Language：Japanese   Publisher：(NPO)日本口腔科学会  

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

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌学会  

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Recently, numerous tumor-suppressive microRNAs (TS-miRs) have been identified in human malignancies. Here, we attempted to identify novel TS-miRs in oral squamous cell carcinoma (OSCC). First, we transfected human OSCC cells individually with 968 synthetic miRs mimicking human mature miRs individually, and the growth of these cells was evaluated using the WST-8 assay. Five miR mimics significantly reduced the cell growth rate by less than 30%, and the miR-1289 mimic had the most potent growth inhibitory effect among these miRs. Subsequently, we assessed the in vivo growth-inhibitory effects of miR-1289 using a mouse model. The administration of the miR-1289 mimic-atelocollagen complex significantly reduced the size of subcutaneously xenografted human OSCC tumors. Next, we investigated the expression of miR-1289 in OSCC tissues using reverse transcription-quantitative PCR. The expression level of miR-1289 was significantly lower in OSCC tissues than in the adjacent normal oral mucosa. Furthermore, 15 genes were identified as target genes of miR-1289 via microarray and Ingenuity Pathway Analysis (IPA) microRNA target filtering. Among these genes, the knockdown of magnesium transporter 1 (MAGT1) resulted in the most remarkable cell growth inhibition in human OSCC cells. These results suggested that miR-1289 functions as a novel TS-miR in OSCC and may be a useful therapeutic tool for patients with OSCC.

DOI： 10.3390/cancers15164138

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Language：Japanese   Publisher：(一社)日本有病者歯科医療学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(一社)日本有病者歯科医療学会  

脊髄硬膜外膿瘍は脊柱管内硬膜外に膿瘍を形成し,脊髄および脊髄根障害を引き起こすまれな疾患である.今回われわれは,口腔内細菌が起因菌と考えられた頸椎硬膜外膿瘍の1例を経験したので報告する.患者は63歳男性.既往歴は心房細動,緑内障,副鼻腔炎であった.頸部痛,咽頭痛,発熱を認め,咽後膿瘍疑いで当院耳鼻咽喉科を受診し,同日緊急入院となった.入院時の造影CT検査では同部に明らかな膿瘍形成は認めなかったため,整形外科に対診の結果,当初は頸長筋炎が疑われた.その後,第4病日に左側第二大臼歯相当部の疼痛精査目的に,当科紹介受診となった.パノラマエックス線検査,造影CT検査では,左側第二大臼歯根尖に透過像を認め,左側上顎洞底に近接していた.両側上顎洞,篩骨洞および蝶形骨洞に不透過像の亢進を認め,左側第二大臼歯根尖性歯周炎,両側副鼻腔炎と診断した.第7病日から再度熱発を認め,血液検査で炎症反応の増悪を認めた.造影CT検査では左側後咽頭間隙の軟部組織陰影の増大および頸椎C2～4の左側硬膜外に膿瘍形成を認めた.発熱と後頸部痛を認めたが,神経根症状は認めず,病期はI期の左側頸椎硬膜外膿瘍と診断した.左側上顎第二大臼歯の根尖病巣から上顎洞炎,篩骨洞炎,蝶形骨洞炎と炎症が波及し,後咽頭間隙を経由して頸椎硬膜外膿瘍を形成した可能性が考えられた.口腔内細菌を標的とし,第10病日からsulbactam/ampicillin(SBT/ABPC)12g/dayを開始し,消炎を行った.第12病日に原因歯と考えられた左側第二大臼歯の抜歯を行った.抜歯時に根尖から採取した検体より,血液培養でも陽性であったStreptococcus intermediusが検出された.第31病日までSBT/ABPC投与を継続したところ,頸椎硬膜外膿瘍は消退し,両側副鼻腔炎も改善を認めた.本症例では神経症状が出現する前に頸椎硬膜外膿瘍と診断されたため,保存的加療で後遺障害なく治癒した.(著者抄録)

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

Human papillomavirus (HPV) is a possible carcinogenetic factor in oral squamous cell carcinoma (OSCC). Previous studies have reported the prevalence of HPV in patients with OSCC. However, the association between HPV and OSCC remains controversial. The present study aimed to clarify the association between HPV infection, p16 protein expression and the clinicopathological characteristics of OSCC. The expression level of HPV-16E6 mRNA and p16 protein, a known surrogate marker of HPV infection, was investigated in 100 OSCC cases using TaqMan reverse transcription-quantitative PCR and immunohistochemistry staining, respectively. HPV-16E6 mRNA expression level was only detected in one case (1%), and positive expression of p16 was found in 10 cases (10%), including an HPV-positive case. Subsequently, the association between p16 expression level and clinicopathological characteristic factors were analyzed; however, no significant association was found. These results suggested that HPV-16 infection was less likely to cause OSCC in Japan and p16 expression was not a suitable marker for HPV infection in OSCC.

DOI： 10.3892/ol.2021.12789

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本口腔腫瘍学会  

近年の治療法の向上にもかかわらず、約30年の間、早期口腔癌の治療成績は改善を認めていない。早期口腔癌における頸部リンパ節転移の有無は最も重要な予後因子である。それゆえに、頸部リンパ節転移の早期発見は予後の改善につながると考えられる。cN0症例における頸部マネージメントについては、経過観察もしくは予防的頸部郭清術のいずれかが選択されてきており、長年の論点となってきた。センチネルリンパ節生検は多くの領域で受け入れられている方法であり、口腔癌においては頸部郭清術の適否を判断する検査法である。本研究ではセンチネルリンパ節生検症例の同定部位、転移陽性レベル等から予防的頸部郭清術の適否について検討を行うとともに、今後の展望について述べる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本口腔腫瘍学会  

近年の治療法の向上にもかかわらず、約30年の間、早期口腔癌の治療成績は改善を認めていない。早期口腔癌における頸部リンパ節転移の有無は最も重要な予後因子である。それゆえに、頸部リンパ節転移の早期発見は予後の改善につながると考えられる。cN0症例における頸部マネージメントについては、経過観察もしくは予防的頸部郭清術のいずれかが選択されてきており、長年の論点となってきた。センチネルリンパ節生検は多くの領域で受け入れられている方法であり、口腔癌においては頸部郭清術の適否を判断する検査法である。本研究ではセンチネルリンパ節生検症例の同定部位、転移陽性レベル等から予防的頸部郭清術の適否について検討を行うとともに、今後の展望について述べる。(著者抄録)

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

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Authorship：Lead author,　Corresponding author  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Failure to detect recurrence and lymph node metastasis early represents a fundamental barrier to the improvement of survival rate in early stage oral squamous cell carcinoma (OSCC). The present study evaluated the association between serum interleukin-6 (IL-6) level and clinical outcomes in patients with early stage OSCC patients defined by sentinel node biopsy (SNB). A total of 53 patients with clinical stage I/II OSCC who underwent SNB were enrolled. SNB was determined by a radioisotope method, and was evaluated by histopathological examination and genetic analysis. Preoperative sera were measured for IL-6 by ELISA. In the clinical stage I/II patients, disease-free survival (DFS) was demonstrated to be higher in patients with negative SNB compared with patients with positive SNB. In total, 13 patients were demonstrated to exhibit lymph node metastasis by SNB or were reclassified to pathological stage T4 subsequent to analysis of the surgically resected specimens. Thus, 40 patients were diagnosed with early stage OSCC. Of these 40 patients, DFS of the patients with low serum IL-6 was significantly higher compared with the patients with high serum IL-6 (P=0.012). In 19 patients with negative SNB and low serum IL-6, the disease-free rate was 100%. These findings suggested that SNB staging and serum IL-6 level have a high prognostic value in patients with early stage OSCC. Additional investigation and longer follow-up times are warranted to improve understanding of the group of patients that may benefit from this procedure.

DOI： 10.3892/ol.2017.7183

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本口腔腫瘍学会  

頸部リンパ節転移の有無は口腔癌の重要な予後因子である。cN0症例に対する治療方針としての、予防的頸部郭清術や経過観察についてはいまだ議論の余地があるのが現状である。センチネルリンパ節生検(SNB)は、様々な癌種において臨床応用がなされてきた。口腔癌におけるSNBの目的は、cN0症例に対し、頸部郭清術を行うか否かを決定することにある。しかしながら、口腔癌のSNBにおいては、以下の4つの問題点がある。すなわち、RIの使用、shine-through現象、潜在転移診断法とEBMの不足である。本稿では、口腔癌におけるセンチネルリンパ節生検の現状について解説する。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Cervical lymph node metastasis is an important prognostic factor in oral squamous cell carcinoma (OSCC), but its accurate assessment after sentinel node biopsy or neck dissection is often limited to the histopathological examination of only one or two sections. Previous our study showed the usefulness of the reverse transcription loop-mediated isothermal amplification (RT-LAMP) targeting keratin 19 (KRT19) mRNA for the genetic detection of lymph node metastasis, but the sensitivity was insufficient. Here, we have attempted to identify novel molecular markers for OSCC cells in lymph nodes. We performed microarray analysis to identify genes overexpressed in 7 metastatic lymph nodes from OSCC patients, compared to 1 normal lymph node and 5 salivary glands from non-cancer patients. We then used real-time quantitative RT-PCR (qRT-PCR) and RT-LAMP to compare the expression of these genes in newly resected metastatic and normal lymph nodes. Of 4 genes identified by microarray analysis, annexin A8 (ANXA8) and desmoglein 3 mRNA were detected by qRT-PCR in metastatic lymph nodes but not in normal lymph nodes. Furthermore, ANXA8 mRNA expression was detected in all KRT19-negative metastatic lymph nodes. Both KRT19 and ANXA8 mRNA may be useful markers for detecting lymph node metastases in OSCC patients.

DOI： 10.18632/oncotarget.6639

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

Oral squamous cell carcinoma (OSCC) frequently metastasizes to cervical lymph nodes, which is the most known prognostic factor. Screening methods to identify sentinel lymph nodes (SLNs) are therefore of great interest for the management of potential neck metastasis. The purpose of this study was to evaluate the clinical benefit of double SLN mapping with indocyanine green (ICG) and 99m-technetium-tin colloid (Tc-99m-tin colloid) for sentinel node navigation surgery (SNNS). Between 2007 and 2010, 16 patients diagnosed with OSCC were investigated by SLN biopsy using the double mapping method. Tc-99m-tin colloid was injected into the peri-tumoural region on the preoperative day, and ICG was administered intraoperatively in the same position to assist in detecting nodes during surgery. Based on the gamma-ray signal and near-infrared (NIR) fluorescence of ICG, SLNs were identified and thereafter assessed pathologically and genetically for cancer involvement. Radio-guided detection was successful for all patients. ICU mapping identified a relatively larger number of nodes, suggesting that several non-SLNs were potentially involved. The double mapping method assisted surgeons to explore SLNs. Since the ICG fluorescence was shielded by the subcutaneous fatty tissue and the muscle layer including platysma and sternocleidomastoid, it was necessary to retract the tissue away from nodes.

DOI： 10.1016/j.ijom.2015.05.008

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

Oncogene addiction can provide therapeutic opportunities in human malignancies. In this study, we aimed to identify critical oncogenes for oral squamous cell carcinoma (OSCC) development and progression. We determined gene expression profiles in 10 primary OSCCs and 10 human OSCC cell lines using Applied Biosystems Human Genome Survey Arrays. Akt1 was the only gene identified that was expressed in all OSCC tissues and cultured cells, but not in non-neoplastic tissues and cells. Subsequently, western blot analysis showed that Aka protein was overexpressed in OSCC tissues and cell lines. Immunohistochemistry also showed Akt1 protein expression in 59 of 63 (94%) primary OSCCs. To clarify the oncogenic function of Akt1 in human OSCC cells, we used RNA interference. We designed and synthesized 5 small interfering RNAs specific for Akt1 (siAkt1). Transfecting human OSCC cells with siAkt1 in vitro markedly suppressed their expression of Akt1 protein and significantly reduced their growth rate. Furthermore, the growth of human OSCC tumors which had been subcutaneously xenografted in athymic nude mice lacking interferon responses was markedly inhibited by atelocollagen-mediated systemic siAkt1 administration. We also found that synthetic siAkt1 had an inhibitory effect on the growth of primary cultured OSCC cells. Finally, we investigated the molecular mechanisms involved in the growth inhibitory effect of Akt1 suppression using microarray analysis of human OSCC cells transfected with siAkt1. Knockdown of Aka induced the expression of CDKN2B, a tumor suppressor gene, and reduced the expression of TGFBR1, which supports malignant phenotypes. These results suggest that Aka functions as a critical oncogene in human OSCC cells and may therefore be an appropriate target for novel OSCC therapies.

DOI： 10.3892/ijo.2015.3134

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：E-CENTURY PUBLISHING CORP  

Peripheral ameloblastoma (PA), a rare and unusual variant of odontogenic tumors, comprises about 1% of all ameloblastomas. PA is an exophytic growth localized to the soft tissues overlying the tooth-bearing areas of the jaws, and the initial diagnosis is often fibrous epulis. PA with histologically low-grade malignant features is extremely rare. We report a case of peripheral ameloblastoma with histologically low-grade malignant features in a 69-year-old woman that presented with a hemorrhage from a tumor on the right buccal mucosa. The tumor was surgically removed by blunt dissection, with no evidence of recurrence after two years and six months. After the case presentation, microscopic and genetic findings are discussed.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Purpose: We investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in patients with oral squamous cell carcinoma (OSCC).
Experimental Design: Fifty OSCC patients who received radical resection of their tumor(s) were enrolled. Preoperative sera were measured for IL-8 by ELISA. Expression of IL-8 and the infiltration of immune cells in tumor tissues were analyzed by an immunohistochemical staining of surgical specimens.
Results: We found that disease-free survival (DFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p=0.001). The tumor expression of IL-8, i.e., IL-8(T) and the density of CD163-positive cells in the tumor invasive front, i.e., CD163(IF) were correlated with the serum IL-8 level (p=0.033 and p=0.038, respectively), and they were associated with poor clinical outcome (p=0.007 and p=0.002, respectively, in DFS) in all patients. A multivariate analysis revealed that N status, IL-8(T) and CD163(IF) significantly affected the DFS of the patients. Further analysis suggested that combination of N status with serum IL-8, IL-8(T) or CD163(IF) may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Interestingly, the in vitro experiments demonstrated that IL-8 enhanced generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10.
Conclusions: These findings indicate that IL-8 may be involved in poor clinical outcomes via generation of CD163-positive M2 macrophages, and that these factors in addition to N status may have prognostic value in patients with resectable OSCSS.

DOI： 10.1371/journal.pone.0110378

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

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-beta but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-beta. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

DOI： 10.1593/neo.13488

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objectives: Oncogene addiction has provided therapeutic opportunities in many human malignancies, but molecular targeted therapy for oral squamous cell carcinoma (OSCC) is not yet available. In this study, we attempted to identify an appropriate target molecule for treatment of patients with OSCC.
Materials and methods: Microarray analysis was performed to determine the gene expression profiles in nine human OSCC cell lines and a non-neoplastic keratinocyte cell line. The expression levels of Aurora kinase A (AURKA) mRNA and protein in human OSCC cells and tissues were examined. We investigated the effect of small interfering RNAs specific for AURKA (siAURKAs) and MLN8237, an AURKA selective inhibitor on the growth of OSCC cells in vitro and in vivo. We also analyzed clinical significance in AURKA mRNA expression levels in OSCC.
Results: AURKA was overexpressed in human OSCC cell lines and tissues. All siAURKAs almost completely suppressed the expression of AURKA protein, and significantly inhibited the growth of OSCC cells by 31-89%. MLN8237 also reduced the cellular growth rate by 38-74%. Both siAURKA and MLN8237 significantly reduced the size of subcutaneously xenografted OSCC tumors by 66% and 40%. Knockdown of AURKA expression and MLN8237 induced the growth inhibition of primary cultured cells established from patients' OSCC tumors. Furthermore, we found a significant association between AURKA mRNA expression levels and histological differentiation and lymph node metastasis.
Conclusions: AURKA plays a critical role in the growth of human OSCC cells and targeting AURKA may be a useful therapeutic strategy for OSCC. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2013.02.002

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(公社)日本口腔外科学会  

61歳女。ビスホスホネート関連顎骨壊死(BRONJ)の悪化にトシリズマブ(TCZ)が関与した機序として次のようなことが考えられた。1)メトトレキサート服用などにより免疫抑制下にある状態で、TCZの投与により骨代謝回転と血管新生が抑制された。2)TCZ投与により発熱やCRP産生が抑制され感染症の重症度が不顕化される"マスキング"によってBRONJの重篤化が引き起こされた。本症例への治療は、MTXおよびトシリズマブの投与を中止し、RAに対してはプレドニゾロン5mg/日およびセレコキシブ200mg/日を行ったところ、中止後、1ヵ月でリンパ節腫脹は著明に縮小し、口腔内病変も治癒が得られた。

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objectives: Lymph node stage is an important prognostic factor in head and neck squamous cell carcinoma (HNSCC). We previously reported the clinical usefulness of sentinel lymph node biopsy diagnosed by genetic analysis using quantitative RT-PCR. However, this method takes about 3 h. In this study, we attempted to develop a more efficient method for the intraoperative genetic detection of lymph node metastasis in HNSCC.
Materials and methods: A total of 312 lymph nodes (65 patients) were diagnosed by the one-step nucleic acid amplification (OSNA) method using GD-100. OSNA consists of a short homogenization step followed by amplification of cytokeratin 19 (CK19) mRNA directly from the lysate. Each lymph node was divided into two to diagnose metastasis. One half was used for the OSNA assay, and the other was subjected to semi-serial sectioning, sliced at 200-mu m intervals and examined by H&E and cytokeratin AE1/AE3 immunohistochemical staining. The accuracy of OSNA assay was evaluated based on histopathological diagnosis.
Results: Sixty-one of 312 lymph nodes were pathologically metastasis-positive. The overall concordance rate between the OSNA assay using breast cancer criteria and histopathology was 94.2%. The optimal cutoff for the copy number of CK19 mRNA in assessing lymph node metastasis of HNSCC was 300 copies/mu l, which had the highest diagnostic accuracy (95.2%). The OSNA assay can be completed within 30 min.
Conclusion: The OSNA assay, which shows high sensitivity and specificity, suggests the possibility to be used as a novel tool for the genetic detection of lymph node metastasis in HNSCC patients. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2012.03.026

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FAT1 [Homo sapiens FAT tumor suppressor homolog 1 (Drosophila)] is an intrinsic membrane protein classified as a member of the Cadherin superfamily The FAT1 gene is a tumor suppressor in humans as well as being the pivotal gene for cell morphogenesis and migration. Deletion of this gene could play a role in the characteristics of oral squamous cell carcinomas (OSCCs), involving cell adhesion, migration and/ or invasion. This study investigated the mechanisms by which FATl is involved in the biological behavior of OSCCs. First, a rat monoclonal antibody was developed against a FAT1 intracellular domain epitope, and used for an immunohistochemical study of FATl in clinically obtained OSCC samples. FATl was localized at lamellipodial edges or cell-cell boundaries in normal cells and well differentiated OSCCs, but showed a diffuse cytoplasmic and nuclear distribution in moderately-poorly differentiated OSCCs. FAT1-siRNA was transfected into OSCCs resulting in a drastic inhibition of cell migration and invasion based on the suppression of FAT1 expression and disorganized localization of β-catenin which is associated with cell polarity and migration. These results suggested that FAT1 may be involved in the migration and invasion mechanisms of OSCCs and, therefore, it could be an important target for the development of new therapeutic strategies.

DOI： 10.3892/or.2011.1324

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

Although replication-competent oncolytic viral vectors have been developed to improve antitumor activity, the generation of high titers of neutralizing antibodies inhibits repetitive viral infection. Many studies have reported that oncolytic virus-infected carrier cells can overcome this viral induced immunogenicity. However, the effects of oncolytic virus-infected carrier cells in human oral squamous cell carcinoma (OSCC) have not yet been examined. In the present study, simulating the clinical trial, we examined the antitumor activity of carrier cells infected with oncolytic adenovirus AdE3-IAI.3B in human OSCC. IAI.3B was highly activated in OSCC cells but not in normal cells. AdE3-IAI.3B killed OSCC cells in vitro but not normal cells. AdE3-IAI.3B-infected A549 carrier cells eradicated OSCC GFP-SAS tumors in nude mice. Anti-adenovirus neutralizing antibodies completely blocked the antitumor effect of AdE3-IAI.3B but did not block that of carrier cells. After the induction of anti-adenoviral CTL responses by immunization of adenovirus, administration of carrier cells induced complete regression of murine squamous cell carcinoma SCC7 tumors. Adenovirus-GM-CSF augmented the antitumor effect of carrier cells. The IAI.3B-driven oncolytic adenovirus-infected carrier cell system might prove useful in the treatment of OSCC and clinical trials of it should be conducted in the near future.

DOI： 10.3892/or.2010.1130

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2010.07.045

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Early phase prostate cancer is usually androgen-dependent, with the androgen/androgen receptor (AR) signaling pathway playing a central role. At this stage, the cancer responds well to androgen ablation therapy, but prostate cancers eventually acquire androgen independence and more aggressive phenotypes. Several studies, however, have shown that the majority of tumors still express functional AR, which is often amplified and mutated. To determine if the AR is a plausible therapeutic target, we investigated the anti-tumor effect of small interfering RNAs targeting the AR (siAR) in the human prostate cancer cells, LNCaP and 22Rv1, which express mutated AR. In both types of cells, transfection of siAR suppressed mutated AR expression and significantly reduced cell growth. Furthermore, atelocollagen-mediated systemic siAR administration markedly inhibited the growth of 22Rv1 cells subcutaneously xenografted in castrated nude mice. These results suggest that the AR is still a key therapeutic target even in androgen-independent prostate cancer (AIPC). Silencing of AR expression in AIPC opens promising therapeutic perspectives. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.12.024

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：愛媛医学会  

口腔扁平上皮癌患者のセンチネルリンパ節生検時に得たリンパ節57検体と頸部郭清術より摘出した190検体を対象に、CK19 mRNAを検出対象とした口腔扁平上皮癌頸部リンパ節転移の分枝診断の有用性を、One Step Nucleic acid Amplication(OSNA)法により検討した。OSNA法は夾雑物存在下においても検出対象であるCK19 mRNAの正確な定量が可能であり、操作性に優れ、診断結果を得るまで約30分と術中応用が十分可能であることが示された。更にOSNA法によるリンパ節転移診断基準基準値を300copies/μlと設定した時に、その診断精度は96.8%となり最も優れることが明らかになった。この結果から口腔扁平上皮癌センチネルリンパ節生検においてOSNA法が有用な検査法であることが示唆された。

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

Hypoxia promotes the invasive and metastatic potential of tumour cells. A recent study has shown that the activation of the chemokine receptor CXCR4 by lack of oxygen in breast cancer is HIF-1-dependent. We have previously demonstrated that CXCR4 signalling is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated a correlation between CXCR4 and HIF-1 alpha expression in OSCC. Immunohistochemistry showed that CXCR4 was expressed in 20 of 85 OSCC tissues, while HIF-1 alpha was expressed in 51 of 85 samples. There was a significant correlation between the expression of CXCR4 and HIF-1 alpha. In human OSCC cells, hypoxia markedly enhanced the expression of both HIF-1 alpha and CXCR4. Furthermore. synthetic small interfering RNA specific for HIF-1 alpha significantly suppressed the expression of this protein, and also attenuated the induction of CXCR4 expression under hypoxic conditions. These results indicated that HIF-1 alpha regulated hypoxia-induced CXCR4 expression in OSCC.

DOI： 10.3892/or_00000275

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

We previously demonstrated that CD151 forms a functional complex with c-Met and integrin alpha 3/alpha 6 in human salivary gland cancer cells. In the current study, we investigated the involvement of CD151, c-Met, and integrin alpha 3/alpha 6 in the cellular morphogenesis of human breast cancer cells, Knockdown of CD151, integrin alpha 3, or integrin alpha 6 expression abolished branching morphogenesis. Decreased c-Met expression in these cells led to the formation of rudimentary networks and prevented their conversion. Furthermore, hepatocyte growth factor (HGF) promoted cellular morphogenesis by accelerating network reorganization. Immunoprecipitation revealed a specific association between CD151 and c-Met, The involvement of CD151 and integrin alpha 3/alpha 6 in HGF-depenclent signaling was confirmed by the decreased Akt phosphorylation in cells lacking CD151, integrin alpha 3, or integrin alpha 6. Hence, the regulation of CD151 expression might contribute to changes in HGF/c-Met signaling and thereby modulate the phenotypic characteristics of cancer cells. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.01.023

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

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been observed in many human malignancies. Using the sequence-specific RNA interference (RNAi) method to switch off Stat3 expression, it may be possible to arrest cancer growth. In this study, we aimed to identify the most effective sequence of a synthetic small interfering RNA (siRNA) specific for Stat3 (Stat3-siRNA) and the effect of Stat3 suppression on the growth of oral squamous cell carcinoma cells. Ten designed siRNAs with known sequences were screened for the best RNAi effect at the working concentrations of 1 and 10 nM. The range of reduction of Stat3 expression varied from 21 to 67% for 10 nM siRNAs, and from 13 to 73% for 1 nM siRNAs. Three out of the 10 screened siRNAs reduced Stat3 expression to lower levels compared with the GFP-siRNA control. The interferon response of some siRNAs was observed at a concentration of 10 nM. However, at I nM, the mRNA levels of interferon response genes (OAS1, OAS2, MX1 and ISFG3 gamma) remained unchanged. The growth of GFP-SAS, HSC-3, HSC-4 and KB cells was strongly inhibited by the use of three effective Stat3-siRNAs in comparison with other Stat3-siRNAs and GFP-siRNA. Moreover, the mRNA levels of genes for which transcription is activated by Stat3 were markedly suppressed. These results suggest that targeting Stat3 using, siRNA may constitute a useful approach for the treatment of oral squamous cell carcinoma.

DOI： 10.3892/or_00000085

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The expression of hepatocyte growth factor (HGF) and c-Met is associated with tumor progression in many human malignancies. A recent study demonstrated HGF and c-Met expression in human salivary gland cancer tissues. Here, we investigated the role of the HGF/c-Met system in the invasive growth of two human salivary gland cancer cell lines: green fluorescent protein-adenoid cystic carcinoma 2 (GFP-ACC2) and GFP-ACCM. HGF enhanced the invasive growth of the two cell lines by activating PI3K/Akt signaling. All Akt isoforms (Akt1, Akt2, and Akt3) were detected in both cell types by Western blot analysis. Knockdown of any of the Akt isoforms using isoform-specific synthetic small-interfering RNAs largely abrogated the invasive growth induced by HGF. Our findings suggest that all of the Akt isoforms are required for the HGF-stimulated invasive growth of human salivary gland cancer cells, and that targeting a single Akt isoform could be effective in treating salivary gland cancers. (c) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.03.042

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本口腔診断学会  

症例は85歳と55歳の男性で、いずれもTNM分類N0の上顎悪性黒色腫で、センチネルリンパ節生検での迅速病理検査で転移陽性と診断されたため患側全頸部郭清術を施行した。2例とも術後の最終的な病理組織検査でセンチネルリンパ節以外のリンパ節に1個の転移巣を認めた。

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Language：Japanese   Publisher：(一社)日本口腔診断学会  

70歳女。患者は開口障害を主訴とした。パノラマX線では右側上顎第二大臼歯根尖部に境界明瞭な透過像が認められ、CTでは右側側咽頭隙から翼突下顎隙にかけて、右側上顎第二大臼歯根尖部と連続する内部不均一な径40mmの腫瘤性病変を認めた。根尖性歯周炎、右側翼突下顎隙膿瘍と診断し、抗菌薬による治療を開始したが、微熱が継続し、白血球数、CRPの上昇を認めた。初診時に軽度胸痛があったことからX線撮影を行なったところ、両側肺野に結節性陰影が数個確認された。またCTでは一部結節の空洞化を認め、結節に肺動脈が連続する像を認めた。白血球数、呼吸数が増加しており、感染による全身性炎症反応症候群と考え、CT、臨床所見から敗血症性肺塞栓症と診断された。以後、抗菌薬の継続により炎症状態の改善、胸部症状の消退、開口量の増加を認めて、原因歯の抜歯を行った。その結果、本症例は根尖性歯周炎による菌塊が塞栓子となり、肺塞栓症を引き起こしたものと考えられた。

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

ヒト全遺伝子型マイクロアレイを用いて,ヒト全遺伝子のうち最も有用性の高い腫瘍マーカーの同定を試みた.初回治療を行った口腔癌2例を対象とした.口腔癌患者由来の血液RNAより全遺伝子発現量を定量化した.比較対照として健常者血液を用いた.口腔扁平上皮癌症例では対照と比較して3倍以上の発現亢進を認めた遺伝子を197種類,唾液腺癌症例では152種類同定した.最も発現亢進を認めた遺伝子を各症例の個別腫瘍マーカーとした.術後,画像検査にて再発および転移が認められないことを確認したのち,再び血液RNAを用いて術前と同様の解析を行った.個別腫瘍マーカーは著明に低下し,正常化した.腫瘍マーカーの個別化が技術的に可能で,癌細胞存在診断において有用となる可能性が示唆された

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-5033

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-720

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-1355

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.oraloncology.2011.06.133

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-145

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

Scopus

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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