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Research Interests: Oncology, Radiation, Molecular Medicine, Cancer, Cell Cycle, and 15 moreCytotoxicity, Cancer Research, Apoptosis, Medicine, Humans, Mutation, Head and Neck Cancer, Cell, Head and neck squamous cell carcinoma, Gene, Cell Proliferation, Cell Cycle Proteins, Cell Survival, Docetaxel, and Head and neck neoplasms
Recent developments in therapeutic strategies have improved the prognosis of head and neck squamous cell carcinoma (HNSCC). Nevertheless, 5-year survival rate remains only 40%, necessitating new therapeutic agents. Oncolytic virotherapy... more
Recent developments in therapeutic strategies have improved the prognosis of head and neck squamous cell carcinoma (HNSCC). Nevertheless, 5-year survival rate remains only 40%, necessitating new therapeutic agents. Oncolytic virotherapy entails use of replication-competent viruses to selectively kill cancer cells. We aimed to explore the potential of HF10 as an oncolytic virus against human or mouse HNSCC cell lines, and primary-cultured HNSCC cells. HF10 replicated well in all the HNSCC cells, in which it induced cytopathic effects and cell killing. Next, we investigated the oncolytic effects of HF10 in ear tumor models with human or mouse tumor cells. We detected HF10-infected cells within the ear tumors based on their expression of green fluorescent protein. HF10 injection suppressed ear tumor growth and prolonged overall survival. In the syngeneic model, HF10 infection induced tumor necrosis with infiltration of CD8-positive cells. Moreover, the splenocytes of HF10-treated mice ...
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Adenoid cystic carcinoma (AdCC), one of the most common salivary gland carcinomas, usually has a fatal outcome. Epidermal growth factor receptor (EGFR) pathway gene mutations are important in predicting a patient's prognosis and... more
Adenoid cystic carcinoma (AdCC), one of the most common salivary gland carcinomas, usually has a fatal outcome. Epidermal growth factor receptor (EGFR) pathway gene mutations are important in predicting a patient's prognosis and estimating the efficacy of molecular therapy targeting the EGFR pathway. In this study of salivary gland AdCC (SAdCC), we looked for gene mutations in family ( and ), and , using a highly sensitive single-base extension multiplex assay, SNaPshot. Out of 70 cases, EGFR pathway missense mutations were found in 13 (18.6%): mutations in 10 (14.3%), in one (1.4%), and in 5 (7.1%). None of the cases showed an deletion by direct sequencing. Concurrent gene mutations were found in three cases (4.3%). EGFR pathway mutations were significantly associated with a shorter disease-free ( = 0.011) and overall survival ( = 0.049) and mutations were as well; ( = 0.010) and ( = 0.024), respectively. The gene fusion status as determined by a FISH assay had no significant a...
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Cancer/testis antigens (CTAs) are detected in cancer cells but not in healthy normal tissues, with the exception of gametogenic tissues. CTAs are highly immunogenic proteins, and thus represent ideal targets for cytotoxic... more
Cancer/testis antigens (CTAs) are detected in cancer cells but not in healthy normal tissues, with the exception of gametogenic tissues. CTAs are highly immunogenic proteins, and thus represent ideal targets for cytotoxic T-lymphocyte-mediated specific immune therapy. The aim of this study was to screen CTA expression in various types of salivary gland carcinoma and to clarify clinicopathological significance of MAGE-A and NY-ESO-1 expression in adenoid cystic carcinomas (AdCCs) of the salivary gland, which is one of the most common salivary gland carcinomas, and usually has a fatal outcome. We used immunohistochemistry to examine the expression of four CTAs (MAGE-A, NY-ESO-1, CT7, and GAGE7) in various types of salivary gland carcinoma (n = 95). When carcinoma cases were divided into low-grade and intermediate/high-grade types, NY-ESO-1 and CT7 were expressed more frequently in intermediate/high-grade carcinomas. We then focused on MAGE-A and NY-ESO-1 expression in a large cohort o...
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Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and the long-term prognosis is poor. In this study, we examined alterations of AdCC-associated genes, MYB, MYBL1, MYBL2, and NFIB, and their target... more
Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and the long-term prognosis is poor. In this study, we examined alterations of AdCC-associated genes, MYB, MYBL1, MYBL2, and NFIB, and their target molecules including MYC. The results were correlated to clinicopathological profile of the patients. Using paraffin tumor sections from 33 cases of salivary gland AdCC, we performed a detailed fluorescence in situ hybridization (FISH) analysis for gene splits and fusions of MYB, MYBL1, MYBL2, and NFIB. We found that 29/33 (88%) AdCC cases showed gene splits in either MYB, MYBL1, or NFIB. None of the cases showed an MYBL2 gene alteration. AdCCs were genetically divided into six gene groups, MYB-NFIB (n=16), MYB-X (n=4), MYBL1-NFIB (n=2), MYBL1-X (n=1), NFIB-X (n=6), and gene-split-negative (n=4). AdCC patients showing the MYB or MYBL1 gene splits were associated with microscopically positive surgical margins (p=0.0148) and overexpression of MYC (p=0.0164...
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A 65-year-old woman was referred to our clinic complaining of white lesions on the palate and of the surface feeling rough when the tongue touched it. She had no special medical problems, and no history of smoking or alcohol. Intraoral... more
A 65-year-old woman was referred to our clinic complaining of white lesions on the palate and of the surface feeling rough when the tongue touched it. She had no special medical problems, and no history of smoking or alcohol. Intraoral findings were of a hard mass on the palate 40×22 mm in diameter and with white lesions on the surface. The white lesions were excised with adequate margins and bone mass under the mucosa was removed surgically. The pathology report diagnosed the white lesion as leukoplakia without atypical cells. The patient had no complications or dysfunction after surgery. Torus palatinus is found in 20-30% of the population and is usually less than 2 cm in diameter. Most torus palatinus are asymptomatic and found by routine oral examination. White lesion of oral mucosa needs differential diagnosis such as candidiasis, lichen planus and leukoplakia. The leukoplakia may occur due to repeat irritation at the site.
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We analyzed the efficacy of treatments that included alternating chemoradiotherapy in laryngeal cancer patients. Alternating chemoradiotherapy consisted of chemotherapy with 5-fluorouracil (600 mg/m(2)/day) on Days 1-6 and cisplatin (80... more
We analyzed the efficacy of treatments that included alternating chemoradiotherapy in laryngeal cancer patients. Alternating chemoradiotherapy consisted of chemotherapy with 5-fluorouracil (600 mg/m(2)/day) on Days 1-6 and cisplatin (80 mg/m(2)) on Day 7 followed by radiotherapy with 30 Gy. Additional chemoradiotherapy was administered to responders, and laryngectomy was performed in non-responders. The contribution of alternating chemoradiotherapy to laryngeal preservation was compared with that of radiotherapy in patients with T2 disease and with that of laryngectomy in patients with T3/T4 disease. Analysis of 87 patients was conducted. The 5-year overall survival rate of T2 patients (n = 46) was 88.9% for definitive radiotherapy and 82.5% for alternating chemoradiotherapy. The laryngectomy-free rate in T2 patients was 90.5% for definitive radiotherapy and 80.0% for alternating chemoradiotherapy. In patients with T3/T4 disease (n = 41), the 5-year overall survival rate was 86.9% f...
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Acquired chemoresistance to 5-fluorouracil (5-FU) remains one of the obstacles for the success of 5-FU-based cancer chemotherapy, and some molecular mechanisms of acquired 5-FU resistance are still unknown. The main action of 5-FU is the... more
Acquired chemoresistance to 5-fluorouracil (5-FU) remains one of the obstacles for the success of 5-FU-based cancer chemotherapy, and some molecular mechanisms of acquired 5-FU resistance are still unknown. The main action of 5-FU is the suppression of DNA replication by inhibiting Thymidylate Synthase (TS). We analyzed 5-FU resistance mechanisms using the head and neck squamous cell carcinoma cell lines, UM-SCC-23, and two different resistant cell lines, UM-SCC-23/WR and UM-SCC-23/MR, which were procured from UM-SCC-23 cells. To acquire resistance, the two cells underwent repeated treatment of 5-FU with different durations and frequency. We determined differences in the cell-cycle distribution and the expression of TS proteins in the three cell lines. Moreover, cell-cycle distribution in cells which acquired resistance after 5-FU treatment, was compared to that of parental cells, using flow cytometric analysis. There was a remarkable increase in TS protein expression levels in UM-S...
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Head and neck squamous cell carcinoma (HNSCC) may be curable with surgery, radiation and chemotherapy in its early stages. However, recurrence and metastasis often prevail following primary treatment in advanced stage cases and are... more
Head and neck squamous cell carcinoma (HNSCC) may be curable with surgery, radiation and chemotherapy in its early stages. However, recurrence and metastasis often prevail following primary treatment in advanced stage cases and are associated with significant morbidity and mortality. In this study we investigated the combination therapy of gemcitabine and cetuximab for HNSCC. The UM-SCC-6 and UM-SCC-23 HNSCC cell lines were analyzed following treatment with gemcitabine and cetuximab. To determine the mechanism of action of this combination treatment, the cell cycle distributions following gemcitabine and/or cetuximab treatment were analyzed by flow cytometry and apoptosis assay. Gemcitabine and cetuximab combination treatment exerted an enhanced cytotoxic effect. The cell cycle analysis demonstrated that cells accumulated in the S phase following gemcitabine treatment and G1 arrest occurred following cetuximab treatment. An increase in sub-G1 phase cells was also observed following ...
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Epithelial mesenchymal transition (EMT) is known to be associated with chemoresistance as well as increased invasion/metastasis. However, the relationship between EMT and resistance to an epidermal growth factor receptor (EGFR) -targeting... more
Epithelial mesenchymal transition (EMT) is known to be associated with chemoresistance as well as increased invasion/metastasis. However, the relationship between EMT and resistance to an epidermal growth factor receptor (EGFR) -targeting drug in head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we investigated the acquisition of EMT by gefitinib in HNSCC cell line (UMSCC81B). We isolated fibroblastoid variant (81B-Fb) from gefitinib-resistant UMSCC81B-GR3 cells obtained after increasing the doses of gefitinib treatment in vitro and examined EMT and its underlying mechanism. 81B-Fb cells exhibited fibroblast-like morphology, increased motility, loss of E-cadherin, acquisition of vimentin and snail expression. In 81B-Fb cells, downregulation of EGFR, which is mediated by increased ubiquitination, and activation of downstream protein kinase B (Akt), glycogen synthase kinase-beta (GSK-3β) signalling and upregulation of snail expression were observed compared...
Research Interests: Biology, Cancer Research, Medicine, Signal Transduction, Humans, and 15 moreMice, Animals, Male, Head and neck squamous cell carcinoma, Phosphorylation, Phenotype, Protein kinase B, Carcinoma, Cell Proliferation, Antineoplastic Agents, Protein Transport, Gefitinib, Quinazolines, Glycogen Synthase Kinase, and Head and neck neoplasms
5-Fluorouracil (5-FU) is widely used in the treatment of head and neck squamous cell carcinoma (HNSCC). However, development of drug resistance is one of the major causes of HNSCC treatment failure. The goal of this study was to... more
5-Fluorouracil (5-FU) is widely used in the treatment of head and neck squamous cell carcinoma (HNSCC). However, development of drug resistance is one of the major causes of HNSCC treatment failure. The goal of this study was to investigate the mechanism of 5-FU resistance and to develop a novel combination therapy with another agent which sensitizes cells to 5-FU. A 5-FU-resistant cell line, UM-SCC-23F/R, was developed from UM-SCC-23 cells. We determined sensitivities to 5-FU, etodolac and a combination treatment and also analyzed the expressions of cyclooxygenase-2 (COX-2) and thymidylate synthase (TS). Selective COX-2 inhibitor, etodolac, sensitized UM-SCC-23F/R cells to 5-FU. Expression of COX-2 decreased after etodolac treatment in both cell lines. While overexpression of TS was observed in UM-SCC-23F/R cells, etodolac inhibited TS expression, suggesting that the sensitizing effect induced by etodolac depends on TS suppression. We demonstrate for the first time an important inh...
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Research Interests: Pathology, Medicine, Humans, Female, Male, and 15 moreMiddle Aged, Carcinoma, Adult, Age Factors, Gene fusion, Salivary Gland, DNA binding proteins, Mucoepidermoid Carcinoma, Malignancy, reverse transcriptase polymerase chain reaction, Disease Free Survival, Neoplasm staging, Reverse transcription polymerase chain reaction, Medical and Health Sciences, and Modern Pathology
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In the treatment of head and neck malignancy, cisplatin and 5-FU have been used the most as chemotherapeutic agents. The difference in efficacies of these is unclear and controversial. To investigate more effective schedule, we analyzed... more
In the treatment of head and neck malignancy, cisplatin and 5-FU have been used the most as chemotherapeutic agents. The difference in efficacies of these is unclear and controversial. To investigate more effective schedule, we analyzed the cytotoxicity in different treatment sequence with two agents in vitro and the mechanism for different effectiveness. UM-SCC-23 and UM-SCC-81B, head and neck squamous cell carcinoma cell lines, were analyzed for cellular killing in alternative sequence treatment with cisplatin and 5-FU. The treatment schedule was designed based on the clinical regimen. To determine the mechanism for the difference of cytotoxicity with each schedule, cell cycle distributions of both cells after 5-FU treatment with various durations were analyzed by flow-cytometry and immunostaining with anti-PCNA and anti-BrdU. 5-FU pretreatment followed by cisplatin treatment showed higher cell killing in both types of cells than the reverse treatment schedule. In the cell cycle analysis and immunostaining after the treatment of 5-FU, the rate of PCNA-positive cells was increased from 24 to 144 h in both cells. The rate of BrdU-positive cells of UM-SCC-81B in flow-cytometry was also increased, while that of UM-SCC-23 was gradually decreased. These data suggested that the cells treated with 5-FU for more than 144 h were still in the S-phase with or without DNA synthesis. In head and neck carcinoma cells, we showed 5-FU pretreatment enhanced cisplatin cytotoxicity. The result of cell cycle analysis and immunostaining showed S-phase arrest by treatment of prolonged 5-FU treatment. The very long arrest in S-phase might be a mechanism to enhance cisplatin cytotoxicity by 5-FU pretreatment. We thus suggest pretreatment with 5-FU to enhance the effectiveness of cisplatin-based chemotherapy.