Kengo Kato

Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin β4

We previously found an inverse relationship between sialidase Neu1 expression and metastatic potential of murine cancer cells. To elucidate the mechanism underlying the cellular events, the human sialidase gene NEU1 was overexpressed or silenced in colon cancer HT-29 cells. When NEU1-overexpressing cells were injected transsplenically into mice, in vivo liver metastasis was significantly reduced. NEU1 suppressed cell migration, invasion and adhesion in vitro, whereas the silencing resulted in the opposite. One of the major molecular changes by NEU1 was decreased sialylation of integrin β4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin β4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway. Moreover, NEU1 caused downregulation of matrix metalloproteinase-7, overexpression of which is associated with cancer metastasis. Treatment of the cells with GalNAc-α-O-benzyl, an inhibitor of O-glycosylation, showed increased PNA-positive integrin β4 with its decreased phosphorylation, indicating that sialic acid removal from the integrin O-glycans results in the decreased phosphorylation. Biotinylation and immunofluorescence staining exhibited some NEU1 molecules to be at the cell surface accessible to the integrin. These results suggest that NEU1 is important in regulation of integrin β4-mediated signaling, leading to suppression of metastasis.

Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with integrin beta4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.

Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Multicenter Study in Japan

Background: The incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) have risen steadily in the USA and in northern Europe. These increases are thought to be a consequence of persistent infection with high-risk human papillomavirus (HPV) in OPSCC patients. HPV is an emerging etiologic factor in OPSCC. In Japan, the incidence of OPSCC has significantly increased over the last three decades. However, the population of HPV-positive OPSCC patients is currently unknown. We examined the nationwide trends with regard to HPV incidence in OPSCC patients at 21 specific sites, and examined the relationship between the presence of HPV and survival in OPSCC patients in Japan. Methods: Tumor samples were obtained from patients with OPSCC prior to treatment, and HPV infection was investigated by polymerase chain reaction (PCR). Hybrid Capture 2 (HC2) was also adopted for swab examination on the surface of fresh tumors. Results: HPV was detected by PCR in 79 (50.3%) out of 157 OPSCC patients. The clinical features of HPV-positive OPSCC were low differentiation, a tendency to involve the lateral wall, and high nodal staging. The sensitivity and specificity of HC2 were 93.7 and 96.2%, respectively, indicating its utility as a screening test. HPV-positive patients had significantly better overall survival and disease-free survival than HPV-negative patients.

Multicenter phase II study of an opioid-based pain control program for head and neck cancer patients receiving chemoradiotherapy

BACKGROUND The aim of this multi-center phase II study was to clarify the clinical benefit of an opioid-based pain control program for head and neck cancer patients during chemoradiotherapy. PATIENTS AND METHODS Head and neck cancer patients who were to receive definitive or postoperative chemoradiotherapy were enrolled. The opioid-based pain control program consisted of a three-step ladder, with basic regimens of: The primary endpoint of this study was compliance with radiotherapy. RESULTS A total of 101 patients from 10 institutions were registered between February 2008 and May 2009 and included in the analysis. The major combination chemotherapy regimen was cisplatin alone (76%). The rate of completion of radiotherapy was 99% and the rate of unplanned breaks in radiotherapy was 13% (13/101, 90% confidence interval: 9.9-16.5%). Median maximum quantity of morphine used per day was 35 mg (range 0-150 mg). CONCLUSIONS Use of a systematic pain control program may improve compliance with CRT.

Upregulation of sialidase NEU3 in head and neck squamous cell carcinoma associated with lymph node metastasis

Regional lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) is a crucial event for its progression, associated with a high rate of mortality. Sialidase, a key enzyme for the regulation of cellular sialic acids through catalyzing the initial step of degradation of glycoproteins and glycolipids, has been implicated in cancer progression. To facilitate the development of novel treatments for HNSCC, we have investigated whether sialidase is involved in the progression of this cancer. We found plasma membrane‐associated sialidase (NEU3) to be significantly upregulated in tumor compared to non‐tumor tissues; particularly, an increase in its mRNA levels was significantly associated with lymph node metastasis. To understand the mechanisms, we analyzed the NEU3‐mediated effects on the malignant phenotype using squamous carcinoma HSC‐2 and SAS cells. NEU3 promoted cell motility and invasion, accompanied by the increased expression of MMP‐9, whereas NEU3 silencing or the activity‐null mutant did not. NEU3 enhanced phosphorylation of epidermal growth factor receptor (EGFR), and an EGFR inhibitor, AG1478, abrogated the NEU3‐induced MMP9 augmentation. These findings identify NEU3 as a participant in HNSCC progression through the regulation of EGFR signaling and thus as a potential target for inhibiting EGFR‐mediated tumor progression.

Effect of local extension sites on survival in locally advanced maxillary sinus cancer.

We analyzed the effects of local extension sites on survival in patients with locally advanced maxillary sinus cancer.

Multi-institutional retrospective study for the evaluation of ocular function-preservation rates in maxillary sinus squamous cell carcinomas with orbital invasion

The purpose of this retrospective analysis was to evaluate ocular function and survival rates among treatment modalities in patients with maxillary sinus cancer with orbital invasion.

Clear cell carcinoma of the nasal cavity: A case report from histopathological viewpoint

We report an extremely rare case of primary clear cell carcinoma (CCC), not otherwise specified (NOS) of the nasal cavity. An 80-year-old woman was referred to our hospital with left nasal obstruction caused by a nasal cavity tumor. The tumor was resected completely with lateral rhinotomy approach. Histopathological examination revealed CCC. CCC metastasis from renal cell carcinoma (RCC), which is at the top of differential diagnosis, was ruled out by the absence of renal tumor at computed tomography (CT). Also, immunohistochemical results of the specimen with vimentin negative and CK7 focally positive excluded the possibility of RCC metastasis. The patient is free from recurrence 1 year after the surgery, and there is no evidence of RCC. In this report histopathological characteristics, especially immunohistochemical properties of primary CCC, NOS of the nasal cavity are presented together with some clinical features of this rare tumor. Also, we refer to histopathogenesis of primary CCC of nasal cavity in relation to myoepithelial carcinoma. Histopathological discussion is further extended to include other CCC and CCC-resembling histologies to confirm the uniqueness of the present case.

Simple laryngeal suspension procedure by suturing the digastric muscle to the periosteum of the mandible in neck dissection for tongue cancer

PURPOSE In this article, a simple, new laryngeal suspension procedure is described. The effect of hyoid bone suspension by suturing the digastric muscle to the periosteum of the mandible is analyzed. MATERIALS AND METHODS To elucidate the effect of hyoid bone suspension, CT scans of 26 patients who underwent ipsilateral neck dissection with primary resection of tongue cancer were retrospectively reviewed, and the distance between the hyoid bone and the mandible was measured on the operated and unoperated sides of the neck. A total of 14 patients who underwent suturing of the digastric muscle to the mandible (digastric muscle-sutured group) and the 12 patients who did not (control group) were compared. RESULTS In the digastric muscle-sutured group, the average distance between the hyoid bone and the mandible was significantly smaller on the operated side (17.8 ± 0.57 mm) than on the unoperated side (19.8 ± 0.93 mm; p < 0.05). In the control group, there was no significant difference between the operated side (21.0 ± 1.42 mm) and the unoperated side (19.7 ± 1.39 mm). The difference in the distance between the operated and unoperated sides was significantly larger in the digastric muscle-sutured group (1.97 ± 0.79 mm) than in the control group (-1.32 ± 0.61; p < 0.05). CONCLUSIONS It was shown for the first time that suturing of the digastric muscle to the periosteum of the mandible in neck dissection with primary resection of tongue cancer resulted in hyoid bone suspension. This simple procedure can be useful for laryngeal suspension.

Five-year history of dysphagia as a sole initial symptom in inclusion body myositis

• sIBM patient manifested dysphagia as an isolated symptom for five years prior to the limb weakness.