鵜澤 一弘

Heat shock factor 1 (HSF1) is responsible for expression of a large class of heat shock proteins that have been implicated in the malignant phenotype of human cancers. Little is known about the effect of a high level of HSF1 on the behavior of oral squamous cell carcinoma (OSCC). In this study, we assessed the value of HSF1 for predicting clinical outcomes in OSCC. Quantitative reverse transcriptase-polymerase chain reaction and Western blotting showed that the expressions of HSF1 mRNA and protein in OSCC-derived cell lines (HSC-2, HSC-3, HSC-4, Sa3, Ca9-22, KON and Ho-1-u-1) were elevated compared with those in human normal oral keratinocytes (P<0.05). Similar to in vitro data. HSF1 m RNA expression in primary OSCCs (n=50) was significantly greater than in normal counterparts (P<0.05). Since HSF1 was observed in the nucleus and cytoplasm by immunohistochemistry, we investigated the correlation between the HSF1 expression status at each subcellular location and the clinical behavior of OSCCs. Among the clinical classifications, higher nuclear HSF1 expression was closely related to tumor size and histopathologic types (P<0.05). These results showed for the first time that nuclear HSF1 expression may contribute to cancer progression and that HSF1 might be a potential diagnostic biomarker and a therapeutic target for OSCCs.

BACKGROUND: Annexins are calcium and phospholipid binding proteins that form an evolutionary conserved multigene family. Considerable evidence indicates that annexin A10 (ANXA10) is involved in tumoral progression, although little is known about its role in human oral carcinogenesis. In this study, we investigated the involvement of ANXA10 in oral squamous cell carcinoma (OSCC). METHODOLOGY/PRINCIPAL FINDINGS: ANXA10 mRNA and protein expressions were assessed by quantitative reverse transcriptase polymerase chain reaction and immunoblotting, and we conducted a proliferation assay and cell-cycle analysis in ANXA10 knockdown cells in vitro. We evaluated the correlation between the ANXA10 expression status in 100 primary OSCCs and the clinicopathological features by immunohistochemistry. ANXA10 mRNA and protein expression levels were up-regulated in all cellular lines examined (n = 7, p<0.05). ANXA10 knockdown cells showed that cellular proliferation decreased by inactivation of extracellular regulated kinase (ERK) (p<0.05), and cell-cycle arrest at the G1 phase resulted from up-regulation of cyclin-dependent kinase inhibitors. ANXA10 protein expression in primary OSCCs was also significantly greater than in normal counterparts (p<0.05), and higher expression was correlated with tumoral size (p = 0.027). CONCLUSIONS/SIGNIFICANCE: Our results proposed for the first time that ANXA10 is an indicator of cellular proliferation in OSCCs. Our results suggested that ANXA10 expression might indicate cellular proliferation and ANXA10 might be a potential therapeutic target for the development of new treatments for OSCCs.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) characterized by a necrotizing ulcer is an uncommon malignant lymphoma thought to be associated with Epstein-Barr virus infection and expression of CD56. We report a case of ENKL that could be observed from the earliest clinical features of the palatal gingiva. A 27-year-old-woman was referred to our hospital because of painful purpura-like lesions in the left side of the palatal gingiva. The purpura-like lesions developed to a necrotizing ulcer in about 1 week. Microscopic examination of a biopsy specimen demonstrated a lymphocytic infiltrate with increasingly atypical histopathological features. The atypical cells were positive for cytoplasmic CD3ε, granzyme B, and EBER-ISH, but negative for CD20 and CD56. Based on the histopathological findings, a final diagnosis of ENKL was made. The patient received radiotherapy to a dose of 50 Gy and three courses of DeVIC (CBDCA, VP-16, IFO, DEX) chemotherapy. There has been no sign of recurrence for 32 months after treatment. This case shows that purpura-like lesions might be one of the earliest clinical features of ENKL.

The development and progression of oral squamous cell carcinoma (OSCC) is a multistep process, which involves many genetic factors. Among them, loss of heterozygosity (LOH) studies have been used to identify regions on chromosomes that may contain putative tumor suppressor genes (TSGs). Here, we searched PubMed for relevant publications including our previous studies and compared results of LOH in OSCCs from the articles. LOHs in OSCCs were observed at various loci on almost all chromosomes, except X and Y. In this review, the LOH in patients with OSCC and the interrelationship between TSGs and OSCC initiation and progression are discussed. © 2011 Japanese Stomatological Society.

Conventional therapies including radiation therapy cannot cure squamous cell carcinoma (SCC), and new treatments are clearly required. Our recent studies have shown that SCC cell lines exhibiting radioresistance show significant upregulation of the fibroblast growth factor receptor 3 (FGFR3) gene. We hypothesized that inhibiting FGFR3 would suppress tumor cell radioresistance and provide a new treatment approach for human SCCs. In the present study, we found that RNA interference-mediated FGFR3 depletion in HSC-2 cells, a radioresistant cell line, induced radiosensitivity and inhibited tumor growth. Use of an FGFR3 inhibitor (PD173074) obtained similar results with suppression of the autophosphorylation extracellular signal-regulated kinase pathway in HSC-2 cells and lung cancer cell lines. Moreover, the antitumor growth effect of the combination of PD173074 and radiation in vivo was also greater than that with either drug alone or radiation alone. Our results provided novel information on which to base further mechanistic study of radiosensitization by inhibiting FGFR3 in human SCC cells and for developing strategies to improve outcomes with concurrent radiotherapy. Oncogene (2011) 30, 4447-4452; doi:10.1038/onc.2011.159; published online 16 May 2011

Dickkopf-1 (Dkk1), a negative regulator of the Wnt signaling pathway, is implicated in tumorigenesis in several types of cancer. The purpose of this study was to determine the involvement of Dkk1 in oral squamous cell carcinoma (OSCC). We found that Dkk1 is frequently upregulated in OSCC-derived cell lines and primary OSCCs compared with normal counterparts. Unexpectedly, Dkk1-positive cases were correlated significantly (P &lt; 0.05) with a low risk of regional lymph node metastasis. We also found that cellular migration and invasiveness increased in Dkk1 knockdown cells and decreased in Dkk1 overexpressed cells. Furthermore, we investigated the relationship between the expression of Dkk1 and distribution of beta-catenin in OSCC cells, since the Wnt signaling pathway is related closely to beta-catenin. Whereas alteration of the beta-catenin levels was not observed in each subcellular fractionation, the phosphorylated beta-catenin levels in nuclei increased in Dkk1 knockdown cells and decreased in Dkk1 overexpressed cells. These data indicated that the high phosphorylation level of beta-catenin in nuclei was correlated with a high risk of tumor invasiveness. The current study suggested that Dkk1 plays an important role in regulating cellular migration and invasiveness, making Dkk1 a potential biomarker for early detection of lymph node metastasis in OSCCs.

Objective: We designed a convenient method of selective intra-arterial infusion chemotherapy to treat oral cancer with low-dose 5-fluorouracil. Patients and methods: Twenty-seven primary cases treated with this method with concomitant external irradiation. The reasons for performing selective continuous intra-arterial infusion were severe systemic disease in four cases, advanced age in seven cases, unresectability in nine cases, preoperative chemotherapy in five cases, and two patients refused surgery. Results: The overall treatment effects were as follows: complete response in 13 cases, partial response in 12 cases, and no change in two cases. None of the patients experienced disease progression while receiving concurrent chemoradiotherapy. Twenty-three toxic adverse events ranging from grades 1 to 4 developed in 25 patients. A grade 1 complication developed in six patients oral and/or pharyngeal mucositis developed frequently in 12 patients. Hematologic adverse events such as leukocytopenia or thrombocytopenia were observed in five patients, but no grade 3 or 4 events developed in any patients. Conclusions: These data indicated that our method is suitable for patients who cannot undergo surgery or systemic chemotherapy due to old age or severe systemic disease. © 2011 Asian Association of Oral and Maxillofacial Surgeons.

Background. The aim of the current study was to identify the antitumor activity of satraplatin in paired cisplatin (CDDP)-resistant oral squamous cell carcinoma (OSCC) cell line and its parental cell line. Methods. CDDP-resistant (KB-R) cells and parental cells (KB) pair were used. Viability was assessed using the MTT and clonogenic assay. Real-time polymerase chain reaction (PCR), glutathione (GSH) assay, and flow cytometric analysis were used for further assessment. Results. KB-R cells did not show cross-resistance to satraplatin. The expression status of almost all transporters was upregulated in the KB-R cells. There was no difference in the GSH levels between the KB and KB-R cells. Flow cytometric analysis indicated that with satraplatin the G2/M phase was arrested in the KB-R cells. KB-R cells contain enriched side population cells. Conclusion. These data suggested that satraplatin has antitumor activity against the CDDP-resistant OSCC cells. The mechanism of cross-resistance to platinum agents seems to be multifactorial. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 309-317, 2011

Thioredoxin reductase 1 (TrxR1) catalyzes the nicotinamide adenine dinucleotide phosphate-dependent reduction of oxidized thioredoxin (Trx). Trx, which is over-expressed in many human tumors, is a selenocysteine-containing protein associated with cell proliferation and apoptosis inhibition. This selenium-containing redox system regulates the activity of various enzymes and counteracts oxidative stress in cells such as hypoxia and cytotoxic agents. Consequently, TrxR1 could play an important role in tumor progression and resistance to chemotherapy due to its anti-apoptotic functions. To characterize cancer-related gene expression changes in oral squamous cell carcinomas (OSCC), we compared the gene expression profiles in OSCC primary tumors with patient-matched normal oral epithelium. Microarray analysis showed TrxR1 upregulation in primary tumors. Gene ontology analysis showed highly significant cancer-related function. The TrxR1 expression examined by immunohistochemistry was correlated with regional lymph node metastasis (P &lt; 0.05) and the clinical stages of 50 patients (P &lt; 0.01). Overexpression of TrxR1 could contribute to cancer progression and might be a potential molecular marker for therapy.

Background: Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho family GTPase, which has been implicated in the malignant phenotype of human cancers. Little is known about the effect of a high level of ECT2 in regulating oral cancer cell behavior. In this study, we investigated the involvement of ECT2 in oral squamous cell carcinoma (OSCC). Methodology/Principal Findings: We analyzed ECT2 expression in OSCC-derived cell lines and primary OSCCs compared with matched normal tissue (n = 96) by quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. We then evaluated the correlation between the ECT2 expression status in primary OSCCs and the clinicopathological features. ECT2 expression was significantly up-regulated in OSCCs in vitro and in vivo (p&lt;0.05). Among the clinical variables analyzed, higher ECT2 expression also was associated with the TNM stage grading (p&lt;0.05). When we performed functional analyses of ECT2 in OSCC-derived cells using the shRNA system, the cellular proliferation of the ECT2 knockdown cells decreased significantly compared with the control cells (p&lt;0.05). Cell cycle analysis by flow cytometry showed arrest of cell cycle progression at the G1 phase in the ECT2 knockdown cells. We also found up-regulation of the Cip/Kip family of the cyclin-dependent kinase inhibitors, p21(cip1) and p27(kip1), and down-regulation of cyclin D1, cyclin E, and CDK4. These data suggested that the elevated Cip/Kip family induced inhibition of the cyclin D1-CDK complex activity leading to cell cycle arrest at the G1 phase. Conclusions/Significance: Our results proposed for the first time that ECT2 is an indicator of cellular proliferation in OSCCs and that ECT2 might be a potential therapeutic target for the development of new treatments for OSCCs.

The authors report a case of right mandibular metastasis from thyroid follicular carcinoma of a 71-year-old woman who suffered from painless swelling in the right retromolar region for 10 months. As pulse was detected through a mass, we suspected that the mass was hemangiosarcoma or A-V malformation. However, by an incisional biopsy, a diagnosis of a metastasis from thyroid follicular carcinoma, was suggested. Under general anesthesia, right lobe thyroid gland resection, mandible segmental resection, neck dissection, and plate reconstruction were performed. Final diagnosis of thyroid follicular carcinoma and metastasis to the right mandible was made. The postoperative period was uneventful and the patient was asymptomatic without signs of recurrence 4 years postoperatively. The present case is the uncommon case of mandibular metastasis from thyroid follicular carcinoma. © 2010 Asian Association of Oral and Maxillofacial Surgeons.

Objective: This study was performed to evaluate the usefulness of continuous-selective intra-arterial injection of antibiotics via the superior thyroid artery for osteoradionecrosis of the mandible. Patients and methods: Three osteoradionecrosis cases were treated with this innovative drug delivery system. Totals of 7200. mg, 7810. mg and 6960. mg of clindamycin (CLDM) were administered in cases 1, 2 and 3, respectively. Patients also received conventional intravenous cefozopran hydrochloride (CZOP) or ceftazidime (CAZ) or moxifloxacin (MFLX) and hyperbaric oxygen therapy (HBO). Results: Both clinical findings and laboratory data improved immediately after these treatments in these cases. Conclusion: The present study indicates that continuous-selective antibiotic injection via the superior thyroid artery might be an additional treatment option if performed in combination with conventional approaches in the refractory cases. © 2010 Asian Association of Oral and Maxillofacial Surgeons.

Serpins (serine protease inhibitors) are known as a diverse family of protease inhibitors; however, various other biological activities including tumor suppression, have been recently reported for these molecules. To clarify whether members of the serpin family are involved in OSCC (oral squamous cell carcinoma), global gene screening using microarray analysis was performed with OSCC-derived cell lines. A trend toward diminished expression was shown for some SERPIN genes located on 11q12-q13.1 and 18q21. mRNA expression of SERPIN genes at these chromosome regions was therefore analyzed using real-time quantitative RT-PCR (qRT-PCR) in 55 OSCC samples and matched normal tissue. Statistically significant decreases in expression were found for SERPINB12 (P=0.001), SERPINB13 (P=0.001), SERPINB4 (P=0.042), SERPINB3 (P&lt;0.001), SERPINB11 (P&lt;0.001), SERPINB7 (P=0.021) and SERPINB2 (P=0.018). All of these genes are located on 18q21, the known location of the serpin gene cluster. The results strongly suggest that this chromosome region plays a crucial role in OSCC. Some serpin members in the region might be involved in tumor suppression, or there might be unidentified tumor suppressor genes within or near the chromosome region.

Oxidative stress results in damage to cellular structures and has been linked to numerous diseases, including cancer. Extracellular superoxide dismutase (EC-SOD) is a principal enzymatic antioxidant in extracellular space. The purpose of this study was to determine whether the expression of EC-SOD protein is altered in the carcinogenetic process of oral squamous-cell carcinoma (OSCC). Immunohistochemical analysis was carried out in matched normal and tumour specimens collected from 58 OSCCs and 20 oral premalignant lesions (OPLs). Correlations between the EC-SOD expression levels and clinicopathological features of OSCC patients were evaluated by Fisher&apos;s exact test. Although EC-SOD protein was consistently expressed on the plasma membrane of cells in normal tissues, plasma membranous EC-SOD expression was lost in almost all the OSCC specimens examined (98%). Instead, positive EC-SOD expression was detected in the cytoplasmic compartments of cancerous cells in both OPLs (65%) and OSCCs (52%), together with a high incidence of lymph node metastasis (p=0.0397). These results suggest that the dysregulation of EC-SOD protein expression is a frequently occuring and early event in oral carcinogenesis, and that cytoplasmic EC-SOD may contribute to the increased aggressiveness of OSCC.

MicroRNAs (miRNAs) are small, noncoding RNAs which regulate cell differentiation, proliferation, development, cell cycle, and apoptosis. Expression profiling of miRNAs has been performed and the data show that some miRNAs are upregulated or downregulated in cancer. Several studies suggest that the expression profiles of miRNAs are associated with clinical outcomes. However, the set of miRNAs with altered expressing differs depending on the type of cancer, suggesting that it is important to understand which miRNAs are related to which cancers. Therefore, this review aimed to discuss potentially crucial miRNAs in head and neck squamous cell carcinoma (HNSCC) and oral squamous cell carcinoma (OSCC). © 2010 by the authors licensee Molecular Diversity Preservation International, Basel, Switzerland.

To determine the involvement of ZIC2 in oral squamous cell carcinoma (OSCC). ZIC2 mRNA and protein expression in primary OSCCs (n = 74), oral premalignant lesions (OPLs, n = 20) and five OSCC-derived cell lines (HSC-2, HSC-3, OK-92, H1, and Sa3) were analyzed by quantitative reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemistry (IHC). In addition, we evaluated the correlation between ZIC2 IHC scores in OSCCs and the clinicopathologic status. Significant up-regulation of ZIC2 was detected in OSCC-derived cell lines (P &lt; 0.05), primary OSCCs (P &lt; 0.05) and OPLs (P &lt; 0.05) compared with normal counterparts. Among the clinical variables analyzed, ZIC2 expression was associated with the histopathologic types of OSCC. Furthermore, the survival rates differed significantly between ZIC2-positive cases and ZIC2-negative cases. These results suggested that ZIC2 expression is correlated with the differentiation type of OSCC and diagnosis and might be a potential prognostic indicator and therapeutic target for OSCCs.

S-1, an oral anticancer drug, is comprised of tegafur (a prodrug of 5-fl uorouracil) and two biochemical modulators that have effect-enhancing and adverse reaction-reducing activities. Neoadjuvant chemotherapy (NAC) using S-1 has not been reported. Between April 2003 and March 2008, 103 patients with previously untreated oral squamous cell carcinoma (OSCC) received some courses of S-1 NAC (S-1 80 mg/m2/day as the NAC until 1 week preoperatively). Tumor size and histopathologic effect were evaluated before and after treatment. Among 103 cases, 10 cases had complete responses and 53 cases had partial responses (overall response rate [RR], 61.2%). Twenty-two (21.4%) patients had adverse events. Most patients had mild toxicities in the bone marrow and digestive tract (grade 1, 19 cases). Only three patients (2.9%) had grade 2 neutropenia or grade 4 thrombocytopenia. We examined the relationship between the RR and the clinicopathologic behaviors. The RR of the pN2 cases (33.3%) was signifi cantly lower than that of the pN0 cases (69.4%). The RR was not correlated with tumor size, differentiation type, distant metastasis, and the period of administration. The data indicates that S-1 caused only mild toxicity and had highly effective antitumor activity. Furthermore, the RR of S-1 NAC might predict regional lymph node metastasis. © 2010 Yokoe H, et al.

Resistance to cisplatin is a major obstacle to successful treatment of head and neck squamous cell carcinoma (HNSCC). To investigate the molecular mechanism of this resistance, we compared the gene expression profiles between the cisplatin-sensitive SCC cell lines (Sa-3, H-1 and KB) and the cisplatin-resistant cell lines established from them (Sa-3R, H-1R and KB-R) using Affymetrix U133 Plus 2.0 microarray. We identified 199 genes differentially expressed in each group. To identify important functional networks and ontologies to cisplatin resistance, the 199 genes were analyzed using the Ingenuity Pathway Analysis Tool. Fifty-one of these genes were mapped to genetic networks, and we validated the top-10 upregulated genes by real-time reverse transcriptase-polymerase chain reaction. Five novel genes, LUM, PDE3B, PDGF-C, NRG1 and PKD2, showed excellent concordance with the microarray data. In 48 patients with oral SCC (OSCC), positive immunohistochemical staining for the five genes correlated with chemoresistance to cisplatin-based combination chemotherapy. In addition, the expression of the five genes predicted the patient outcomes with chemotherapy. Furthermore, siRNA-directed suppressed expression of the five genes resulted in enhanced susceptibility to cisplatin-mediated apoptosis. These results suggested that these five novel genes have great potential for predicting the efficacy of cisplatin-based chemotherapy against OSCC. Global gene analysis of cisplatin-resistant cell lines may provide new insights into the mechanisms underlying clinical. cisplatin resistance and improve the efficacy of chemotherapy for human HNSCC.

Homeobox (HOX) A10, the regulator of embryonic morphogenesis and differentiation, is aberrantly expressed in several cancer types. Our previous study using microarray technology showed that significant up-regulation of HOXA10 occurs in oral squamous cell carcinoma (OSCC)-derived cell lines compared to human normal oral keratinocytes (HNOKs). The aim of the current study was to examine the status of HOXA10 mRNA and protein expression in OSCC-derived cell lines and human primary OSCCs. HOXA10 mRNA was up-regulated in six OSCC-derived cell lines compared with HNOKs and in primary OSCCs by using real-time quantitative reverse transcriptase-polymerase chain reaction. Immunohistochemistry data indicated that HOXA10 protein expression levels were consistent with mRNA expression status in OSCC-derived cell lines and primary OSCCs. Furthermore, HOXA10 expression status was correlated with the TNM stage (P&lt;0.05). These results indicate that HOXA10 expression could contribute to cancer progression and prognosis and that HOXA10 may be a potential diagnostic marker and a therapeutic target for OSCCs.

Oncolytic virotherapy utilizes viruses that can selectively destroy cancer cells without harming normal tissues. Clinical trials of oncolytic viruses show that most oncolytic agents are well tolerated and safe. The virotherapeutic agents currently in use have limited potency when administered alone; however, combination therapy using virotherapeutic agents and conventional anticancer agents, such as chemotherapeutics, radiation, and gene therapy, exhibits encouraging levels of efficacy. Advances in recombinant DNA technology have allowed the development of viruses that are tumor-selective and armed with transgenes, increasing the application potential and efficacy of this novel anticancer therapy. Here, we review the development of oncolytic viruses and the clinical trials of oncolytic virotherapy for oral cancers. We discuss current issues and perspectives of this evolving anticancer therapy, highlighting the potential applications of a unique, naturally occurring oncolytic virus, Sindbis virus. (C) 2009 Elsevier Ltd. All rights reserved.

The purpose of this study was to characterize changes in the expression of copper-zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD (Mn-SOD) in oral squamous-cell carcinoma (OSCC). Real-time quantitative reverse transcriptase-polymerase chain reaction analysis of Cu/Zn-SOD and Mn-SOD mRNA expression was carried out in 50 pairs of OSCC tissue specimens and corresponding normal tissues. Mn-SOD protein expression was evaluated further in 65 OSCC tissue samples and 33 oral premalignant lesions (OPLs) using immunohistochemistry. Significant (P &lt; 0.001) upregulation of Mn-SOD mRNA expression was observed in OSCC tissues compared with the normal tissue counterparts, whereas no significant difference was detected in Cu/Zn-SOD expression. Significant increases in Mn-SOD protein expression were seen in both OPLs (P &lt; 0.001) and OSCC tissue (P &lt; 0.001) together with a high incidence of lymph node metastasis (P = 0.04). Our findings suggested that Mn-SOD overexpression is a frequent and early event during oral carcinogenesis and could contribute to aggressive OSCC.

The molecular mechanism playing a role in the development of benign prostate hypertrophy (BPH) and prostate cancer (PC) is not well defined. We performed microarray analysis to assess the gene expression change in BPH and PC, and performed network analysis. Normal prostate, BPH and PC tissues were obtained from patients who underwent an operation at Chiba University Hospital. Using Affymetrix Human Genome U133 Plus2.0 Array, we identified genes differentially expressed. The identified genes were analyzed using the Ingenuity Pathway Analysis (IPA) to investigate the functional network and gene ontology. The microarray analysis identified 402 genes in BPH and 141 genes in PC, which were up- or down-regulated at least 5.0-fold change in PC at all dose points. Analysis using IPA software revealed eight networks in BPH and five networks in PC. We narrowed these down to the top five genes, which were up- or down-regulated on the networks in their characteristic manner. From this new perspective, comparing BPH and PC in microarray studies, our data showing gene expression profiles provide candidate genes for better understanding of disease and new therapeutic targets.

BACKGROUND: Sindbis virus (SIN) infection causes no or only mild symptoms (fever, rash, and arthralgia) in humans. However, SIN has a strong cytopathic effect (CPE) on various cancer cells. This study focuses on the oncolytic activity of SIN AR399 on oral cancer cells compared with reovirus, a well-known oncolytic virus that targets cancer cells. METHODS: We analysed the cytotoxicity and growth of SIN in 13 oral squamous cell carcinoma (OSCC) cell lines (HSC-2, HSC-3, HSC-4, Ca9-22, H-1, Sa-3, KON, KOSC-2, OK-92, HO-1-N1, SCC-4, SAT, SKN-3) and normal human oral keratinocytes (NHOKs). RESULTS: Sindbis virus infection induced CPE in 12 OSCC cell lines at a low multiplicity of infection (MOI) of 0.01, but not in the OSCC cell line, HSC-4 or NHOKs. Sindbis viral growth was not observed in NHOKs, whereas high SIN growth was observed in all OSCC cell lines, including HCS-4. The cytotoxicity and growth of SIN was the same as reovirus at an MOI of 20 in 12 OSCC cell lines. The CPE was shown, by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labelling assays, to be apoptotic cell death. Furthermore, quantitative RT-PCR of mRNA in HSC-3 and HSC-4 cells after SIN infection showed that activation of caspases, cytochrome c, and I kappa B alpha was associated with SIN-induced apoptosis. CONCLUSION: As a replication-competent oncolytic virus, SIN may be a useful therapeutic modality for oral cancers. British Journal of Cancer (2009) 101, 684-690. doi: 10.1038/sj.bjc.6605209 www.bjcancer.com Published online 28 July 2009 (C) 2009 Cancer Research UK

To determine the potential involvement of ANXA1 in oral squamous-cell carcinoma (OSCC), we evaluated the ANXA1 protein expression in oral premalignant lesions (OPLs) and OSCCs and correlated the results with clinicopathologic variables. Matched normal and tumour specimens of 44 primary OSCCs and 28 OPLs were analyzed for ANXA1 subcellular localization and protein expression level by immunohistochemistry (IHC). Correlations between ANXA1-IHC staining scores of OSCCs and clinicopathologic features were evaluated by Fisher's exact test. Markedly down-regulation of ANXA1 protein expression was identified on the plasma membrane of epithelial cells in OSCCs (P &lt; 0.001) and OPLs (P = 0.001) compared with normal counterparts. Moreover, loss of plasma membranous ANXA1 expression was significantly correlated with the poorly differentiated status of OSCC cells (P = 0.012). Our findings suggest that loss of ANXA1 is frequent and early event during oral carcinogenesis and that ANXA1 could contribute to maintaining epithelial differentiation in OSCC.

We previously established H-1R cells, a cisplatin (CDDP)-resistant cell line, from H-1 cells, a CDDP-sensitive oral carcinoma cell line. The aim of this study was to identify the molecular mechanism of cross-resistance to antitumor drugs containing a platinum agent in H-1R cells. The 3-(3, 4-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and clonogenecity assay indicated that H-1R cells showed strong cross-resistance to carboplatin, nedaplatin and oxaliplatin. The expression status of the copper transporter and organic cation transporters was confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction. The transporters ATP7A, ATP7B, hCtrl, hOCT1 and hOCT2 were up-regulated, whereas hOCT3 was down-regulated. The cellular glutathione level was elevated 2-fold in H-1R cells compared with H-1 cells. Our results suggested that H-1 and H-1R cells may be useful in searching for candidate genes responsible for cross-resistance to platinum derivatives and for further studies to understand the mechanism of platinum resistance.

Objectives: To identify changes in the expression patterns of the TSLC1 (tumour suppressor in lung cancer 1) gene family in oral squamous cell carcinoma. Materials and Methods: DNA microarray was performed to analyse gene expression of the TSLC1 gene family in oral squamous cell carcinoma-derived cell lines (HSC2, HSC3, Ca9-22, and Sa3) when compared with normal oral keratinocytes using high-density Affymetrix U133 plus 2.0 GeneChip arrays containing 54,675 probe sets. Comparison of TSLC1 mRNA expression levels between 30 primary oral squamous cell carcinomas and normal tissues was performed by real-time quantitative reverse transcriptase-polymerase chain reaction, which was used to confirm the microarray results. Results: Microarray analysis demonstrated TSLC1 expression levels that were downregulated at least 2-fold or more in 3 of 4 oral squamous cell carcinoma-derived cell lines (75%) compared with normal oral keratinocytes. Significant downregulation of TSLC1 expression levels was shown by real-time quantitative reverse transcriptase-polymerase chain reaction analysis in all oral squamous cell carcinoma-derived cell lines and 23 (77%) of 30 primary oral squamous cell carcinomas (p &lt 0.01, Mann-Whitney U test), consistent with the microarray data. Conclusions: These results suggest that the TSLC1 gene is frequently altered in oral squamous cell carcinoma. This alteration may contribute to carcinogenesis in oral cancer. © 2009 Asian Association of Oral and Maxillofacial Surgeons.

Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest because it is involved in various developmental processes and various diseases including cancer. autophagy-related 16-like 1 is a component of a large protein complex essential for autophagosome formation. We previously applied proteomic methods to characterize differentially expressed proteins in oral squamous cell carcinoma cells and detected significantly high expression levels of autophagy-related 16-like 1 in oral squamous cell carcinoma-derived cell lines compared to human normal oral keratinocytes, in the current study, to further determine the potential involvement of autophagy-related 16-like 1 in oral squamous cell carcinoma, We evaluated the state of autophagy-related 16-like 1 protein expression in human oral premalignant lesions and primary oral squamous cell carcinomas, and correlated the results with clinicopathologic variables. Autophagy-related 16-like 1 immunoreaction was predominant in a variety of subcellular components of oral squamous cell carcinoma tissues, including the cytoplasm and plasma membrane of malignant cells (45% and 39%, respectively) and peritumoral and intratumoral stroma (52%), whereas all of the components in normal tissues had no or faint autophagy-related 16-like 1 expression. In addition, high stromal expression of autophagy-related 16-like 1 was associated significantly with lymphovascular invasion of tumor cells (P=.037) and positive lymph node status (P=.015). Furthermore, cytoplasmic and plasma membranous autophagy-related 16-like 1 were also expressed in abundance in the oral premalignant lesion cells (74% and 32%, respectively). Our finding suggests that dysregulation of autophagy-related 6-like 1 protein expression is a frequent and early event during oral carcinogenesis and could affect the malignant behavior of oral squamous cell carcinoma cells. (c) 2009 Elsevier Inc. All rights reserved.

Objective: To identify genes associated with therapeutic targets of oral squamous cell carcinoma (OSCC), we compared gene expression profiles in OSCC-derived cell lines with human normal oral keratinocytes. Methods: We analyzed the gene expression profiles of OSCCs using Affymetrix Gene-Chip analysis. The identified genes were analyzed by an Ingenuity Pathway Analysis tool to identify networks of interacting genes. A candidate gene was further evaluated for the expression status of the mRNA and protein in OSCC-derived cell lines and primary OSCCs. Results: The microarray data identified 188 genes downregulated in OSCC-derived cell lines, and the genetic pathways associated with expression changes were generated. Among the genes mapped to the network with the highest significance, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was analyzed further. CEACAM1 mRNA and protein were frequently downregulated in OSCC-derived cell lines compared with human normal oral keratinocytes. Immunohistochemical analysis showed that primary OSCCs were significantly decreased in CEACAM1. Moreover, CEACAM1 expression was correlated with the TNM staging. We also found that CEACAM1-negative expression was significant both for disease-free (p = 0.036) and overall survival (p = 0.032). Conclusion: Repression of CEACAM1 could contribute to cancer progression and may indicate a poor prognosis for patients with OSCC. Copyright (C) 2009 S. Karger AG, Basel

KAI1 was originally identified in prostate cancer as a metastasis suppressor gene, and frequent down-regulation of KAI1 expression was reported in many tumor types. The aim of the present study was to examine whether suppressed expression of KAI1 could contribute to the progression and metastasis of tongue squamous cell carcinoma (SCC). We analyzed mutational status of the KAI1 gene, and both the mRNA and protein level in a series of tongue SCC (25 pre-cancerous lesions, 41 primary tongue SCCs, and 15 metastatic lymph node tumors). We found no mutation of the KAI1 gene by PCR-SSCP analysis, however, immunohistochemistry revealed high frequencies of KAI1 down-regulation not only in metastatic tumors (100%, 15/15) but also in primary tongue SCCs (85%, 35/41) and pre-cancerous lesions (44%, 11/25). There was a significant relationship between down-regulation of KAI1 protein expression and primary tumors with lymph node metastases (P=0.044). Moreover, differentially suppressed expression levels of KAI1 were detected through multiple steps of tumor progression (from normal tissue to carcinoma or metastatic tumor) (P<0.01). Our data suggest that suppressed regulation of KAI1 protein expression is associated with regional lymph node metastasis and that the down-regulation of KAI1 is involved in the tumor progression.

Background and purpose: Heavy ion beams are high linear energy transfer (LET) radiation characterized by a higher relative biologic effectiveness than low LET radiation. The aim of the current study was to determine the difference of gene expression between heavy ion beams and X-rays in oral squamous cell carcinoma (OSCC)-derived cells. Materials and methods: The OSCC cells were irradiated with accelerated carbon or neon ion irradiation or X-rays using three different doses. We sought to identify genes the expression of which is affected by carbon and neon ion irradiation using Affymetrix GeneChip analysis. The identified genes were analyzed using the Ingenuity Pathway Analysis Tool to investigate the functional network and gene ontology. Changes in mRNA expression in the genes were assessed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Results: The microarray analysis identified 84 genes that were modulated by carbon and neon ion irradiation at all doses in OSCC cells. Among the genes, three genes (TGFBR2, SMURF2, and BMP7) and two genes (CCND1 and E2F3), respectively, were found to be involved in the transforming growth factor P-signaling pathway and cell cycle:G1/S checkpoint regulation pathway. The qRT-PCR data from the five genes after heavy ion irradiation were consistent with the microarray data (P &lt; 0.01). Conclusion: Our findings should serve as a basis for global characterization of radiation-regulated genes and pathways in heavy ion-irradiated OSCC. (c) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 89 (2008) 237-244.

30の口腔扁平上皮癌臨床組織検体と9種の口腔癌由来細胞株におけるheadpinの発現について調べ、更に脱メチル化剤5-AzaC処理による発現減弱の回復について検討した。RT-PCR解析にて、30の臨床組織検体のうち17検体(56.7%)、9種の細胞株のうち5種(55.6%);SAS,HSC-3,OK92,HO-l-N-1,SCC4でheadpinの発現減弱を認めた。更に、これら5種細胞株において4種(80.0%);SAS,HSC-3,OK92,SCC4で脱メチル化剤5-AzaC処理による発現の回復が確認された。これらの結果から、headpinの発現減弱が口腔扁平上皮癌の進展に関与しており、その機序において過メチル化が関与していることが示唆された。

口腔癌のうち、多発癌症例の特徴を明らかにするために、多発癌症例と単発癌症例とを比較した。過去6年間に診断された口腔癌は151症例で、多発癌:13症例(8.6%)、単発癌:138症例(91.4%)であった。多発癌症例のうち、第1癌診断から第2癌発生までは平均3年7ヵ月で、9例(69.2%)は第1癌診断から5年以内に第2癌が発生していた。T3以上の割合、所属リンパ節転移の割合、Stage III以上の割合は多発癌よりも単発癌が多かったが、5年累積生存率は多発癌第1癌:73.8%、単発癌:87.0%であった。また、多発癌第1癌は歯肉(61.5%)、単発癌は舌(38.4%)の発生が多く、多発癌第1癌の61.5%、第2癌の76.9%、単発癌の78.3%は高分化型であった。多発癌の治療は困難で、この報告で対象とした多発癌症例には放射線、喫煙、飲酒との関連がないことから免疫力の低下、遺伝子の変化などの宿主要因が強く関与していることが疑われた。

舌扁平上皮癌症例に絞り、舌癌における8p染色体上の異常集積部位を検索するためにヘテ口接合性消失(LOH)分析を行った。さらに、その異常集積部位周辺に存在する2つの癌関連遺伝子(EEZ1遺伝子とカテプシンB遺伝子)の発現状態を調べ、第8番染色体短腕(8p)と舌扁平上皮癌との関連を評価した。外科切除時に、舌癌患者20例から原発性腫瘍組織とこれに対応する正常組織を採取した。8pの欠失地図を作成し、高頻度でLOHが認められたD8S258およびD8S87領域は8p22における共通欠失領域と考えた。EEZ1遺伝子が舌癌組織検体で正常組織と比較して5分の1以下に発現減弱していた症例は20例中の8例であった。カテプシンB遺伝子が正常組織と比較して舌癌組織検体で5倍以上発現増強していた症例は20例中の13例であった。カテプシンB遺伝子の発現は癌組織検体で有意に亢進していた。

PTEN is a tumor suppressor gene located on chromosome 10q23.3. In addition to genetic mutations and deletions, the down-regulation of PTEN has been found in various malignant tumors. However, little is known about the profile of PTEN gene in oral carcinomas. In this study, the expression profiles and genetic alterations of PTEN were examined in 113 oral squamous cell carcinoma (OSCC) cases and 9 OSCC-derived cell lines. An immunohistochemical analysis showed statistically significant differences in the immunohistochemical (IHC) scores for PTEN protein in normal tissues and in cancerous regions (P=0.0104), suggesting that PTEN protein expression is down-regulated in OSCC. No significant correlations existed between the down-regulation of PTEN protein expression and the clinicopathological features of the tumor. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a lower PTEN mRNA expression in the 9 OSCC-derived cell lines examined, as compared to the normal oral epithelium cells. However, treatment with a demethylating reagent restored PTEN mRNA expression in 4 cell lines. No genetic mutations were detected in these cell lines by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. The results suggest that epigenetic changes may be related to the down-regulation of PTEN expression. We therefore conclude that PTEN is a crucial molecule in the tumorigenesis of OSCC.

To characterize cancer-related gene expression changes in oral squamous cell carcinomas (OSCCs), we compared the gene expression profiles in OSCC-derived cell lines with human normal oral keratinocytes (HNOKs). Microarray analysis identified 166 genes that were up-regulated in OSCC-derived cell lines. Gene ontology analysis showed that cancer-related function had the highest significance. Among the genes mapped to the cancer-related network with the highest significance, the receptor for hyaluronan-mediated motility (RHAMM) was evaluated further for mRNA and protein expression in the OSCC cell lines, primary OSCCs. Overexpression of RHAMM protein was observed in all cell lines compared to HNOKs. Immunohistochernical analysis showed highly expressed RHAMM in primary OSCCs, whereas most corresponding normal tissues had no or significant down-regulation of protein immunoreactivity. Real-time quantitative reverse transcriptase-polymerase chain reaction data agreed with the protein expression. Moreover, the RHAMM expression status was correlated with the TNM stage (P &lt; 0.001). The results suggested that RHAMM expression may be correlated with tumor aggressiveness and offer clues to the development of new treatments for human OSCCs.

Background: Gelsolin-like actin-capping protein (CapG) is a ubiquitous gelsolin-family actin-modulating protein involved in cell signalling, receptor-mediated membrane ruffling, phagocytosis, and motility. CapG has generated great interest due to its oncogenic function in the control of cell migration or invasion in a variety of cancer cells. We previously applied proteomic methods to characterize differentially expressed proteins in oral squamous-cell carcinoma (OSCC) cells and detected significantly high expression levels of CapG in OSCC-derived cell lines compared to human normal oral keratinocytes. In the current study, to further determine the potential involvement of CapG in OSCC, we evaluated the status of CapG protein and mRNA expression in human oral premalignant lesions (OPLs) and primary OSCCs and correlated the results with clinicopathologic variables. Methods: Matched normal and tumour tissue sections of 79 human primary OSCCs and 28 OPLs were analyzed for CapG expression by immunohistochemistry (IHC). Correlations between CapG-immunohistochemical staining scores of OSCCs and clinicopathologic features were evaluated by Fisher&apos;s exact test. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to estimate CapG expression at the mRNA level. Results: In IHC, substantial up-regulation of CapG protein was observed in primary OSCCs (52%) and OPLs (64%), whereas corresponding normal tissues showed consistently weak or absent immunoreactivity of CapG. qRT-PCR data were consistent with the protein expression status. Moreover, CapG expression was correlated with the TNM stage grading of OSCCs. Conclusion: Our finding of frequent dysregulated expression of CapG in premalignant and malignant lesions together with an association with an advanced clinical disease stage suggests that CapG could contribute to cancer development and progression and that CapG may have potential as a biomarker and a therapeutic target for OSCC.

染体色8p領域に存在するcathepsin B遺伝子の発現について検索し、口腔癌症例における臨床諸指標との関連について検討した。口腔癌手術検体47例からmRNAを抽出して、定量的リアルタイムRT-PCR法にてcathepsin BのmRNAの発現を調べた。その結果、健常組織での発現と比較してcathepsin B遺伝子の発現が亢進していたのは全47例中38例(80.9%)で、また、その発現量の比較でも舌癌と正常組織ではcathepsin B遺伝子の発現量中央値は各々2.10及び0.89であり、有意にcathepsin B遺伝子の発現亢進がみられた。臨床諸指標とcathepsin B遺伝子発現との関連では、分化度の低いもの、腫瘍の大きさが大きいもの、頸部リンパ節転移を認めるもの、病期が進んでいるものほどcathepsin B遺伝子発現が亢進していた。以上から、cathepsin B遺伝子発現の亢進が口腔癌において認められることが示され、舌癌における染色体8p22領域の重要性が示唆された。

51歳女性。患者は他医にて右側上顎骨肉腫に対する炭素イオン重粒子線治療後に局所再発し、根治的手術療法が施行されたが、術後1年5ヵ月(初回治療後3年目)目に局所再発を更に認め、著者らの施設へ紹介入院となった。精査の結果、頭蓋内浸潤を伴った右側上顎骨肉腫の再発と診断され、根治的手術は困難と考え、多剤併用の化学療法が行なわれる方針となった。化学療法はHD-MTX、CDDP、DXR、IFMの4剤を中心に構築したところ、第4クール終了時にはPRが得られた。だが、その後も腫瘍は再び増大傾向を示し、第10クール以降は化学療法による制御が困難で腫瘍減圧術が4回施行され、総計14クールの化学療法が行なわれたが、患者は入院1年後に呼吸不全のために死亡となった。

Our previous study using proteomic profiling demonstrated significant up-regulation of Septin 1, a conserved family of GTPase proteins, in oral squamous-cell carcinoma (OSCC)-derived cell lines. In the current study, to determine the potential involvement of Septin 1 in oral carcinogenesis, we evaluated the state of septin 1 protein/mRNA expression in OSCC-derived cell lines, oral premalignant lesions (OPLs), and primary OSCCs. A significant (P &lt; 0.05) increase in Septin 1 expression was evident in all OSCC-derived cell lines examined compared to human normal oral keratinocytes (HNOKs) and OPLs. In immunohistochemistry, while the vast majority of the OSCCs (89%) were positive for Septin1, no immunoreaction was observed in corresponding normal tissues and OPLs. In addition, real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) data were consistent with the protein expression status. These results suggest that Septin 1 expression could contribute to cancer progression, proliferation, or both, and that Septin 1 may be a potential diagnostic marker of highly active cancer and a therapeutic target for OSCCs.

Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/ VEL13/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCCderived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated)3-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P &lt; 0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis.

症例は16歳男性で、右側上顎第二小臼歯の動揺を主訴に近医を受診し、パノラマX線写真で右側上顎骨内の透過像を指摘された。精査したところ、右側上顎骨内に皮質骨の明瞭な境界を有する類球形の拇指頭大の病巣を認めた。病巣は未萠出の右側第一小臼歯の歯冠を含むと共に小石灰化物の点在が見られた。外科的摘出の適応と考え、全身麻酔下で埋伏歯牙と主要本体を一塊として摘出した。病理組織検査では腫瘍実質に富み、間質に乏しく、くわえて腺管様構造や高円柱状細胞が2列に向き合って配列した花冠状構造も見られ、腺様歯原性腫瘍と診断した。術後は再発もなく、術前に見られた臨在歯の歯根離開と動揺も改善して健全な口腔機能を回復しており、経過良好である。

To investigate the mechanism of the resistance to cisplatin (CDDP), we established the CDDP-resistant cell line, KB-R, from CDDP-sensitive oral carcinoma cell line, KB. The 3-(3, 4-dimethyl-thiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay indicated that KB-R is 5.5-fold more resistant to CDDP than KB. Microarray analysis indicated that the expression levels of 1,718 genes were elevated at least fivefold or more in KB-R, compared with KB. The expression status of ATP binding cassette (ABC) transporter genes, which belong to multi-drug resistance genes, was confirmed by semi-quantitative reverse transcriptase-polymerase chain reaction and real-time PCR. MRP1 and MRP2 were up-regulated, whereas MDR1 was down-regulated. Pathway and ontology analysis using the Ingenuity Pathway Analysis tool indicated three highly significant genetic networks including 105 of the 1,718 overexpressed genes and one network including 35 'cell-to-cell signaling and interaction' related genes. Our results suggested that these cell lines, KB and KB-R, may be useful for searching the candidate genes responsible for CDDP-resistance and for further study to understand the mechanism of CDDP-resistance.

Ku80 is an important component of DNA double-strand break repair, and Ku80 deficiency leads to extreme sensitivity to ionizing radiation. We studied whether radiation therapy combined with Ku80 silencing by small interfering RNA enhances radiation sensitivity in vitro and in vivo. Seven human cancer cell lines were transfected with Ku80 siRNA included in hemagglutinating virus of Japan envelope vector. H1299 cells were implanted into male BALB/C nu/nu nude mice treated with Ku80 siRNA and irradiation. The survival rate of cell lines transfected with Ku80 siRNA decreased by 10% to 26% with 2-Gy irradiation compared with untransfected cell lines. The gamma-H2AX phosphorylation-positive rates of Ku80 siRNA combined treatment 0.5 h after irradiation in A549 cells and 6 h in H1299 cells were significantly higher (77.6%, p=0.033 and 76.7%, p=0.026, respectively), compared with the groups not treated with siRNA. H1299 xenograft tumors treated with combined therapy decreased in volume and re-grew slowly compared with radiation alone. Our results indicate that combined therapy consisting of Ku80 siRNA and irradiation contributes to inhibition of tumor growth and may be a novel strategy for cancer treatment.

To identify genes associated with radioresistant oral squamous cell carcinoma (OSCC), we compared gene expression signatures between OSCC cell lines exhibiting radioresistance and cells with radiosensitivity after X-ray irradiation in a dose-dependent manner using Affymetrix GeneChip analysis with Human Genome-U133 plus 2.0 GeneChip. The microarray data identified 167 genes that were significantly overexpressed in radioresistant cells after X-ray irradiation. Among the genes identified, 40 were mapped to 3 highly significant genetic networks identified by the Ingenuity Pathway Analysis tool. Gene ontology analysis showed that cancer-related function had the highest significance. The 40 genes included 25 cancer-related genes that formed I network and were categorized by function into growth and proliferation, apoptosis, and adhesion. Furthermore, real-time quantitative reverse transcriptase-polymerase chain reaction showed that the mRNA expression levels of the 25 genes were higher in radioresistant cells than in radiosensitive cells in a dose-dependent manner and in a time-dependent manner. Our results suggest that the identified genes help to elucidate the molecular mechanisms of the radioresistance of OSCC and could be radiotherapeutic molecular markers for choosing the appropriate radiotherapy for this disease. (c) 2007 Wiley-Liss, Inc.

1990年1月から10年間に千葉大学医学部付属病院歯科口腔外科において経験した慢性下顎骨骨髄炎は14症例であった。内訳は男性10例、女性4例で、年齢は50歳以上が9例と多数を占めていた。主訴は腫脹と疼痛が多く、他覚的にはX線所見で骨溶解像、皮質骨の肥厚といった所見がみられた。原因は歯性感染症と考えられ、1例を除いて大臼歯が原因歯であった。病名は根尖性歯周炎、辺縁性歯周炎、智歯周囲炎が多く、起炎菌は6例がStreptococcus sp.、5例がNeisseria sp.であった。全症例に抗菌薬投与を行い、9例には外科処置、6例には高圧酸素療法を併用した。遷延化した症例は3例で、そのうち2例は11歳と14歳であった。若年者で慢性化してしまった下顎骨骨髄炎は難治性となり易いと考えられた。

The oncogenic transcription factor PAX5 is an important developmental regulator and is implicated in the pathogenesis of several malignancies. The PAX5 gene is involved in medulloblastoma, non-Hodgkin's lymphoma, transitional cell carcinoma of the bladder, neuroblastoma, breast cancer and SCC. In the current study, to determine the potential involvement of PAX5 in oral squamous-cell carcinoma (OSCC) and leukoplakias, we evaluated the status of PAX5 mRNA and protein expression in OSCC cell lines, human primary OSCCs, and leukoplakias by real-time quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry. A significant increase in PAX5 expression was observed in all OSCC-derived cell lines examined compared to human normal oral keratinocytes (HNOKs). In immunohistochemistry, 78% of tumors and 42% of leukoplakias examined were positive for PAX5, while no immunoreaction was observed in corresponding normal tissues. The results suggest that PAX5 plays an important role during oral carcinogenesis, especially in the early stage, and that the gene may have potential as a biomarker and therapeutic target for OSCC.