Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Expression and characterization of PGD<inf>2</inf> receptors in chronic rhinosinusitis: Modulation of DP and CRTH2 by PGD<inf>2</inf> International journal

Miki Yamamoto, Mitsuhiro Okano, Tazuko Fujiwara, Shin Kariya, Takaya Higaki, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Masao Yamada, Tadashi Yoshino, Yoshihiro Urade, Kazunori Nishizaki

International Archives of Allergy and Immunology 148 ( 2 ) 127 - 136 2009.1

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

Background: Prostaglandin D2 (PGD2) participates in airway inflammation. We reported that levels of hematopoietic-type PGD 2 synthase (h-PGDS) in sinonasal tissues may play an important role in the pathophysiology of chronic rhinosinusitis (CRS). Two PGD2 receptors have been isolated, DP and CRTH2, but whether they participate in CRS remains unclear. We sought to determine the expression and characterization of DP and CRTH2 in CRS. Methods: Expression of DP and CRTH2 in nasal polyps (NP) and uncinate process mucosae (UPM) was examined by in situ hybridization and immunohistochemistry and evaluated by real-time quantitative PCR. h-PGDS, IL-5, eotaxin and RANTES expression was also determined. In addition, the effect of PGD2 on the expression of both receptors in UPM was assessed. Results: DP was widely expressed, not only in infiltrating inflammatory cells but also in constitutive cells such as vascular endothelial cells and ciliated columnar epithelia. CRTH2 was selectively expressed in inflammatory cells and some glands. Significantly greater levels of DP mRNA and conversely decreased levels of CRTH2 mRNA were observed in NP compared with UPM. DP and CRTH2 mRNA levels were not only positively and inversely correlated with levels of h-PGDS but also with eotaxin, respectively. Furthermore, addition of PGD2 significantly increased DP expression and conversely reduced CRTH2 expression in UPM. Conclusions: These results suggest that distinct expression of DP and CRTH2 is associated with the pathophysiology of CRS, including NP formation, and the expression of these receptors may be regulated by h-PGDS and PGD 2. Copyright © 2008 S. Karger AG.

DOI： 10.1159/000155743

Patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma exhibit favorable prognosis despite a non-germinal center B-cell-like phenotype International journal

Yasuharu Sato, Naoko Onishi, Toshiaki Morito, Katsuyoshi Takata, Kohichi Mizobuchi, Hitoshi Nagatsuka, Kouichi Ichimura, Takehiro Tanaka, Maiko Tamura, Tadashi Yoshino

Cancer Science 100 ( 1 ) 42 - 46 2009

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

Diffuse large B-cell lymphomas are detected frequently in the oral cavity. Although tonsillar lymphomas have been rather well characterized, lymphomas originating from non-tonsillar regions, such as the gingiva, palate, and tongue, have not been well studied. We examined the pathology of clinical samples obtained from 21 patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma. Immunohistological examination of CD10, Bcl-6, and MUM1 determined that 17 of 21 (81%) samples exhibited non-germinal center B-cell type, an increased proportion of non-germinal center B-cell type compared with previous reports in samples of tonsillar origin (P < 0.05). The four remaining samples exhibited germinal center B-cell type, although one sample expressed MUM1. Follow-up clinical survival data were obtained from the 17 patients over a range from 4 to 173 months (mean 52 months). All patients were treated with chemotherapies, irradiation, or surgical resection. Sixteen patients achieved complete remission and two patients relapsed, but no patient has died of disease. Extranodal diffuse large B-cell lymphomas of non-germinal center B-cell type are generally characterized by poor prognosis, regardless of localized disease. Interestingly, our results indicate that, unlike similar lymphomas of tonsillar origin, localized primary non-tonsillar oral diffuse large B-cell lymphomas exhibit favorable prognosis, suggesting that these lymphomas may be clinicopathologically distinct. © 2009 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2008.00995.x

Wingless-type protein-1 (Wnt-1) expression in primary conventional and unicystic ameloblastomas and their recurrent tumors

Kee Seng Chuah, Chong Huat Siar, Keisuke Nakano, Hitoshi Nagatsuka, Suan Phaik Khoo, Kok Han Ng, Toshiyuki Kawakami

Journal of Hard Tissue Biology 18 ( 2 ) 63 - 70 2009

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

Wingless-type protein (Wnt) is a family of 19 secreted glycoproteins that function as signaling transducers for cell-cell interaction, cell growth and differentiation. Wnt-1, a highly transforming member, has been implicated in tumorigenesis. The aim of this study was to elucidate the role of this cell signaling molecule in the development and progression of primary ameloblastoma and their recurrent tumors. Wnt-1 expression patterns were examined immunohistochemically in 22 primary and 14 recurrent ameloblastomas. These collectively consisted of the following subtypes: conventional (CA) (n=22), desmoplastic (DA) (n=2) and unicystic (UA) (n=12) ameloblastoma. Results demonstrated that CA (n=20/22; 90.9%), DA (n =2/2; 100%) and UA (11/12; 91.7%) showed high Wnt-1 expression percentages. Strong staining intensity for Wnt-1 was observed more frequently in primary CA (n =10/13; 76.9%) than in their recurrent counterparts (n= 2/9; 22.2%) (p<0.05). Conversely, in UA, recurrent tumors (n=3/5; 60.0%) tend to stain strongly for Wnt-1 more frequently than their primary lesions (n=3/7; 42.9%) (p>0.05). Keratinizing cells in areas of squamous metaplasia also expressed Wnt-1 more intensely compared to their surrounding polyhedral stellate reticulum-like cells. Tumor islands containing granular cells were also Wnt-1 positive. Present findings confirmed that the Wnt signaling pathway is activated in ameloblastoma. Strong Wnt-1 expression in primary conventional and recurrent unicystic ameloblastoma suggests that Wnt-1 plays a more critical role in these subtypes. Positive expression of Wnt-1 in keratinizing ameloblastomatous tumor epithelium and granular cells complies with the anti-apoptotic properties of Wnt-1. Negative reactivity for Wnt-1 in 3 cases of ameloblastoma suggests that the development and progression of ameloblastoma may occur independent of this cell signaling molecule. © The Hard Tissue Biology Network Association.

DOI： 10.2485/jhtb.18.63

Immunohistochemical detection of erythropoietin, platelet-derived growth factor and their receptors in ameloblastomas

Xiaodong Yin, Jiankai Xu, Jinna Shi, Kewen Lv, Eryang Zhao, Tenglong Hu, Ryo Tamamura, Hitoshi Nagatsuka, Xiaohui Jiao

Journal of Hard Tissue Biology 18 ( 1 ) 19 - 26 2009

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

Ameloblastoma (AB) is the most common odontogenic epithelium-derived tumor, but has unclear etiology. Various ligand/receptor systems are implicated in ameloblastoma development. In this study, we explored the expression of erythropoietin (EPO), platelet-derived growth factor (PDGF) and their receptors (EPOR, PDGFR) in ABs, and the potential origins of ABs from keratocystic odontogenic tumors (KCOTs) and tooth germs in control groups. Immunostaining was performed using antibodies for EPO, EPOR, PDGF-A and PDGFR-ct. Statistical analysis was performed based on immunoreactivity. We found that EPOR expression was significantly higher in ABs than in KCOTs (P<0.05), but was similar to that of tooth germs. EPOR expression was also significantly different between the AB subtypes (P<0.05). Nevertheless, EPO expression was only significantly different between tooth germs and KCOTs (P<0.05). Immunoreactivity for PDGFR-α and PDGF-A was stronger in ABs than in KCOTs and tooth germs. However, significant differences were only found between individual groups or among types or subtypes of ABs (P<0.05 or P<0.01). In addition, the expression of both EPOR and PDGFR-α in the recrudescent ABs was significantly greater than in primary ABs (P<0.01). We conclude that EPO, EPOR, PDGF-A and PDGFR-α are essential for the growth of human teeth as well as for oncogenesis, development, cell differentiation and biological behavior of odontogenic neoplasm. © 2009 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

DOI： 10.2485/jhtb.18.19

P53 tumor baskilayici genin 72. kodon polimorfizminin bas-boyun kanserlerindeki prognostic rolu.

Gunduz E, Gunduz M, Beder L, Yamanaka N, Shimizu K, Nagatsuka H

Yeni Tip Dergisi 2009

Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells International journal

Kazufumi Sakurama, Yoshio Naomoto, Toshiaki Ohara, Nobuyuki Watanabe, Munenori Takaoka, Hitoshi Nagatsuka, Yasuko Tomono, Toru Tanida, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Seiichi Hirota, Takahiro Taguchi, Noriaki Tanaka

Oncology Reports 21 ( 2 ) 407 - 411 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

There is currently no suitable animal model of metastasis using cultured human gastrointestinal stromal tumor cells even though the molecular mechanisms of c-KIT-mediated progression and metastasis should be clarified. Ba/F3 murine lymphocyte cells transduced with mutant c-KIT have been utilized to analyze some molecular mechanisms related to a constitutively activated c-KIT signaling and to assess the efficacy of molecular-targeted inhibitors. Using this cellular system, we coincidentally discovered the development of axillary and inguinal lymph node swelling three weeks after subcutaneous injection of Ba/F3 cells with c-KIT mutation into nude mice. Mutation-specific PCR detected c-KIT mutation in the swollen lymph nodes but not in unmetastasized normal lymph nodes, indicating that the lymph nodes contain tumor cells which should come from a primary subcutaneous tumor. Microscopic observation revealed tumor cells infiltrating through lymphatic follicles with Ki-67-positive staining to distinguish them from lymphocytes. The significance of this model is helpful to understand the molecular mechanisms of c-KIT-mediated metastasis and is useful for assessments of molecular therapeutics and in vivo imaging.

DOI： 10.3892/or_00000237

Prolactin may stimulate proliferation in the olfactory epithelium of the female mouse

Saeko Orita, Junko Yoshinobu, Yorihisa Orita, Hidetsugu Tsujigiwa, Masashi Kakiuchi, Hitoshi Nagatsuka, Shigenobu Nomiya, Noriyuki Nagai, Kazunori Nishizaki

American Journal of Rhinology and Allergy 23 ( 2 ) 135 - 138 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：OCEAN SIDE PUBLICATIONS INC

Background: Although it is well known that olfactory receptor neurons differentiated from stem cells have an unusual lifelong ability to continue neurogenesis, effective treatment of patients with sensorineural olfactory loss is still lacking. The purpose of this study was to determine whether intranasal prolactin (PRL) is an effective inducer of proliferation in the olfactory epithelium (OE). Methods: The OE of mice treated with PRL for 6 consecutive days and of pregnant mice on gestation day (GD) 7 was investigated by immunohistochemical study using antibodies to bromodeoxyuridine. Results: The number of bromodeoxyuridine -labeled cells in the OE increased significantly in PRL-treated female mice and GD 7 mice (but not PRL-treated male mice) compared with controls. Conclusion: Pregnancy may induce proliferation in the OE, and administration of intranasal PRL may have almost the same effect as pregnancy on the OE of female mice. Copyright © 2009, OceanSide Publications, Inc., U.S.A..

DOI： 10.2500/ajra.2009.23.3282

Histopathological and immunohistochemical background of orthodontic treatment.

Kawakami T, Nakano K, Shimizu T, Kimura A, Okafuji N, Tsujigiwa H, Hasegawa H, Nagatsuka H

Int J Med Biol Front 2009

Influence of the microenvironment on gene and protein expression of odontogenic-like and osteogenic-like cells International journal

Andrea P. Rodriguez, Hidetsugu Tsujigiwa, Mehmet Gunduz, Beyhan Cengiz, Noriyuki Nagai, Ryo Tamamura, Silvia S. Borkosky, Tohru Takagi, Miho Inoue, Hitoshi Nagatsuka

Biocell 33 ( 1 ) 39 - 47 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：INST HISTOL EMBRIOL-CONICET

Progenitor cells play an important biological role in tooth and bone formation, and previous analyses during bone and dentine induction have indicated that they may be a good alternative for tissue engineering. Thus, to clarify the influence of the microenvironment on protein and gene expression, MDPC-23 cells (mouse dental papilla cell line) and KUSA/Al cells (bone marrow stromal cell line) were used, both in vitro cell culture and in intra-abdominal diffusion chambers implanted in 4-week-old male immunodefficient mice (SCID mice). Our results indicate that KUSA/Al cells differentiated into osteoblast-like cells and induced bone tissue inside the chamber, whereas, MDPC-23 showed odontoblast-like characteristics but with a low ability to induce dentin formation. This study shows that MDPC-23 cells are especial cells, which possess morphological and functional characteristics of odontoblast-like cells expressing dentin sialophosphoprotein in vivo. In contrast, dentin sialophosphoprotein gene and protein expression was not detected in both cell lines in vitro. The intra-abdominal diffusion chamber appears as an interesting experimental model for studying phenotypic expression of dental pulp cells in vivo.

Potential usage of ING family members in cancer diagnostics and molecular therapy International journal

Mehmet Gunduz, Kadir Demircan, Esra Gunduz, Naoki Katase, Ryo Tamamura, Hitoshi Nagatsuka

Current Drug Targets 10 ( 5 ) 465 - 476 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：BENTHAM SCIENCE PUBL LTD

The Inhibitor of Growth (ING) gene family is an emerging putative type II tumor suppressor gene (TSG). Proteins of INGs (ING1-5), critical modulator of the histone code via PHD fingers, are able to suppress cell growth and proliferation, induce apoptosis, and modulate cell cycle progression. ING proteins are involved in transcriptional regulation of genes, such as the p53-inducible gene p21. ING proteins also serve as shuttling proteins between nucleus and cytoplasm, and dysregulation of this nucleocytoplasmic traffic has been shown in some cancer cells. In cancer cells, ING mRNA levels are often lost or suppressed but the genes are rarely mutated. Recently the potential roles of ING proteins as prognostic biomarkers, detection of aggressive behavior of the tumor as well as prediction of chemo-radiotherapy response have also emerged. In this review, we summarize the up-to-date knowledge on functions of the ING proteins, the protein status in human tumors and discuss as a potential target in the molecular diagnostics and therapy of cancer. © 2009 Bentham Science Publishers Ltd.

DOI： 10.2174/138945009788185086

hTERT in cancer chemotherapy: A novel target of histone deacetylase inhibitors

Jun Murakami, Jun ichi Asaumi, Hidetsugu Tsujigiwa, Masao Yamada, Susumu Kokeguchi, Hitoshi Nagatsuka, Tatsuo Yamamoto, You Jin Lee

Bacterial DNA, DNA Polymerase and DNA Helicases 187 - 224 2009

Publishing type：Part of collection (book)

Chromatin structure plays an important role in the regulation of gene transcription. Chromatin structure can be modified by various post-translational modifications, including histone acetylation, phosphorylation, methylation and ribosylation. Among those modifications, histone acetylation/deacetylation is the most important mechanism for regulating transcription and is regulated by a group of enzymes known as histone acetyltransferases/histone deacetylases (HDACs). Recently, HDAC inhibitors have been shown to be a novel and promising new class of anti-cancer agent that can regulate the transcription of genes by disrupting the balance of acetylation/deacetylation in particular regions of chromatin. A number of HDAC inhibitors are currently in phase I and II clinical trials against a variety of cancers. Although some promising candidates have been identified (e.g., p21WAF1 and c-Myc), the precise molecular targets remain uncertain. In this article, we focus on one of the DNA polymerases, telomerase, as a new candidate molecular target for HDAC inhibitors. Telomerase is composed primarily of the catalytic subunit (hTERT) and the RNA template (hTERC), and its activity correlates with levels of hTERT mRNA. hTERT expression is apparently governed by complicated regulatory pathways. Based on recent studies, the hTERT gene is likely to be targeted by histone acetylation/deacetylation. © 2010 by Nova Science Publishers, Inc. All rights reserved.

Heparanase and its related molecules in odontogenic tumors.

Nagatsuka H, Katase N, Han PP, Tsujigiwa H, Siar CH, Nakajima M, Naomoto Y, Tamamura R, Kawakami T, Gunduz M

Oral Med Pathol 2009

Influence of the microenvironment on gene and protein expression of odontogenic-like and osteogenic-like cells

ANDREA P. RODRIGUEZ, HIDETSUGU TSUJIGIWA, MEHMET GUNDUZ, BEYHAN CENGIZ, NORIYUKI NAGAI, RYO TAMAMURA, SILVIA S. BORKOSKY, TOHRU TAKAGI, MIHO INOUE, HITOSHI NAGATSUKA

BIOCELL 33 ( 1 ) 39 - 47 2009

Loss of heterozygosity at chromosome 14q is associated with poor prognosis in head and neck squamous cell carcinomas International journal

Davut Pehlivan, Esra Gunduz, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Bekir Beder, Beyhan Cengiz, Rosario S. Rivera, Kunihiro Fukushima, Sukru Palanduz, Sukru Ozturk, Noboru Yamanaka, Kenji Shimizu

Journal of Cancer Research and Clinical Oncology 134 ( 12 ) 1267 - 1276 2008.12

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

Purpose and methods: Loss of heterozygosity (LOH) in a chromosomal location indicates the presence of an inactivated tumor suppressor gene (TSG). Inactivation of TSG has a functional role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Based on the recent evidences of a putative TSG on chromosome 14, we examined LOH on chromosome 14q using eight polymorphic microsatellite markers in 50 cases of HNSCCs. Results: Three regions were detected to have a high LOH rate which included 14q21.2-22.3 (42.5%), 14q31 (55%), and 14q32.1 (37%). The correlation between LOH and clinicopathological findings was investigated through statistical analyses. A strong correlation was observed between the highest LOH marker and the overall and disease-free survival. Conclusions: The results suggest that the distal part of chromosome 14 may host a TSG that may lead to the development and/or progression of HNSCCs. Several genes such as CHES1, BMP4, SAV, and PNN have arisen as candidate tumor suppressors in the region. © 2008 Springer-Verlag.

DOI： 10.1007/s00432-008-0423-1

Notch signaling in benign and malignant ameloblastic neoplasms

Keisuke Nakano, C. H. Siar, H. Tsujigiwa, H. Nagatsuka, N. Nagai, T. Kawakami

European Journal of Medical Research 13 ( 10 ) 476 - 480 2008.10

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

Background: In general, Notch is a representative signal which controls morphosis and differentiation of cells, but its role in human odontogenic neoplasms, especially in ameloblastoma and its malignant counter-part, ameloblastic carcinoma, is not known. Methods: We examined Notch1 peptide and its gene (mRNA) in an ameloblastoma (case 1: 27-year-old female, right mandibular tumor) and an ameloblastic carcinoma (case 2: 93-year-old female, right mandibular tumor), using immunohistochemistry (IHC) and in situ hybridization (ISH) techniques. Results: Notch1 intracellular domain (NICD) positive products were observed in the cells at the peripheral layer of most proliferating epithelial tumor nests in case 1. In case 2, positive products were similarly detected. In particular, small numbers of mitoses were identified in the nuclear region with intense NICD positive reaction. Conclusions: Notch signaling plays some role in cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells of odontogenic neoplasms, including ameloblastoma and ameloblastic carcinoma. Notch1 may also contribute to cell cycle arrest induced by Notch1 activation in ameloblastic carcinoma. © I. Holzapfel Publishers 2008.

Stromal cells promote bone invasion by suppressing bone formation in ameloblastoma

G. S.A. Sathi, H. Nagatsuka, R. Tamamura, M. Fujii, M. Gunduz, M. Inoue, R. S. Rivera, N. Nagai

Histopathology 53 ( 4 ) 458 - 467 2008.10

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

Aims: To study the stromal variation and role of stromal-tumour cell interaction in impaired bone formation as well as enhanced bone resorption in ameloblastoma. Methods and results: Four types of stroma were observed histologically; fibrous, desmoplastic, myxoid and myxoid with hyalinization. Osteoblast and osteoclast were counted using haematoxylin and eosin sections and immunohistochemistry with CD68. After histomorphometric analysis, only fibrous and myxoid types of stroma were distinctly identified. Secreted frizzled-related peptide (sFRP)-2, transforming growth factor-beta 1 and receptor activator of nuclear factor-κB ligand (RANKL) revealed strong expression in myxoid type compared with the normal stroma. Bone morphogenetic protein (BMP)-2 was negative in myxoid type, but positive in normal stroma. Fibrous-type stroma showed weak expression of all antigens except RANKL compared with myxoid type. Conclusions: The results suggest that stroma does not act only in bone resorption, but also in the suppression of new bone formation. sFRP-2 is the main factor for impaired bone formation. The expression of markers related to osteoclastogenesis and suppression of osteoblast formation is higher in myxoid-type than in fibrous-type stroma. Tumour cells create a favourable environment for impaired bone formation by secreting sFRP-2 as well as bone resorption by secreting RANKL and interleukin-6. © 2008 The Authors.

DOI： 10.1111/j.1365-2559.2008.03127.x

Expression of human β-defensin -1, -2, and -3 in non-inflamed pseudocyst, mucoceles

M. K. Frederic, T. Yamaai, N. Mizukawa, Y. Kaneda, N. Katase, M. Gunduz, H. Nagatsuka, T. Sugahara

Oral Diseases 14 ( 7 ) 652 - 657 2008.10

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

Objectives and design: The expressions of human beta defensin-1 (HBD-1), -2 (HBD-2) and -3 (HBD-3) in non-inflamed pseudocysts such as mucoceles were investigated immunohistochemically in this study. Materials and methods: Mucocele specimens were obtained from 21 patients. The expression of HBDs was studied immunohistochemically by using antibodies directed against HBD-1, -2, and -3. Statistical analyses were carried out on serial sections stained with antibodies. Results: Cells expressing HBDs were found in mucoceles. The expression of HBD-2 was observed in floating cells in all the specimens, whereas HBD-1 and HBD-3-expressing cells were detected in 93% and 73% of the mucoceles, respectively. The HBD-2 signal was the most intense and the HBD-3 signal intensity was weaker than that of HBD-1. HBDs were expressed in neutrophils and in other floating cells. Interestingly, the signal intensity and the population of positive cells located close to the centers of cysts were higher than those located in the peripheral areas of cysts. Conclusion: The expression of HBDs was found even in non-inflamed pseudocysts such as mucoceles. These results suggest that an unknown mechanism not involved in biophylaxis for the expression of HBDs may exist. © 2008 The Authors.

DOI： 10.1111/j.1601-0825.2008.01451.x

Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-I receptor exhibits anticancer effect in esophageal adenocarcinoma in vitro and in vivo International journal

Nobuyuki Watanabe, Munenori Takaoka, Kazufumi Sakurama, Yasuko Tomono, Shinji Hatakeyama, Osamu Ohmori, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Minoru Haisa, Junji Matsuoka, David G. Beer, Hitoshi Nagatsuka, Noriaki Tanaka, Yoshio Naomoto

Clinical Cancer Research 14 ( 14 ) 4631 - 4639 2008.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor - mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma. Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo. Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226. Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma. © 2008 American Association for Cancer Research.

DOI： 10.1158/1078-0432.CCR-07-4755

The inhibitor of growth (ING) gene family: Potential role in cancer therapy International journal

Mehmet Gunduz, Esra Gunduz, Rosario S. Rivera, Hitoshi Nagatsuka

Current Cancer Drug Targets 8 ( 4 ) 275 - 284 2008.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BENTHAM SCIENCE PUBL LTD

The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor. © 2008 Bentham Science Publishers Ltd.

DOI： 10.2174/156800908784533454

Involvement of EphA2 in head and neck squamous cell carcinoma: mRNA expression, loss of heterozygosity and immunohistochemical studies International journal

Rosario S. Rivera, Mehmet Gunduz, Hitoshi Nagatsuka, Esra Gunduz, Beyhan Cengiz, Kunihiro Fukushima, Levent Bekir Beder, Davut Pehlivan, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

Oncology Reports 19 ( 5 ) 1079 - 1084 2008.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

EphA2 is a 130-kDa transmembrane protein primarily found in adult human epithelial cells and is a member of one of the largest receptor tyrosine kinases. It is located on 1p36.1, a genetic hot spot in cancer. EphA2 over-expression has been observed in aggressive solid tumors and its potential role in tumorigenesis, which includes cell growth, survival, migration and angiogenesis have been reported. However, the role of EphA2 remains unknown in head and neck cancer. In this study, we investigated the genetic profile of EphA2 in primary head and neck squamous cell carcinoma (HNSCC) by determining mRNA level, status of loss of heterozygosity and protein expression. mRNA expression was also correlated with clinicopathological data. Infrequent loss of heterozygosity (20%) was observed, though a 10-fold increase of mRNA expression in tumors compared to normal tissues was noted. A significant number of samples with normal to high mRNA expression was observed among patients with regional metastasis, with T3-T4 tumor size and with moderate to poor differentiation. However, statistical studies did not show any correlation between mRNA expression and any of the clinicopathological parameters. Tumor cells expressed EphA2 protein, but only weakly. These results suggest thate EphA2 might be involved in the early development of HNSCC although not directly responsible for its progression.

DOI： 10.3892/or.19.5.1079

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