Takashi Saku

Niigata University, Niahi-niigata, Niigata, Japan

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Publications (199)330.56 Total impact

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    ABSTRACT: The aim of this study was to characterize the histologic and immunohistochemical profiles of paradental cyst-lining epithelia to clarify its histopathogenesis. Ten surgical specimens of paradental cysts were examined for clinical profiles and to determine the histopathologic characteristics of the lining epithelia. Immunohistochemical profiles for keratin (K) subtypes, as well as for perlecan, UEA-I lectin binding, and proliferating cell nuclear antigen (PCNA), were determined and compared. The paradental cyst was clinically characterized by its occurrence in young adults (mean age, 36.8 years; male, 42.8, female 27.8). Eight of the 10 cases arose in the retromolar area. The cyst wall was basically granulation tissue that was attached to the periodontal ligament space. Thin irregular anastomosing epithelial cords lined the cyst walls of immature granulation tissue with vascular dilation and hemorrhage. The intercellular space of the lining epithelia was widened with inflammatory cell infiltrates. Immunohistochemically, the lining was positive for K13, K14, K17, K19, UEA-I binding, and perlecan, suggesting its junctional/sulcular epithelial character. The results showed that the paradental cyst was lined by epithelial cells with characteristics of the junctional/sulcular epithelium. The cyst can thus be considered as a kind of inclusion cyst arising in the periodontal pocket, most frequently of the mandibular third molars of young adults. Copyright © 2015 Elsevier Inc. All rights reserved.
    04/2015; 120(2). DOI:10.1016/j.oooo.2015.04.001
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    ABSTRACT: Based on our previous finding that protease-activated receptor 2 (PAR-2) regulates hemophagocytosis of oral squamous cell carcinoma (SCC) cells, which induces their heme oxygenase 1-dependent keratinization, we have formulated a hypothesis that PAR-2 functions in wider activities of SCC cells. To confirm this hypothesis, we investigated immunohistochemical profiles of PAR-2 in oral SCC tissues and its functional roles in cell proliferation and invasion in SCC cells in culture. The PAR-2 expression modes were determined in 48 surgical tissue specimens of oral SCC. Using oral SCC-derived cell systems, we determined both gene and protein expression levels of PAR-2. SCC cell proliferation and invasive properties were also examined in conditions in which PAR-2 was activated by the synthetic peptide SLIGRL. PAR-2 was immunolocalized in oral SCC and carcinoma in situ cells, especially in those on the periphery of carcinoma cell foci (100% of cases), but not in normal oral epithelia. Its expression at both gene and protein levels was confirmed in 3 oral SCC cell lines including ZK-1. Activation of PAR-2 induced ZK-1 cell proliferation in a dose-dependent manner. PAR-2-activated ZK-1 cells invaded faster than nonactivated ones. The expression of PAR-2 is specific to oral malignancies, and PAR-2 regulates the growth and invasion of oral SCC cells. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 03/2015; 46(7). DOI:10.1016/j.humpath.2015.03.003 · 2.77 Impact Factor
  • Masayuki Tsuneki · Joseph A. Madri · Takashi Saku ·
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    ABSTRACT: Although many studies have examined the crosstalk between tumor cells and extracellular matrix during tumorigenesis, the role of this crosstalk is incompletely understood. This crosstalk is regulated by dynamic reciprocal interactions among tumor cells, stroma, and stromal cells in the tumor microenvironment. Our recent findings have led us to focus on selected adhesion molecules and signaling pathways, specifically podoplanin, CD44, and Hippo pathway, that regulate cell–extracellular matrix interactions. Our studies have shown that interactions among these molecules and the Hippo pathway modulate the behavior of specific tumors and stromal cells.
    Journal of Oral Biosciences 03/2015; 57(2). DOI:10.1016/j.job.2015.02.004
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    ABSTRACT: Expression of keratin (K) 13 is replaced with that of K17 when squamous cells of the oral mucosa transform from normal and dysplastic epithelia to carcinoma in situ (CIS) and squamous cell carcinoma (SCC). Since 14-3-3 sigma is functionally associated with K17, we examined possible relationships between expression of K17 and 14-3-3 sigma in oral CIS and SCC tissues by immunohistochemistry. We furthermore examined whether or not K17 expression or knockdown by small interfering RNA (siRNA) modulates the behavior of SCC cells in culture in terms of cell proliferation and migration. In tissue specimens of oral SCC and CIS, the pattern of cytoplasmic expression of 14-3-3 sigma and K17 was similar but neither was expressed in normal or dysplastic epithelia. Both proteins were demonstrated in the cytoplasm of control oral SCC ZK-1 cells, but expression of 14-3-3 sigma changed from cytoplasmic to nuclear upon knockdown of K17. In carcinoma cells, therefore, cytoplasmic localization of 14-3-3 sigma seems to accompany expression of K17. In K17-knockdown cells, proliferation was significantly suppressed at 4 days after seeding. In addition, the cell size of K17-knockdown cells was significantly smaller than that of control cells; as a result of which in the migration experiments, we found delayed closure of scratch wounds but migration as such was not affected. We conclude that K17 expression promotes SCC cell growth and cell size but does not affect cell migration. K17 expression is accompanied by cytoplasmic expression of 14-3-3 sigma, indicative of their functional relationship.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2015; 466(5). DOI:10.1007/s00428-015-1735-6 · 2.65 Impact Factor
  • Md Shahidul Ahsan · Jun Cheng · Satoshi Maruyama · Takashi Saku ·

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 03/2015; 119(3):e178. DOI:10.1016/j.oooo.2014.07.336 · 1.46 Impact Factor

  • 03/2015; 119(3):e146-e147. DOI:10.1016/j.oooo.2014.07.193
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    Journal of medical cases 01/2015; 6(9):393-398. DOI:10.14740/jmc2249w
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    ABSTRACT: Background Oral pemphigus vulgaris (PV), an autoimmune blistering disease, is mainly mediated by autoantibodies against desmoglein (Dsg) 3. However, no attention has been paid to IgG subclasses of the autoantibodies against Dsg3 in the diagnostic procedure for PV. Thus, our aim in this study was to investigate whether Dsg3 and any of IgG subclasses are immunohistochemically colocalized in tissue sections of PV oral mucosa.Materials and Methods Serial sections cut from formalin-fixed paraffin blocks of biopsy specimens of 9 PV cases and those of normal buccal mucosa surgically removed for fibro-epithelial polyps were comparatively examined for immunohistochemical localizations for Dsg3, IgG4, and IgG.ResultsDsg3 was demonstrated in a dot-like pattern on the cell border and in the cytoplasm of the whole epithelial layer in both normal and PV specimens, while its staining was irregular among floating epithelial sheets of PV. IgG4 was also demonstrated in a punctuated fashion on the cell border among floating epithelial sheets, which was nearly identical to the immunohistochemical profile of Dsg3. In addition to being detected in the epithelial part, IgG4 signals were prominently localized in plasma cells scattered in the granulation tissue, where ratios of IgG4-positive (+) plasma cells to IgG+ cells were extraordinarily higher (mean 28%) than those in normal mucosa.DiscussionThese findings confirmed for the first time that autoantibodies against Dsg3 are mainly composed of IgG4 in oral PV and that the combined immunohistochemistry for Dsg3 and IgG4 can be a valuable aid in confirming a histopathological diagnosis of PV.
    Journal of Oral Pathology and Medicine 11/2014; 44(10). DOI:10.1111/jop.12290 · 1.93 Impact Factor
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    ABSTRACT: Lines of evidence have shown that betel-quid chewing is constantly associated with oral cancer. Myanmar is one of the betel-chewing prevalent countries where oral cancer and precancerous lesions are not uncommon. However, the prevalence of oral cancer in Myanmar was obviously lower than that of the other betel-chewing prevalent countries such as India. How or what factors contributed to this lower prevalence of oral cancer in this country is not yet known. Thus, we carried out a community-based, cross-sectional study aimed to elicit the prevalence of oral mucosal changes as well as its risk and preventive factors among residents of betel-quid abundant areas of Myanmar. A total of 897 participants from all betel-quid abundant areas of Taungu District were randomly selected to answer the face-to-face interviews from 2012 to 2013. After each interview, oral examinations were performed. Multiple logistic regression analyses were done by adjusting all the confounding factors. The prevalence of oral mucosal changes was alarmingly high (41%). Indian ingredients in betel-quid and poor oral hygiene were risk factors of oral mucosal changes. Sufficient beta-carotene in daily diets was a preventive factor. The risk of Indian-type quid and the benefit of beta-carotene should be notified to the residents.
    Pathology 10/2014; 46:S95. DOI:10.1097/01.PAT.0000454426.61897.1d · 2.19 Impact Factor
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    ABSTRACT: Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) is a secreted glycoprotein that promotes clearance of apoptotic cells by bridging phosphatidylserine on apoptotic cells and integrin αvβ3/5 on phagocytes. High expression of MFG-E8 has been reported in various types of cancer in humans. Apoptotic figures are frequently found in the surgical samples of oral squamous cell carcinoma (SCC) and carcinoma in situ, and we have often observed apoptotic carcinoma cells engulfed by macrophages or even by neighboring carcinoma cells. Thus we hypothesized that MFG-E8 might promote engulfment of apoptotic carcinoma cells by living carcinoma cells and that MFG-E8 expressed by carcinoma cells could contribute to tumor progression. The aim of this study was to elucidate the biological role of MFG-E8 in oral SCC. Fifty-three surgical specimens of oral SCC were used for immunohistochemistry for MFG-E8, and the expression profiles were correlated with clinicopathological properties. Also, we examined the MFG-E8 expression patterns and functions using three human oral SCC cell lines. Most of the cases had MFG-E8-positive SCC cells, and the expression of MFG-E8 was correlated with such clinicopathological features as tumor size, pathological stage, locoregional recurrence, scattering invasion pattern, and SCC cell figures engulfing apoptotic SCC cells. The MFG-E8 staining was enhanced in apoptotic SCC cells, some of which were apparently engulfed by the neighboring SCC cells. ZK-1 cells showed high MFG-E8 expression, and its localization was found in the cytoplasm and the cell surface. Transient MFG-E8 knockdown by siRNA in ZK-1 decreased cell proliferation and invasiveness and increased cell death. Thus we have demonstrated that MFG-E8 promotes tumor progression in oral SCC and that it might be involved in the clearance of apoptotic SCC cells by living SCC cells.Laboratory Investigation advance online publication, 29 September 2014; doi:10.1038/labinvest.2014.108.
    Laboratory Investigation 09/2014; 94(11). DOI:10.1038/labinvest.2014.108 · 3.68 Impact Factor
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    ABSTRACT: We report a rare case of radiation-induced undifferentiated high-grade pleomorphic sarcoma (UPS) (malignant fibrous histiocytoma, MFH) in the right mandible of a 44-year-old woman. The patient had suffered from osteomyelitis of the same region of the mandible for several years, which was considered to be due to radiotherapy for a malignant lymphoma in her right neck 19 years before. The tumor appeared as an exophytic and invasive growth in the molar region of the mandible. Histopathologically, the tumor consisted of an interlacing proliferation of vimentin-immunopositive spindle-shaped fibroblastic cells with bizarre nuclei with high Ki-67 labeling scores, and tumor cells showed storiform patterns mixed with pleomorphic cells. Taking the history of radiation into consideration, we diagnosed the lesion as radiation-induced UPS. Including the present case, there have been only 14 documented cases of radiation-induced UPS in the jawbone, and this is the first case arising in the follow-up period of long-standing osteomyelitis.
    Pathology - Research and Practice 07/2014; 210(12). DOI:10.1016/j.prp.2014.06.028 · 1.40 Impact Factor
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    ABSTRACT: Objective: This article documents the process that led to the publication of the ". Oral CIS (JSOP) Catalog" by the Working Committee on New Histopathological Criteria for Borderline Malignancies of the Oral Mucosa, a group which was organized within the Japanese Society of Oral Pathology between 2004 and 2007. Methods: The committee collected 160 cases histologically diagnosed as oral carcinoma in-situ (CIS) at 20 hospitals to which the committee members belonged, and five sets of hematoxylin and eosin stained sections of those cases were circulated in five routes among 25 committee members for reviewing for their own diagnoses. Their diagnoses were collected, and cases diagnosed as CIS by more than 70% of the members were selected for further discussion. Results: Committee members wanted to emphasize that oral CIS contained greater histological variety than had previously been defined, and they came to the eventual conclusion that two major histological variations of oral CIS, basaloid and differentiated, were distinguishable. In particular, they emphasized that oral CIS had a definite tendency toward keratinization or that it was well differentiated. They also recommended the use of immunohistochemistry for Ki-67 and keratin subtypes as an essential aid tool for oral CIS diagnosis. Conclusion: By referring to the Catalog, which explains histopathological variations, pathologists can more easily make a diagnosis of oral CIS, and oral surgeons can carry out appropriate clinical interventions for treating oral borderline malignancies.
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    ABSTRACT: Background: Local recurrence remains a challenging clinical issue for the treatment of oral squamous cell carcinoma (SCC). We analyzed retrospectively how effective the frozen section technique (FS) was against recurrences of oral SCC. Methods: We screened 343 surgical samples from 236 patients who had oral SCC, carcinoma in situ (CIS), or epithelial dysplasia, and we followed up their clinical outcomes for at least 5 years. Histopathological states of surgical margins were compared between FS and surgical materials in relapse and relapse-free groups, respectively. Results: Among the 236 patients, 191 were classified into the relapse-free group, and 45 into the relapse group. FS was more frequently performed in the relapse-free group (128/191) than in the relapse group (83/152). Histopathologically, moderate dysplasia or CIS (borderline malignancies) and SCC were recognized in 55 samples of the relapse-free group and in 57 of the relapse group. For those surgical margins with borderline malignancies, additional incisions were performed in 38 of the 55 relapse-free cases, which reduced to 20 from the 38 margins with borderline malignancies (47.4% reduction), and in 39 of the 57 relapse cases, which reduced to only 3 of 39 (7.7% reduction). Conclusions: The intraoperative assessment of surgical margins by FS is essential in preventing recurrences of oral mucosal malignancies.
    BioMed Research International 06/2014; 2014:823968. DOI:10.1155/2014/823968 · 1.58 Impact Factor
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    ABSTRACT: Background We have reported that neutrophilic infiltration was associated with round-shaped dyskeratosis foci, a kind of keratin pearl, of oral carcinoma in situ and that those inflammatory cells are recruited from intra-epithelially entrapped blood vessels. Based on these lines of evidence, we have formulated a hypothesis that keratin pearls are terminally degraded by neutrophils. To confirm this hypothesis, we investigated immunohistochemically stepwise degradation of keratin pearls in oral squamous cell carcinoma (SCC) to clarify any other type scavenger cells in addition to neutrophils are involved in this particular degradation process. Methods Neutrophils (neutrophil elastase) and macrophage subpopulations (CD68, CD163 and CD204) were immunohistochemically localized in 30 cases of oral SCC with typical round-shaped keratin pearls. SCC cells were revealed by immunohistochemistry for keratin (K) 17, and blood vessels were demonstrated by CD31. ResultsKeratin pearl degradation process was divided into four steps: (i) intact stage: no macrophage infiltration but minimal neutrophils were found in keratin pearls; (ii) neutrophil recruit stage: no macrophage infiltration but focal neutrophilic infiltration within the pearls; (iii) neutrophil predominant stage: dense neutrophil infiltration with minimal macrophages and segregated keratinized cancer cells strongly positive for K17; and (iv) macrophage predominant stage: dense infiltration of CD68-, CD163 (mononuclear)- and CD204 (multinucleated)-positive macrophages engulfing detached keratinized SCC cells. Conclusion Keratin pearl degradation in oral SCC is strictly regulated by two types of scavenger cells: neutrophils, which perform initial tasks, and macrophages, which reciprocally take over from neutrophils the role to finalize the degradation processes.
    Journal of Oral Pathology and Medicine 06/2014; 43(10). DOI:10.1111/jop.12197 · 1.93 Impact Factor
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    ABSTRACT: Background We have demonstrated the induction of perlecan-rich stroma of oral squamous cell carcinoma (SCC) on and after its start of invasion. However, it remains unknown how such a neoplastic stroma is actually arranged in tumor tissues.Methods To this end, tissue microarray samples, in which keratin and perlecan were contrastively labeled by immunohistochemistry, were three-dimensionally analyzed using digital images and image analysis software to demonstrate the relationship between SCC foci and the perlecan-positive stromal space or that between carcinoma in situ (CIS) and invasive SCC foci.ResultsThe three-dimensional (3D) reconstruction demonstrated three kinds of perlecan profiles for inside (I) and outside (O) areas of the carcinoma cell focus: mode 1, I+/O−; mode 2, I+/O+; and mode 3, I−/O+. Mode 1 was seen in CIS as well as SCC tumor massifs in the surface part. Mode 2 was seen in small SCC foci, which seemed isolated in 2D sections but were mostly continuous with the tumor massif in 3D reconstructions. Mode 3 was limited to small SCC foci, which were truly segregated from the tumor massif.Conclusions The results indicated that the 2D SCC focus isolation could not be regarded as invasion but that the SCC foci surrounded by perlecan-positive stroma (modes 2 and 3) could be regarded as a more objective measure for invasion of SCC. This is the first 3D tissue-level demonstration of the neoplastic stroma space induced with oral SCC invasion, the presence of which we have predicted based on our previous 2D and tissue culture evidence.
    Journal of Oral Pathology and Medicine 04/2014; 43(8). DOI:10.1111/jop.12184 · 1.93 Impact Factor
  • Takashi Saku ·

    04/2014; 26(2). DOI:10.1016/j.ajoms.2013.12.005
  • Takashi Saku ·

    04/2014; 26(2). DOI:10.1016/j.ajoms.2013.12.006
  • Takashi Saku ·

Publication Stats

3k Citations
330.56 Total Impact Points


  • 1992-2015
    • Niigata University
      • • Department of Tissue Regeneration and Reconstruction
      • • Graduate School of Medical and Dental Sciences
      • • Division of Oral Pathology
      • • Department of Pathology
      • • Faculty of Dentistry
      • • Division of Oral and Maxillofacial Surgery
      Niahi-niigata, Niigata, Japan
    • Tokyo Medical and Dental University
      Edo, Tōkyō, Japan
  • 2004
    • Sichuan University
      • Department of Pathology
      Chengdu, Sichuan Sheng, China
  • 2002
    • The University of Tokyo
      • Department of Biotechnology
      白山, Tōkyō, Japan
  • 1984-1991
    • Nagasaki University
      • Department of Pathology
      Nagasaki, Nagasaki, Japan