Hideo Shigeishi

Hiroshima University, Hirosima, Hiroshima, Japan

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Publications (54)134.91 Total impact

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    Preview · Article · Nov 2015
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    Hideo Shigeishi · Kouji Ohta · Masaaki Takechi
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    ABSTRACT: Objective The objective of this study was to clarify significant risk factors for postoperative complications in the oral cavity in patients who underwent oral surgery, excluding those with oral cancer. Material and Methods This study reviewed the records of 324 patients who underwent mildly to moderately invasive oral surgery (e.g., impacted tooth extraction, cyst excision, fixation of mandibular and maxillary fractures, osteotomy, resection of a benign tumor, sinus lifting, bone grafting, removal of a sialolith, among others) under general anesthesia or intravenous sedation from 2012 to 2014 at the Department of Oral and Maxillofacial Reconstructive Surgery, Hiroshima University Hospital. Results Univariate analysis showed a statistical relationship between postoperative complications (i.e., surgical site infection, anastomotic leak) and diabetes (p=0.033), preoperative serum albumin level (p=0.009), and operation duration (p=0.0093). Furthermore, preoperative serum albumin level (<4.0 g/dL) and operation time (≥120 minutes) were found to be independent factors affecting postoperative complications in multiple logistic regression analysis results (odds ratio 3.82, p=0.0074; odds ratio 2.83, p=0.0086, respectively). Conclusion Our results indicate that a low level of albumin in serum and prolonged operation duration are important risk factors for postoperative complications occurring in the oral cavity following oral surgery.
    Preview · Article · Sep 2015 · Journal of applied oral science: revista FOB
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    ABSTRACT: BackgroundCD44 and aldehyde dehydrogenase 1 (ALDH1) have been shown to be useful markers for identification of cancer stem cells (CSCs). We previously reported that glycogen synthase kinase 3β (GSK3β) is involved in regulation of the self-renewal ability of head and neck squamous cell carcinoma (HNSCC) CSCs. The purpose of the present study was to clarify the role of GSK3β in CD44high/ALDH1high HNSCC cells.Methods Cells with greater expression of CD44 and higher ALDH1 enzymatic activity were FACS sorted from the OM-1 HNSCC cell line. The self-renewal ability of CD44high/ALDH1high cells was then examined using a tumor sphere formation assay. mRNA expressions of the stem cell markers Sox2, Oct4, and Nanog, as well as GSK3β were evaluated by real-time RT-PCR.ResultsCD44high/ALDH1high cells exhibited higher tumor sphere forming ability and increased expression of stem cell markers as compared with CD44high/ALDH1low cells. Interestingly, spindle-shaped cells positive for vimentin were found in the CD44high/ALDH1high but not the CD44high/ALDH1low cell population. In addition, the ALDH1 activity and sphere forming ability of CD44high/ALDH1high cells was significantly inhibited by GSK3β knockdown. On the other hand, CD44high/ALDH1low cells exhibited high epidermal growth factor receptor (EGFR) expression and increased cell growth.Conclusions Our results show that GSK3β plays a major role in maintenance of stemness of CD44high/ALDH1high HNSCC cells. Additionally, they indicate a close relationship between CSC and mesenchymal characteristics in HNSCC.
    No preview · Article · Sep 2015 · Journal of Oral Pathology and Medicine
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    ABSTRACT: Malignant salivary gland tumors are rare and exhibit a broad spectrum of phenotypic heterogeneity. The objective of this study was to investigate prognostic factors in patients with salivary gland carcinomas and review the results in light of other reports. We retrospectively reviewed 40 patients with primary salivary gland carcinomas who were diagnosed and treated at our institution between 1991 and 2014. Of the 40 tumors, 19 (47.5%) were mucoepidermoid carcinomas, 11 (27.5%) were adenoid cystic carcinomas, 7 (17.5%) were acinic cell carcinomas, 2 (5.0%) were myoepithelial carcinomas and 1 (2.5%) was a squamous cell carcinoma. Clinically positive lymph nodes were present in 4 patients (10.0%). As regards clinical stage, 15 cases (37.5%) were stage I, 13 (32.5%) were stage II, 1 (2.5%) was stage III and 11 (27.5%) were stage IVA. The majority of the patients (97.5%) were treated with surgery, of whom 25 (62.5%) received surgery alone and 14 (35.0%) underwent surgery in combination with chemotherapy or chemotherapy and radiotherapy. The median follow-up time for all the patients was 48 months. The disease-specific survival rate at 5 years was 87.1%. We identified a significant correlation between poor survival rate and histological grade (intermediate/high), tumor size (T3/T4), lymph node metastasis (node-positive) and clinical stage (III/IV) using the Kaplan-Meier method (P<0.05 for each). In addition, the Cox proportional hazards regression analysis confirmed that lymph node metastasis and tumor size were independent prognostic factors for disease-specific survival (hazard ratio = 18.7 and 15.1, respectively; P=0.023 and 0.037, respectively). Furthermore, tumor size was found to be a predictive factor regarding recurrence in the multivariate logistic regression analysis (odds ratio = 8.35; P=0.025). Our results suggest that lymph node metastasis and tumor size are significant prognostic factors for patients with salivary gland carcinomas.
    Preview · Article · Jan 2015 · Molecular and Clinical Oncology
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    ABSTRACT: Background: Innate immune response by oral mucosal cells may be the first line of host defense against viral infection. Retinoic acid-inducible gene-I (RIG-I) recognizes viral dsRNA in the cytoplasm, and RIG-I-mediated signaling regulates antiviral type I IFN, and inflammatory chemokine production. Here, we tested the hypothesis that oral mucosal cell participation in host defense against viral infection via RIG-I. Methods: RIG-I expression was detected in immortalized oral keratinocytes (RT7), oral fibroblasts (GT1) using and RT-PCR and immunohistochemistry. RT7 and GT1 were exposed to dsRNA virus mimic Poly I:C-LMW/LyoVec (PLV). Expression of IFN-β and CXCL10 via RIG-I was examined by Real-time RT-PCR and ELISA. Phosphorylation of IRF3 and STAT1 were detected by western blotting. Results: RT7 and GT1 constitutively expressed RIG-I in the cytoplasm. Furthermore, PLV increased IFN-β and CXCL10 productions in both RT7 and GT1 via RIG-I concurrent with phosphorylation of IRF3 and STAT1. PLV-induced CXCL10 production was attenuated by neutralization of IFN-β and blocking of IFN-α/β receptor (IFNAR), indicating primal IFN-β production via the RIG-I-IRF3 axis, which eventually induces CXCL10 production via the IFNAR -STAT1 axis. Conclusion: We propose that RIG-I in oral keratinocytes and fibroblasts may cumulatively develop host-defense mechanisms against viral infection in oral mucosa. © 2014 S. Karger AG, Basel.
    No preview · Article · Oct 2014 · Journal of Oral and Maxillofacial Surgery
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    ABSTRACT: Background Cancer stem cells (CSCs) are involved in both tumourigenesis and in tumour recurrence after therapy. In head and neck squamous cell carcinoma (HNSCC), there are two biologically different CSC phenotypes both of which express high levels of CD44 but differ in their expression levels of epithelial-specific antigen (ESA). One phenotype is CD44high/ESAhigh and has epithelial features (Epi-CSCs), while the other is CD44high/ESAlow, has undergone epithelial to mesenchymal transition (EMT-CSCs), has mesenchymal features and is migratory (Biddle et al., 2011). CSCs are resistant to therapeutically induced apoptosis but the molecular mechanisms by which they develop apoptotic resistance remains unclear. However, glycogen synthase kinase 3β (GSK3β) contributes to regulation of both the self-renewal and switching of these two CSC phenotypes (Shigeishi et al., 2013).MethodsCD44high/ESAlow, CD44high/ESAhigh and CD44low cells were FACS sorted from the HNSCC cell line LUC4, and 5-FU-induced apoptosis was analysed by Annexin V staining followed by flow cytometry analysis.ResultsCD44high/ESAlow cells exhibited marked resistance to 5-FU-induced apoptosis and had high expression of dihydropyrimidine dehydrogenase (DPD). The DPD inhibitor, 5-chloro-2, 4-dihydroxypyridine (CDHP) significantly enhanced 5-FU-induced apoptosis of CD44high/ESAlow cells. Inhibition of GSK3β induced CD44high/ESAlow cells to undergo mesenchymal-to-epithelial transition (MET) to CD44high/ESAhigh cells and pre-existing CD44high/ESAhigh cells to differentiate. Apoptosis induced by 5-FU was thus facilitated. Combination of both CDHP and GSK3β inhibitors markedly enhanced 5-FU-induced apoptosis of CD44high/ESAlow cells.Conclusions Our results suggest potentially new approaches for the elimination of the therapy resistant HNSCC CSC population.
    Full-text · Article · Aug 2014 · Journal of Oral Pathology and Medicine
  • Hideo Shigeishi · Koichiro Higashikawa · Masaaki Takechi
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    ABSTRACT: The receptor for hyaluronan (HA)-mediated motility (RHAMM) is a HA-binding protein located in the cytoskeleton and centrosome. RHAMM has multiple functions that manifest with different cellular localizations, for example, modulation of growth factor receptor, regulation of cell signaling pathways, and mitotic spindle assembly. In addition, its increased expression has major roles in tumorigenesis and can induce genomic instability and cancer progression. In head and neck cancers, increased expression of RHAMM is associated with high proliferation of cancer cells and decreased survival. CD44, a cell-adhesion molecule and HA receptor, can modulate intracellular signaling by forming complexes with RHAMM to promote invasion and metastasis of cancer cells. In this review, we provide an overview of the biological functions of RHAMM in non-neoplastic cells and cancer cells, as well as its association with CD44, and also introduce studies that particularly implicate RHAMM in the pathogenesis of head and neck cancers.
    No preview · Article · Mar 2014 · Journal of Cancer Research and Clinical Oncology
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    ABSTRACT: Cells sorted from head and neck cancers on the basis of their high expression of CD44 have high potency for tumor initiation. These cells are also involved in epithelial to mesenchymal transition (EMT) and we have previously reported that cancer stem cells (CSCs) exist as two biologically distinct phenotypes. Both phenotypes are CD44(high) but whereas one is also ESA(high) and maintains epithelial characteristics, the other is ESA(low) , has mesenchymal characteristics and is migratory. Examining CD44-regulated signal pathways in these cells we show that CD44, and also RHAMM, act to inhibit phosphorylation of glycogen synthase kinase 3β (GSK3β) and that such inhibition reduces the formation of both "tumour spheres" and "holoclone" colonies, functional indicators of stemness. GSK3β inhibition also reduces the expression of stem cell markers such as Oct4, Sox2 and Nanog and up-regulates expression of the differentiation markers Calgranulin B and Involucrin in the CD44(high) /ESA(high) cell fraction. Transition of CSCs out of EMT and back to the epithelial CSC phenotype is induced by GSK3β knockdown. These results indicate that GSK3β plays a central role in determining and maintaining the phenotypes and behavior of CSCs in vitro and are likely to be involved in controlling the growth and spread of tumours in vivo.
    No preview · Article · Oct 2013 · Stem Cells
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    ABSTRACT: In this study, we found that wounding of a confluent monolayer of squamous cell carcinoma (SCC) cells induced epithelial-mesenchymal transition (EMT) specifically at the edge of the wound. This process required the combined stimulation of TGFβ, TNFα and PDGF-D. Such a combined cytokine treatment of confluent monolayers of the cells upregulated the expression levels of Snail and Slug via PI3K. The PI3K downstream effector, AKT, was dispensable for the upregulation of Snail and Slug, but essential for enabling EMT in response to upregulation of Snail and Slug. In a pool of freshly prepared cells expressing exogenous Snail via a retroviral vector to avoid clonal effects, only 20% of the growing cells displayed the EMT phenotype. The population of cells undergoing EMT was diminished when the cells formed a confluent monolayer. However, upon wounding of the confluent monolayer, EMT was induced in the collectively migrating cells at the wound edge. Moreover, co-expression of a constitutively active AKT mutant with Snail increased the incidence of EMT concomitantly with the accelerated collective cell motility. Based on these findings, we conclude that the plasticity of Snail family-mediated EMT in SCC cells is regulated by the PI3K-AKT axis in response to the environmental condition. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Sep 2013 · Journal of Cellular Biochemistry
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    ABSTRACT: Fibro-osseous lesions of the jaw are poorly understood because of a significant overlap of clinical, radiological and histological features among the various types, though they present distinct patterns of disease progression. An ossifying fibroma is associated with significant cosmetic and functional disturbances, as it shows expansive proliferation. Thus, it is important to establish a specific marker, as well as clearly elucidate its etiology for diagnosis and proper treatment. We previously established immortalized cell lines from human ossifying fibromas of the jaw and found that they highly expressed the receptor for hyaluronan (HA)-mediated motility (RHAMM). In this study, we examined the expression of RHAMM mRNA in 65 fibro-osseous lesions, including ossifying fibroma, fibrous dysplasia and osseous dysplasia, as well as 5 normal jaws, using real-time RT-PCR and immunohistochemistry assays. RHAMM mRNA and protein expression were significantly elevated in the ossifying fibroma specimens. These results suggest that detection of upregulated RHAMM expression in an ossifying fibroma assists with differential diagnosis and has a key role in elucidation of its pathophysiology.
    No preview · Article · Feb 2013 · Histology and histopathology
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    ABSTRACT: Background Various instruments have been developed for collecting bone debris during intraoral autogenous bone graft procedures in implant surgery. The aim of this study was to quantitatively determine the degree of contamination in bone debris collected by different devices. Methods Twelve patients underwent autogenous bone collection using a bone chisel, bone scraper, trephine drill, and bone filter during bone augmentation surgery as a part of implant therapy, and the total bacterial count in bone debris collected by each was determined. Results Following anaerobic incubation, bacterial colony formation was found in all of the samples. The mean colony forming units (CFU)/g in samples collected by the trephine drill was found to be significantly lower than that of samples obtained with the other devices, while those values for samples collected by the bone scraper and bone filter was significantly higher as compared to the bone chisel and trephine drill. Conclusion The bacterial levels may still carry the infection risk. Thus prophylactic antibiotic therapy maybe indicated when using bone particles for intraoral augmentation procedures.
    Preview · Article · Jan 2013 · Head & Face Medicine
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    ABSTRACT: Oral keratinocytes and fibroblasts may be the first line of host defense against oral microorganisms. Here, we tested the hypothesis that oral keratinocytes and fibroblasts recognize microbial components via Toll-like receptors (TLRs) and participate in development of oral inflammation. Our results showed that immortalized oral keratinocytes (RT7), fibroblasts (GT1) and primary cells expressed mRNA of TLRs 1-10. Interleukin-8 (IL-8) production from RT7 cells was induced by treatment with TLR1-9 except for TLR7 agonist, while, GT1 cells were induced to produce IL-8 by all TLR agonists tested except for TLR7 and TLR9. GT1 cells showed increased CXCL10 production following treatment with agonists for TLR1/2, TLR3, TLR4 and TLR5, while only those for only TLR3 and TLR5 increased CXCL10 production in RT7 cells. Moreover, TLR agonists differentially regulated TNF-α-induced IL-8 and CXCL10 production by the tested cell types. These findings suggest that recognition of microorganism-derived pathogen in oral keratinocytes and fibroblasts by TLR may have important role to orchestrate host immune responses via production of various chemokines.
    No preview · Article · Dec 2012 · Microbiology and Immunology
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    ABSTRACT: We previously identified genes associated with Snail-mediated squamous cell carcinoma (SCC) invasiveness, in which we observed significant elevation of Cyr61 expression. In this study, SCC cell lines overexpressing Cyr61 exhibited constitutive activation of Rho A and upregulated invasiveness without the disruption of hemophilic cell attachment. Humoral Cyr61 enhanced further production of endogenous Cyr61 by SCC cells, which stimulated collective cell migration and the development of an invasive tumor nest. We propose a Cyr61-dependent model for the development of invasive SCC nest, whereby a subset of tumor cells that highly produce Cyr61 may direct other tumor cells to undergo collective cell migration, resulting in a formation of primary SCC mass.
    No preview · Article · Nov 2012 · Cancer letters
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    ABSTRACT: Objective: Involvement of epithelial-to-mesenchymal transition (EMT) in cancer invasion and metastasis has recently been highlighted. Stromal signals (e.g., TFGß) induce EMT with altered expression of epithelial and mesenchymal markers, changes in cellular morphology, and increased ability to migrate and invade. The EMT process induced in cancer cells at the margins of in vitro epithelial wounds was investigated as a model of the invasive tumour margin. Method: Control, and TGFß and TNFa-treated Ca1 cell populations, were examined to determine EMT levels. Cells cultured in medium with/without TGFß/TFGß-inhibitor were scraped to produce denuded areas and coverage by migrating cells, cell morphology, and vimentin and twist immunopositivity, examined. The EMT (CD44hi/ESAlow) and non-EMT (CD44hi/ESAhi) fractions of CSC were independently isolated, scratch-assayed and analysed. Result: Markedly increased EMT levels were induced by TGFß and TNFa, and reduced by specific inhibitors. After 12h, control cells showed migration of elongated, vimentin-positive cells into denuded areas, with their partial closure by 48h. TGFß-treatment led to a significant increase in the coverage of denuded areas at 24h (3-fold) compared to controls, and also to increased vimentin immunostaining. Conversely, coverage was lower when TGFß-inhibitor was added. Scratch assays of Ca1 cells FACS-sorted independently into EMT and non-EMT subpopulations showed co-staining of vimentin and twist, and this was higher for the EMT cells. Conclusion: In vitro assays provide consistent data for EMT changes occurring in the CSC fraction of OSCC. TGFß induction of higher expression of vimentin and twist in migrating cells, together with induction of higher motility and faster wound closure, confirm that the EMT process occurring in malignant cells is responsive to agents known to induce EMT in normal tissues and that such in vitro systems can provide suitable models for analysis of cytokine interactions during cancer invasion in vivo.
    No preview · Conference Paper · Jun 2012
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    ABSTRACT: Oral Diseases (2012) 18, 756–762 Objectives: An odontoma, which shows proliferating odontogenic epithelium and mesenchymal tissue, is one of the most common odontogenic tumors encountered. These are commonly found in tooth-bearing regions, although the etiology remains unknown. There are no previous reports of an established line of immortalized human odontoma cells. Methods: Using odontoma fragments obtained from a girl treated at our department, we established an immortalized human odontoma cell line and investigated cell morphology, dynamic proliferation, the presence of contamination, and karyotype. Moreover, cell characterization was examined using osteogenic and odontogenic markers. Results: We successfully established a mesenchymal odontoma cell (mOd cells). The cells were found to be fibroblastic and had a high level of telomerase activity. Cell growth was confirmed after more than 200 population doublings without significant growth retardation. mOd cells expressed mRNA for differentiation markers, including collagen type I (COLI), alkaline phosphatase, bone sialoprotein, osteopontin, osteocalcin, cementum-derived protein (CP-23), dentin sialophosphoprotein (DSPP), and distal-less homeobox 3 (DLX3), as well as bone morphogenetic proteins (BMPs). In addition, they showed a high level of calcified nodule formation activity in vitro. Conclusions: We successfully established a cell line that may be useful for investigating the mechanisms of normal odontogenesis as well as characteristics of odontoma tumors.
    No preview · Article · Apr 2012 · Oral Diseases
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    ABSTRACT: The aim of this study was to evaluate the clinical behavior and the histological aspects of interconnected porous hydroxyapatite ceramics (IP-CHA) in maxillary sinus floor augmentation procedures. A 59-year-old female patient received one-stage implant integration with right maxillary sinus floor augmentation with mixture grafts from the cortical bone and IP-CHA. Implant stability of each fixture increased at 9 months after fixture installation compared with the first operation and adequate fixation of each fixture could be obtained. Histological analysis revealed there was new bone formation in the majority of pores of IP-CHA. Moreover, on a panoramic radiograph taken at 33 months the mixture grafts were distinctly observed as a radiopacity in the right sinus cavity, and marked absorption of mixture grafts was not found. Our results suggest that IP-CHA has the potential to provide a major scaffold for osteoprogenitor cells and is a useful grafting material for maxillary sinus augmentation.
    Preview · Article · Feb 2012 · Dental Materials Journal
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    ABSTRACT: Calcifying cystic odontogenic tumor is a comparatively rare tumor that often occurs in young people. Histopathologically, it is characterized by odontgenic epithelium and ghost cells with calcification. We report a case of calcifying cystic odontogenic tumor occurring in the mandible of an elderly woman, along with a discussion of the literature. A 92-year-old woman noticed swelling and pain at the left molar region of the mandible about 2 years before presentation. Because the swelling recurred several times after incisional drainage performed at a nearby dental clinic, she visited the department of oral and maxillofacial surgery of another hospital. Biopsy with histopathological examination revealed a calcifying cystic odontogenic tumor, and she was referred to our hospital. She was edentulous and had a bone-like firm bulge extending from the left molar region to the front of the ramus. Panoramic photography and computed tomography showed a radiolucent image with a clear border in the region. The tumor was surgically resected under sedation and local anesthesia. There has been no recurrence during the 15 months of follow-up.
    No preview · Article · Jan 2012 · Nippon Koku Geka Gakkai zasshi
  • H Shigeishi · K Higashikawa · N Kamata

    No preview · Article · Nov 2011
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    ABSTRACT: Receptor for hyaluronan (HA)-mediated motility (RHAMM) was first described as a soluble HA binding protein released by sub-confluent migrating cells. We previously found that RHAMM was highly expressed and plays an important role in proliferation in the human cementifying fibroma (HCF) cell line, which we previously established. HCF is a benign fibro-osseous neoplasm of the jaw and is composed of fibrous tissue containing varying amounts of mineralized material. However, the pathogenesis of HCF is not clear. In this paper, we examined the roles of RHAMM in osteoblastic cells. We generated RHAMM-overexpressing MC3T3-E1 cells and examined the cell proliferation and differentiation of osteoblastic cells. In MC3T3-E1 cells, overexpressing RHAMM was located intracellular and activated ERK1/2. Interestingly, the ERK1/2 activated by RHAMM overexpression promoted cell proliferation and suppressed the differentiation of osteoblastic cells. Our findings strongly suggest that RHAMM may play a key role in the osteoblastic differentiation process. The rupture of balance from differentiation to proliferation induced by RHAMM overexpression may link to the pathogenesis of bone neoplasms such as HCF.
    No preview · Article · Sep 2011 · Journal of Bone and Mineral Metabolism
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    ABSTRACT: Approximately 85% of human malignant tumors express increased levels of telomerase. The marked association of telomerase activity with malignant tissue provides strong evidence that telomerase activity is a significant marker for the diagnosis of cancer. In this study, telomerase activity was examined in 12 benign salivary gland tumors (8 pleomorphic adenomas and 4 adenolymphomas), 24 malignant tumors (15 mucoepidermoid carcinomas, 6 adenoid cystic carcinomas and 3 acinic cell carcinomas) and 6 non-neoplastic salivary glands. The mRNA expression of the human telomerase reverse transcriptase (hTERT) and additional telomerase‑associated proteins (hTEP1, p23, Hsp90 and dyskerin) was also examined. Of the 24 malignant tumors, 15 revealed strong telomerase activity. The non-neoplastic salivary glands appeared to have a negative telomerase expression. Furthermore, telomerase activity was significantly higher in high-grade mucoepidermoid carcinomas compared to low‑grade ones (Student's t-test, p<0.05). A significant correlation was found between telomerase activity and mRNA expression of hTERT in 15 cases, including non-neoplastic salivary glands and tumors (Spearman's rank correlation test, p<0.05). Furthermore, a significant correlation was found between telomerase activity and mRNA expression of EGFR (Spearman's rank correlation test, p<0.001). The results suggest that not only hTERT, but also EGFR play a significant role in the activation of telomerase. In conclusion, the results suggest that telomerase activity and hTERT/EGFR mRNA expression are useful markers for the detection of malignant cells in salivary gland carcinomas. Moreover, our results indicated that telomerase activity determines the degree of malignancy of mucoepidermoid carcinoma.
    Full-text · Article · Sep 2011 · Oncology letters

Publication Stats

786 Citations
134.91 Total Impact Points


  • 2001-2015
    • Hiroshima University
      • • Institute of Biomedical and Health Sciences
      • • Department of Oral and Maxillofacial Surgery
      • • Faculty of Medicine
      Hirosima, Hiroshima, Japan
  • 2013-2014
    • Queen Mary, University of London
      Londinium, England, United Kingdom
  • 2002
    • Nara Medical University
      • Department of Molecular Pathology
      Kashihara, Nara, Japan