or tissues. Collected human neoplasm cases, such as osteosarcoma appearing in the oral and craniofacial region, are examined regarding the immunohistochemical expression of some morphogenesis regulation factors. Furthermore, examination of Notch signaling is also conducted for some odontogenic neoplasms. This chapter mainly describes the examination results of some morphogenesis regulation factors, such as Notch signaling, in the neoplastic cells originating in the oral and craniofacial region, especially in the odontogenic neoplasms, in both well-differentiated and poorly-differentiated neoplasms of tooth germ enamel organ-derived neoplasm. In general, these morphogenesis regulation factors are responsible for cytological regulation of cell fate, morphogenesis and/or development. The results suggest that these factors play some role in cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells. Furthermore, there would appear to be a relationship between the cytological differentiation in the oral and craniofacial neoplastic cells and the physiological development and differentiation of their originating mother cells and tissues of the oral and craniofacial region. © 2007 by Nova Science Publishers, Inc. All rights reserved.

C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma International journal

Rosario S. Rivera, Hitoshi Nagatsuka, Mehmet Gunduz, Beyhan Cengiz, Esra Gunduz, Chong Huat Siar, Hidetsugu Tsujigiwa, Ryo Tamamura, Kok Ng Han, Noriyuki Nagai

Virchows Archiv 452 ( 1 ) 27 - 32 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

C-kit is a trans-membrane receptor tyrosine kinase (RTK) encoded by the proto-oncogene KIT located at 4q11-12. Gain-of-function mutations arising to c-kit activation independent of its ligand were observed in various tumors related to germ cells, mast cells, and interstitial cells of Cajal. C-kit also participates in melanocyte development; hence, its involvement in oral mucosal melanoma (OMM) tumorigenesis was investigated. Immunohistochemistry and mutation analysis were performed using 18 cases of human primary OMM. Results revealed 16 cases positive to c-kit protein. Atypical melanocytes expressed c-kit. All in situ components expressed c-kit, but only four cases exhibited intense expression in the invasive component. Missense mutations were observed in four cases, and two of those correlated with increased protein expression. C-kit expression in atypical melanocytes suggests the role of c-kit in the early stage of OMM tumorigenesis. C-kit protein expression correlated with activating mutations indicating the pertinent role of the proto-oncogene KIT in the tumorigenesis of OMM. © 2007 Springer-Verlag.

DOI： 10.1007/s00428-007-0524-2

Deletion at Dickkopf (Dkk)-3 locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinomas International journal

Naoki Katase, Mehmet Gunduz, Levent Beder, Esra Gunduz, Mathieu Lefeuvre, Omer Faruk Hatipoglu, Silvia Susana Borkosky, Ryo Tamamura, Susumu Tominaga, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai, Hitoshi Nagatsuka

Oncology Research 17 ( 6 ) 273 - 282 2008

Language：English Publishing type：Research paper (scientific journal)

Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer, and despite improvement of its treatment methods, including chemotherapy, radiotherapy, and surgery, the improvement of survival remains poor. Recent advances in molecular biology of human cancer indicated various molecular abnormalities in HNSCC, including activation of oncogenes and inactivation of tumor suppressor genes (TSGs). Dickkopf (Dkk)-3 gene is known as a negative regulator of Wnt signaling and is suggested to function as TSG in several kinds of malignancies. We hypothesized that Dkk-3 might play an important role in HNSCC, too. Thus, in the current study, we analyzed allelic alteration of Dkk-3 locus (chromosome 11p15.2) by means of loss of heterozygosity (LOH) analysis. The study population consisted of 50 patients with HNSCC (mean age of 65 years old). Furthermore, we also examined the correlation between LOH findings of Dkk-3 locus with clinicopathological parameters to investigate its use as a biomarker in HNSCC. A remarkable LOH ratio (57%) was detected in the cases studied, implying that Dkk-3 is likely to be involved in HNSCC carcinogenesis. However, interestingly and in contrast to the expectations, we found that the group with LOH of Dkk-3 locus had less lymph node metastasis, and showed a favorable overall survival compared to the patients with retention of Dkk-3 area in survival analysis. These results indicate that Dkk-3 can play a role in HNSCC carcinogenesis with unknown mechanism. Moreover, allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC. © 2008 Cognizant Comm. Corp. All rights reserved.

DOI： 10.3727/096504008786991594

Lack of B-RAF mutations in head and neck squamous cell carcinoma

M. Al Sheikh Ali, Mehmet Gunduz, E. Gunduz, R. Tamamura, L. Beder, S. Tominaga, T. Onoda, N. Yamanaka, R. Grenman, K. Shimizu, N. Nagai, H. Nagatsuka

Folia Biologica 54 ( 5 ) 157 - 161 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：CHARLES UNIV PRAGUE, FIRST FACULTY MEDICINE

B-RAF is one of the most commonly mutated oncogenes in human cancer. However, the mutation status of B-RAF has not been established completely in HNSCC. We have analysed the mutation status of the kinase domain of the B-RAF gene (exons 11 and 15) in 91 Japanese HNSCC patients as well as 12 HNSCC cell lines. DNA was extracted and amplified by PCR. Mutations were then analysed by SSCP mutation detection method. Since V600EB-RAF constitutes 90% of the mutations identified in B-RAF in human cancers, we also used MASA analysis to specifically detect this mutation in exon 15 of B-RAF. Using both methods, no mutation was found in both exon 11 and 15 in all patients and cell lines. Mutations are absent or rare in the kinase domain of B-RAF in Japanese HNSCC. However, more studies are still needed to determine its usefulness as a target for molecular therapy in these patients.

Expression and mutation analysis of epidermal growth factor receptor in head and neck squamous cell carcinoma International journal

Mahmoud A.L. Sheikh Ali, Mehmet Gunduz, Hitoshi Nagatsuka, Esra Gunduz, Beyhan Cengiz, Kunihiro Fukushima, Levent Bekir Beder, Kadir Demircan, Masae Fujii, Noboru Yamanaka, Kenji Shimizu, Reidar Grenman, Noriyuki Nagai

Cancer Science 99 ( 8 ) 1589 - 1594 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

The epidermal growth factor receptor (EGFR)-RAS-RAF-mitogen-activated protein kinase signaling cascade is an important pathway in cancer development and recent reports show that EGFR and its downstream signaling molecules are mutated in a number of cancers. We have analyzed 91 Japanese head and neck squamous cell carcinomas (HNSCC) and 12 HNSCC cell lines for mutations in EGFR, ErbB2, and K-ras. Exons encoding the hot-spot regions in the tyrosine kinase domain of both EGFR (exons 18, 19, and 21) and ErbB2 (exons 18-23), as well as exons 1 and 2 of K-ras were amplified by polymerase chain reaction and sequenced directly. EGFR expression was also analyzed in 65 HNSCC patients using immunohistochemistry. Only one silent mutation, C836T, was found in exon 21 of EGFR in the UT-SCC-16A cell line and its corresponding metastasic cell line UT-SCC-16B. No other mutation was found in EGFR, ErbB2, or K-ras. All tumors showed EGFR expression. In 21 (32%) tumors, EGFR was expressed weakly (+1). In 27 (42%) tumors it was expressed (+2) moderately, and in 17 (26%) tumors high expression (+3) was detected. Overexpression (+2, +3) was found in 44 tumors (68%). A worse tumor differentiation and a positive nodal stage were significantly associated with EGFR overexpression (P = 0.02, P = 0.032, respectively). Similar to patients from western ethnicity, mutations are absent or rare in Japanese HNSCC. Protein overexpression rather than mutation might be responsible for activation of the EGFR pathway in HNSCC. © 2008 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2008.00861.x

A spindle cell carcinoma presenting with osseous metaplasia in the gingiva: A case report with immunohistochemical analysis International journal

Naoki Katase, Ryo Tamamura, Mehmet Gunduz, Jun Murakami, Jun Ichi Asaumi, Goichi Tsukamoto, Akira Sasaki, Hitoshi Nagatsuka

Head and Face Medicine 4 ( 1 ) 28 - 28 2008

Language：English Publishing type：Research paper (scientific journal)

Background. Spindle cell carcinoma (SpCC) is a rare, high malignant variant of squamous cell carcinoma (SCC), which shows biphasic proliferation of conventional SCC component and malignant spindle shape cells with sarcomatous appearance. Methods. A case of Spindle cell carcinoma with bone-like calcified materials, occurring at the mandibular molar region of 71-years-old Japanese male patient was presented with gross finding, histological findings and MRI image. To identify the characteristics of the bone-like materials, immunohistochemistry were performed. Results. Histologically, the cancer cells were composed of spindle cells and epithelial cells which form nests with prominent keratinization. Histological findings showed typical histology of the SpCC, however, as an uncommon finding, spatters of calcified, bone-like materials were observed in between the cancer cells. Immunohistochemistry revealed that cancer cells were positive for cytokeratins and vimentin to a varying degree and negative for Desmin, S-100, Osteopontin, BMP-2 or BMP-4. These findings implied that the calcified materials were formed by metaplasia of the stromal cells. Discussion. Bone-like materials formation by osseous and/or cartilaginous metaplasia of the stroma in the carcinoma has been reported. However, the detailed mechanism of these metaplasia and affection on the clinical feature, prognosis and therapies are not well established. In summary, we presented an unique case of SpCC, which has not been described in the literature. © 2008 Katase et al; licensee BioMed Central Ltd.

DOI： 10.1186/1746-160X-4-28

Immunohistochemical characteristics of odontogenic neoplasms and their physiological counterparts

Keisuke Nakano, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Mehmet Gunduz, Naoki Katase, Chong Huat Siar, Toshiyuki Kawakami

Journal of Hard Tissue Biology 17 ( 3 ) 79 - 90 2008

Language：English Publisher：JOURNAL HARD TISSUE BIOLOGY

Development of the tooth is a complex and fascinating set of processes which require a sequential integration of numerous biological steps. For dental doctors, interest is particularly high, because the tooth is mainly composed of surface ectodermal epithelium and neural crest derived neuroectodermal mesenchyma, and formed by epithelial-mesenchymal interactions. There are many different types of odontogenic neoplasms. In general, proliferation, development and cytological differentiation of the neoplastic cells reflect the normal physiological development of the outbreak mother cells and/or tissues. There would appear to be a relationship between the cytological differentiation of odontogenic neoplastic cells and the physiological development and differentiation of tooth germ. We describe some morphogenesis regulation factors, such as Notch signaling, in the odontogenic neoplastic cells, in both well-differentiated and poorly-differentiated neoplasms. Our results suggest that these factors play some role in cytological differentiation or acquisition of tissue-specific characteristics in neoplastic cells. © 2008 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

DOI： 10.2485/jhtb.17.79

Chemical analysis of a novel coating material, CaTiO3-aC

Mika Okauchi-Yabuuchi, Ryo Tamamura, Noriyuki Nagaoka, Shin Takagi, Etsuo Kishimoto, Tohru Takagi, Andrea Rodriguez, Miho Inoue, Hitoshi Nagatsuka, Masaru Akao, Noriyuki Nagai

Journal of Hard Tissue Biology 17 ( 3 ) 115 - 120 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

In the current study, we compared the recently developed CaTiO 3-amorphous carbon (CaTiO 3-aC) as a bone inducing coating material with HA from aspects of surface electric charge and solubility. CaTiO 3,-aC had negative surface electric charge similar to HA. Thus similar tissue reaction and bone inducing ability were considered to obtain. On the other hand solubility of CaTiO 3-aC coating was lower than HA. Moreover though CaTiO 3-aC itself showed low solubility, CaCO 3 was found to be included in it, and long-term slow Ca 2+ release occurred. Thus the sample was suggested to be used as an ion exchange material. When the implant using Ti/CaTiO 3-aC/HA double layer coating was developed, first bioactive state of the implant will continue due to HA character. Then even early resorption of HA occurs, bioactive state will continue due to CaTiO 3-aC layer. Therefore Ti base will not expose. This result is supposed to contribute long term success of the implant. © 2008 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

DOI： 10.2485/jhtb.17.115

Development of new titanium coating material (CaTiO<inf>3</inf>-aC) with modified thermal decomposition method

Noriyuki Nagai, Mika Okauchi, Andrea Rodriguez, Mehmet Gunduz, Hailong Hu, Midori Kubota, Noriyuki Nagaoka, Miho Inoue, Hitoshi Nagatsuka, Tohru Takagi, Masaru Akao

Journal of Hard Tissue Biology 17 ( 2 ) 47 - 54 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

We dveloped a novel method for titanium coating material using modified thermal decomposition technique, specifically focusing on presence of CaTiO 3 and carbon C. Two layers of thin film coating composed of CaTiO3-amorphous carbon compound (CaTiOa-aC) and hydroxyapatite (HA) were generated on titanium surface. In this method, ratios of Ca/P as well as Ca/Ti, sintering temperature and sintering velocity were carefully planned. Within crystal structure of CaTiO3 granules, 4 atomic % of carbon in amorphous state was included. By our method, inclusion of carbon in HA suggested formation of carbonate apatite. Regarding with attachment-detachment experiment at titanium surface, adhesion strength was 2.5 times stronger in CaTiO 3aC/HA coating substrate as compared to HA only coating material. Results of the novel developed modified thermal decomposition method suggested that the 2 layers biomaterial composed of CaTiO3-aC (0.6 μm) and carbonate apatite-included HA (2.4 μm) can be used as a coating material on titanium surface. © 2008 The Hard Tissue Biology Network.

DOI： 10.2485/jhtb.17.47

Juxta-epithelial hyalinization inhibits tumor growth and invasion in ameloblastoma

Gul San Ara Sathi, Masae Fujii, Silvia Susana Borkosky Ryo Tamamura, Naoki Katase, Toshiyuki Kawakami, Hitoshi Nagatsuka, Noriyuki Nagai

Journal of Hard Tissue Biology 17 ( 2 ) 63 - 68 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

In histological examination of ameloblastoma, marked juxta-epithelial hyalinization of the connective tissue adjacent to the epithelium was observed in many cases. However, the physicochemical mechanism of these changes and its role in ameloblastoma is still not understood. To analyze the expression pattern of the different types of basement membrane related molecules, apoptosis-related factors and their possible role in juxta-epithelial hyalinization, six cases of ameloblastoma were examined. Immunohistochemical staining was done using cell surface type heparan sulfate (HS), 10E4, basement membrane type HS, JM403, Heparanase, Caspase-6, BCL-2 and CD34 antibodies. Hyalinized area in all sections, were strongly positive to 10E4, but negative to heparanase. There was no CD34 positive endothelial cells within the hyalinization area. Tumor cells adjacent to this area were positive to 10E4, heparanase and caspase-6. This result suggests that hyalinization have an effect on tumor growth and stop stromal-tumor cell interaction by the help of HSPGs, resulting in the inhibition of the function of heparanase and angiogenesis. Finally, tumor cells adjacent to the hyalinization undergoes program cell death. © 2008 The Society for Hard Tissue Regenerative Biology.

DOI： 10.2485/jhtb.17.63

Inhibitor of growth (ING) family: An emerging molecular target for cancer therapy

Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Ryo Tamamura, Hitoshi Nagatsuka, Noriyuki Nagai

Journal of Hard Tissue Biology 17 ( 1 ) 1 - 10 2008

Language：English Publisher：JOURNAL HARD TISSUE BIOLOGY

ING1 gene, the founding member of the ING tumor suppressor family, was originally identified through subtractive hybridization between normal mammary epithelial cells and breast cancer cell lines, and subsequent in vivo selection of genetic suppressor element that displayed oncogenic features. Soon after identification of ING1, four additional members of the ING family (ING2-5) were cloned and all the gene products contain a highly conserved plant homeodomain (PHD) finger motif in the carboxy (C)-terminal end, that plays important role for their function. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with historie acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although exact functions of ING family genes have not been clarified, the gene products are involved in transcriptional regulation, apoptosis, cell cyle, angiogenesis and DNA repair through p53-dependent and -independent pathways. Chromosomal deletion and decreased expression of each ING family member gene in various cancer types strongly suggested products of these genes as tumor suppressor factors. Rare mutation but frequent allelic loss and epigenetic changes have been shown in ING family genes, suggesting them as a class II tumor suppressor gene. This review summarizes the known biological functions of the ING tumor suppressors and signaling related pathways. © 2008 The Hard Tunis Biology Network Printed in. Japan, All rights reserved.

DOI： 10.2485/jhtb.17.1

Localization of oxytalan fiber, type iii collagen and bmp family in conventional and desmoplastic ameloblastoma

Masahisa Inoue, Hitoshi Nagatsuka, Ryo Tamamura, Chong Uuat Siar, Hidetsugu Tsujigiwa, Silvia Borkosky, M. Fujii, Noriyuki Nagai, Kojun Setsu

Journal of Hard Tissue Biology 17 ( 1 ) 23 - 30 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

The histologic hallmark distinguishing desmoplastic ameloblastoma (DA) from conventional ameloblastoma (CA) is its pronounced stromal desmoplasia, and this formed the basis of this investigation. To elucidate the stromal characteristics, localization patterns of oxytalan fibers, type III collagen and BMP family in DA (n=8) was compared with CA (n=24), and periodontal ligament (PL) («= 8). Oxytalan fibers formed apico-occlusal bundles in PL, thick radial bundles around tumor nests in DA, and as scanty fibers in CA. Type III collagen was identified in PL, strongly expressed in DA stroma, but weakly in CA. BMP-2, -3, 4 and -7 expression patterns in tumor epithelium and stroma were more pronounced in DA (including sites of bone formation), than CA. No immunoreactivity for BMP-5 and -6 were detected. Current findings suggest that the stroma in DA is neoplastic and derived from odontogenic ectomesenchyme, and recommends its reclassification as an odontogenic epithelial-ectomcsenchymal neoplasm. © 2008 The Hard Tissue Biology Network Printed in. Japan, All rights reserved.

DOI： 10.2485/jhtb.17.23

Deletion mapping of chromosome 4q22-35 and identification of four frequently deleted regions in head and neck cancers

E. Cetin, B. Cengiz, E. Gunduz, M. Gunduz, H. Nagatsuka, L. Bekir Beder, K. Fukushima, D. Pehlivan, M. Ozaslan, N. Yamanaka, K. Nishizaki, K. Shimizu, N. Nagai

Neoplasma 55 ( 4 ) 299 - 304 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：VEDA, SLOVAK ACAD SCIENCES

Head and neck squamous cell carcinoma (HNSCC) is a diverse group of cancers that are frequently aggressive in their biologic behavior. Inactivation of tumor suppressor gene (TSG) is one of the most critical steps leading to HNSCC. Loss of heterozygosity analysis is very sensitive method for the detection of frequent allelic loss in a chromosomal locus. This method has been considered as an important evidence for the localization of TSGs. We analyzed loss of heterozygosity (LOH) at chromosome 4q22-35 region by using 14 polymorphic microsatellite markers in 83 matched normal and HNSCC tissues. LOH was detected at least in one location in 71 of 83 (86%) tumor tissues. Frequent deletions were detected at the location of microsatellite markers, D4S2909 (46%), D4S2623 (51%), D4S406 (48%), D4S1644 (45%) and D4S2979 (40%). Four different frequently deleted regions at 4q22, 4q25, 4q31 and 4q34-35 were observed. These regions include several putative TSGs such as Caspase-6, SMARCAD1, SMARCA5, SAP30 and ING2. Further molecular analysis of each gene should be performed to clarify their roles in head and neck squamous cell carcinogenesis.

Notch signaling in mandibular condylar cartilage development(Poster Session,The 16th Annual Meeting of the Society for Hard Tissue Regenerative Biology in Matsumoto Dental University)

Shimizu Takako, Nakano Keisuke, Tsujigiwa Hidetsugu, Nagatsuka Hitoshi, Watanabe Takehiro, Okafuji Norimasa, Kurihara Saburo, Hasegawa Hiromasa, Nagai Noriyuki, Kawakam Toshiyuki

Journal of hard tissue biology 16 ( 3 ) 154 - 155 2007.12

Immunolocalization of cell signaling molecules in the granular cell ameloblastoma

Gul San Ara Sathi, Phuu Pwint Han, Ryo Tamamura, Hitoshi Nagatsuka, Hailong Hu, Naoki Katase, Noriyuki Nagai

Journal of Oral Pathology and Medicine 36 ( 10 ) 609 - 614 2007.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Background: Bone morphogenic protein (BMP) and Wnt signaling pathway molecules play important roles in cytodifferentiation and cell proliferation. We attempted to localize these signaling molecules in the granular cell ameloblastoma. Materials and methods: Four samples of paraffin-embedded ameloblastoma with granular cells were studied. Immunohistochemistry was performed to detect basement membrane type heparan sulfate (HS) (JM403), cell surface type HS (10E4), heparanase, Wnt-5a, Wnt-2, β-catenin, and BMP-4. Results: In all four samples, strong expression of β-catenin and Wnt-5a was detected within the granular cells, while BMP-4 expression was weak and Wnt-2 was negative. Immunoreactivities of basement membrane type HS, cell surface type HS, and heparanase were variable within granular cells in ameloblastoma. Conclusion: Granular cells in ameloblastoma exhibit abnormal biological behaviors, particularly synthesis and secretion of protein. Synthesis of signaling molecules is upregulated, but secretion is arrested in some cases, while both are lost in other cases. © 2007 The Authors.

DOI： 10.1111/j.1600-0714.2007.00580.x

Notch signaling in mandibular condylar cartilage developmemt

Takako Shimizu, K. Nakano, H. Tsujigiwa, H. Nagatsuka, T. Watanabe, N. Okafuji, S. Kurihara, H. Hasegawa, N. Nagai, T. Kawakami

European Journal of Medical Research 12 ( 10 ) 515 - 519 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：I HOLZAPFEL VERLAG GMBH

Objective: The purpose of this study was to investigate the expression pattern of Notch signaling in mandibular condylar cartilage, as a type of secondary cartilage. Methods: Mandibular condyle of ddY mice were fixed from embryonic day 14 (E14) through just after birth (equivalent to E19). Samples were cut into 4 μ serial sections through the central area of the mandibular condyle at the sagittal plane. Serial sections were examined using histological, immunohistochemical (IHC) and in situ hybridization (ISH) techniques. Results: At E14, there were no developmental features of mandibular condyle. At the distal upper portion of developmental mandibular bone, mesenchymal cell proliferation and condensation without metacholomatic reaction to toluidine blue (TB) were seen. At E15, mandibular condylar cartilage was clearly evident, as TB metacholomasia. In IHC specimens at E14, expression of Notchl intracellular domain (NICD) was observed in the nuclei of coagulating mesenchymal cells. After E15, NICD appeared in the nuclei and the cytoplasms of cells. In ISH examination at E14, expressions of Notch1 mRNA appeared in cytoplasm of proliferating chondrocytes. From E15 to E19, Notch1 mRNA was detected throughout almost all cytoplasm in all layers. Conclusion: These IHC and ISH results suggest that Notch signaling plays an essential role for mandibular condylar cartilage morphogenesis and development. © I. Holzapfel Publishers 2007.

Analysis of the neoplastic nature and biological potential of sporadic and nevoid basal cell carcinoma syndrome-associated keratocystic odontogenic tumor

Naoki Katase, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Mehmet Gunduz, Ryo Tamamura, Han Phuu Pwint, Rosario Santos Rivera, Motowo Nakajima, Yoshio Naomoto, Noriyuki Nagai

Journal of Oral Pathology and Medicine 36 ( 9 ) 550 - 554 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Background: Keratocystic odontogenic tumor (KCOT), also known as odontogenic keratocyst, is a benign cystic neoplasm, which may be associated with nevoid basal cell carcinoma syndrome (NBCCS) and if it does, will occur as multiple cystic lesions. KCOT is locally destructive despite its bland histological features. However, the neoplastic nature of KCOT is not well established. Heparanase is an endo-d-glucuronidase enzyme that specifically cleaves heparan sulfate (HS) and the increase of its level in tumors promotes invasion, angiogenesis, and metastasis. Methods: To investigate the neoplastic character of KCOT, we studied the localization patterns of heparanase in KCOT, focusing on the differences between sporadic and NBCCS-associated KCOTs, by immunohistochemistry and in situ hybridization. To compare the expression pattern of these cysts with non-tumorous odontogenic developmental cyst, dentigerous cyst was included. Results: All the odontogenic cysts showed positive immunoreaction for heparanase protein in various intensities. The expression pattern of heparanase gene corresponded to that of protein expression. Interestingly, intense gene and protein expressions were observed in KCOT associated with NBCCS compared with sporadic ones and dentigerous cyst. Conclusions: The results implied that heparanase expression may be correlated with the neoplastic properties of KCOT, particularly in NBCCS-associated cases. © 2007 The Authors.

DOI： 10.1111/j.1600-0714.2007.00578.x

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