Pancreatic adenocarcinoma up-regulated factor has oncogenic functions in oral squamous cell carcinoma.

AIMS: Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel secretory protein which promotes tumour progression, metastasis and poor prognosis in pancreatic, cervical and colorectal carcinoma. It is also associated with gemcitabine resistance in pancreatic cancer cells. However, the expression and function of PAUF in oral squamous cell carcinoma (OSCC) remain unknown. METHODS AND RESULTS: We performed an immunohistochemical analysis of PAUF in 222 clinicopathologically characterized cases of OSCC. We also investigated the growth, invasion, apoptosis induction and cisplatin resistance of OSCC cells under PAUF knockdown treatment. PAUF was localized in normal salivary glands. In OSCC, immunostaining for PAUF was found in 52 of 222 patients (23.4%), and correlated with nodal metastasis (P < 0.0001) and poor prognosis (P < 0.0001). Multivariate analysis using the Cox proportional hazards model identified that PAUF expression was an independent predictor of disease-free survival in OSCC (P < 0.0001). The down-regulation of PAUF in OSCC cells suppressed cell growth and invasion and induced apoptosis and cisplatin sensitivity. CONCLUSIONS: Our results suggest that PAUF has tumour-promoting functions in OSCC. It may thus be a useful diagnostic and therapeutic marker for OSCC.

LEM domain containing 1 promotes oral squamous cell carcinoma invasion and endothelial transmigration.

BACKGROUND: Oral squamous cell carcinomas have high potential for locoregional invasion and nodal metastasis. Thus, early detection and elucidation of detailed molecular mechanisms of OSCCs are important. Roles of LEM domain containing 1 (LEMD1), a novel cancer-testis antigen, in OSCCs are unclear. METHODS: We performed immunohistochemical analysis of LEMD1 in 289 OSCC patients and examined functions of LEMD1 in these carcinomas. RESULTS: Immunohistochemical analysis showed that 101 patients were positive for LEMD1. LEM domain containing 1 expression levels in OSCCs significantly correlated with tumour progression (T factor and clinical stage), nodal metastasis, and poor prognosis. LEM domain containing 1 expression was an independent predictor of disease-free survival in OSCC patients. In OSCCs, LEMD1 knockdown suppressed cancer cell invasion. Moreover, downregulation of LEMD1 expression inhibited adhesion and transmigration of OSCCs and vascular or lymphatic vascular endothelial cells. CONCLUSIONS: Our findings suggest that LEMD1 is a novel tumour progressive factor and may be a useful diagnostic and therapeutic target in OSCCs.

[18F]fluoro-2-deoxyglucose-positron emission tomography for the assessment of histopathological response after preoperative chemoradiotherapy in advanced oral squamous cell carcinoma.

BACKGROUND: [(18)F]fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) is widely used to evaluate tumor metabolic activity. The aim of this study was to evaluate the usefulness of FDG-PET in assessing the histopathological response to preoperative concurrent chemoradiotherapy (CRT) in patients with oral squamous cell carcinoma (OSCC). METHODS: Forty-five patients with resectable advanced OSCC who had received preoperative CRT followed by tumor ablative surgery between January 2004 and December 2011 were included in the study. All patients underwent FDG-PET before and after preoperative CRT. The maximum standardized uptake value (SUVmax) before (pre-SUV) and after preoperative CRT (post-SUV) and the SUVmax reduction rate (ΔSUV %) were used to evaluate the response to preoperative CRT. Correlations among SUVmax, histopathological response, and expression of cancer antigen Ki-67 and hypoxia-inducible factor-1α (HIF-1α) were analyzed. RESULTS: Preoperative CRT significantly reduced intratumoral FDG uptake (P < 0.001). The pre-SUV and post-SUV were significantly lower in patients with a pathological complete response (pCR) than in those with a non-pCR (pre-SUV P = 0.037; post-SUV P = 0.001). ΔSUV % was higher in patients with pCR than in those with non-pCR (P = 0.029). The pre-SUV was significantly correlated with Ki-67 and HIF-1α expression in pretreatment biopsy specimens (Ki-67 P = 0.046, R = 0.292; HIF-1α P = 0.007, R = 0.385). The expression of both Ki-67 and HIF-1α was significantly lower in patients with pCR than in those with non-pCR (Ki-67 P < 0.001; HIF-1α P < 0.001). CONCLUSIONS: Low pre-SUV and post-SUV and high ΔSUV % may predict a good histopathological response to preoperative CRT. Ki-67 and HIF-1α expression in pretreatment biopsy specimens were predictors of histopathological response to preoperative CRT.

HuD promotes progression of oral squamous cell carcinoma.

Head and neck cancer, including oral squamous cell carcinoma (OSCC), ranks as the sixth most common malignancy worldwide. Overall 5-year survival rates of OSCC have not significantly improved during the past 3 decades and the 5-year survival rate is less than 50%. Several invasion grading systems have been employed in OSCC, however, their utility is still controversial. HuD belongs to the Hu protein family and acts as an RNA-binding protein involved in mRNA stability and translational regulation. Although HuD has a pivotal role for neuronal differentiation, the functional role of HuD in OSCCs is still unclear. In this study, we examined HuD expression in 82 OSCC cases. Expression of HuD was observed in 36.6% of OSCCs and significantly associated with histological differentiation, nodal metastasis and mode of invasion. HuD expression in high-metastatic HSC3 cells was higher than in low-metastatic HSC4 cells, and inhibition of invasion ability and activation of caspase-3 were shown by HuD siRNA-treated HSC3 cells. Furthermore, we clarified that HuD regulates expression of vascular endothelial growth factor (VEGF)-A, VEGF-D, matrix metallopeptidase (MMP)-2 and MMP-9. These results suggest that HuD is a useful diagnostic and therapeutic target in OSCCs.

Possible peripheral mechanism for taste disorder in rats administered S-1.

BACKGROUND: Taste disorders are frequently observed in cancer patients undergoing chemotherapy and are serious adverse events which impair the quality of life (QoL) of the cancer patient. Nevertheless, taste disorder mechanisms in cancer patients undergoing chemotherapy have not yet been fully elucidated. The aim of this study was to reveal taste disorder-related peripheral mechanisms using the two-bottle preference test (TBPT) and histological examination of tongues by hematoxylin-eosin staining and immunohistochemistry with protein-gene product 9.5. METHODS: In the TBPT, one bottle was filled with the 0.01 mM quinine hydrochloride (quinine), as a bitter compound, and the other was filled with water. Doses of 50 and 100 mg kg(-1) day(-1) S-1 (tegafur/gimeracil/oteracil potassium) are lethal to Wistar rats. Therefore, doses ranging from 2-20 mg kg(-1) day(-1) were administered to the rats for 3 weeks. The S-1 dose of 2 mg kg(-1) day(-1) corresponds to the clinical dose administered to cancer patients. The part of the tongue containing the circumvallate papillae was excised the following TBPT. RESULTS: The rate of increase in terms of the average preference rate for the quinine vs. all intake (quinine plus water) was significant from the initial S-1 period to the final one, compared with that in control rats, suggesting the possibility of a worsening sensation for the bitter taste. In S-1 rats, the area of taste nerve fibers were significantly decreased and the rate of degeneration of intra-tongue ganglionic nerve cells was significantly increased. These changes were significantly correlated with the rate of increase in average preference rate of the quinine. CONCLUSION: Neuropathy of the gustatory nerve at the periphery may be involved in taste disorders induced by an anticancer drug.

Downregulation of runt-related transcription factor 3 associated with poor prognosis of adenoid cystic and mucoepidermoid carcinomas of the salivary gland.

Runt-related transcription factor 3 (RUNX3) is a transcription factor of the transforming growth factor (TGF)-ß superfamily and acts as a tumor suppressor gene, which is silenced by hypermethylation of the promoter region in various cancers. In this study, we examined the expression and methylation status of RUNX3 in the salivary gland cancers pleomorphic adenoma (PA), adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC). The cytoplasmic expression rates of RUNX3 in PA, ACC and MEC were 65% (13/20), 22.2% (8/36) and 20.6% (7/34), respectively. Low expression or deletion of RUNX3 in ACC and MEC was significantly associated with tumor progression and poor prognosis. Using microdissected cDNA, we found that RUNX3 mRNA expression was lower in ACC and MEC than in PA and noncancerous salivary glands; furthermore, hypermethylation of RUNX3 was detected more frequently in PA (2/8, 25%), ACC (6/8, 75%) and MEC (7/8, 87.5%) than in noncancerous salivary glands (0/8, 0%). Our results suggest that low expression or deletion of RUNX3 in salivary gland tumors might play a pivotal role in tumorigenesis and tumor progression and poor prognosis in the case of salivary gland ACC and MEC. Recovery of the tumor suppressive function of RUNX3 might inhibit tumorigenesis and cancer progression in the human salivary gland.

Maxillofacial fractures resulting from falls.

PURPOSE: The purpose of this study was to analyze maxillofacial fractures resulting from falls in terms of the demographics, the circumstance of injury, the site and severity of fracture, and the treatment. PATIENTS AND METHODS: Data of 457 patients treated for fall-related maxillofacial fractures at the Department of Oral and Maxillofacial Surgery, Nara Medical University, Nara, Japan, from 1981 to 2007 were retrospectively analyzed. RESULTS: Patients were 163 males and 116 females with an average age of 51.3 years who had fallen on a level surface (simple fall), and 110 males and 68 females with an average age of 31.9 years in falls from a greater height (fall from height), respectively. Fractures of the mandible were more frequently observed than those of the midface. In the mandible, fracture lines were exclusively observed at the condyle, especially in simple falls. In the midface, the zygoma was most frequently involved. Facial Injury Severity Scale ranged from 1 to 6, with an average of 1.78 in simple falls, and from 1 to 9, with an average of 2.04 in falls from height, respectively. These were dependent on the causes and height of the fall. Fractures at the other sites of the body were found in 14 patients (5.0%) with simple falls and 38 (21.3%) with falls from height. Maxillomandibular fixation was most frequently chosen for mandibular fractures and observation for midface fractures. Open reduction and fixation was more frequently chosen in patients with falls from height than those with simple falls and in patients with a higher Facial Injury Severity Scale score. CONCLUSIONS: Maxillofacial fractures resulting from falls showed characteristic features in the demographics, the circumstance of injury, and the site and severity of fracture. Treatment was chosen according to these features.

Fate of developing tooth buds located in relation to mandibular fractures in three infancy cases.

The fate of developing tooth buds located in relation to mandibular fractures was investigated in three infancy cases. Three infants, 2 girls and a boy, aged from 1 year and 5-months old to 2 years and 6-months old, were treated for dislocated mandibular fracture in the symphyseal region by manual reduction and fixation with a thermoforming splint and circumferential wiring under general anesthesia. Fracture healing was uneventful in all cases. A few years later, no obvious deformity of the jaw or malocclusion was observed; however, malformation of the crown was found in one of the permanent teeth on the fracture line in the first case. In the second case, no abnormality was observed in one of the permanent teeth on the fracture line, but the effect on the other tooth could not be evaluated due to abnormality of the tooth probably not related to the injury. In the third case, root formation was arrested in one of the permanent teeth on the fracture line and the tooth was lost early after eruption. The development of tooth buds on the fracture line is not predictable and therefore, should be monitored by regular follow up.

Downregulation of DHRS9 is associated with poor prognosis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) has a high potential for local invasion and nodal metastasis. Therefore, early detection and elucidation of the detailed molecular mechanisms underlying OSCC are essential. Dehydrogenase/reductase member 9 (DHRS9) is downregulated in recurrent OSCC. Although DHRS9 is reported to act as a tumour suppressor in several malignancies, its expression in OSCC cells is unknown. In this study, we examined DHRS9 expression immunohistochemically in specimens from a sample of 98 OSCC patients. Reduced DHRS9 expression was observed in 68 of 98 patients (69.4%) with OSCC. A significant association was found between low DHRS9 expression and local progression (T factor) (p = 0.0135). Furthermore, patients with low DHRS9 expression had a significantly poorer prognosis than those with high DHRS9 expression (p = 0.0443). In multivariate analysis using the Cox proportional hazards model, decreased DHRS9 expression strongly correlated with worse prognosis. The study findings suggest that DHRS9 might be a useful diagnostic and prognostic marker for OSCC.

A Foreign Body Granuloma of the Buccal Mucosa Induced by Honeybee Sting.

A foreign body granuloma of the buccal mucosa induced by honeybee sting was reported. The patient was an 82-year-old female who presented with a submucous mass at the right buccal mucosa. The mass was 20 mm in diameter, elastically firm, partly mobile without pain or tenderness, and covered with almost normal mucosa. MR image did not delineate the lesion clearly. Under clinical diagnosis of a benign tumor, the lesion was excised under local anesthesia. The excised lesion was 14 × 11 × 9 mm in size and solid and yellowish in cut surface. Histologically, the lesion consisted of granulomatous tissue with a few narrow, curved, eosinophilic structures compatible with decomposed fragments of a honeybee sting and was diagnosed as a foreign body granuloma, although the patient did not recall being stung.

Risks of postextraction bleeding after receiving direct oral anticoagulants or warfarin: a retrospective cohort study.

OBJECTIVE: The effect of direct oral anticoagulants (DOACs) on the risk of bleeding after tooth extraction remains unclear. This study aimed to evaluate the incidence of postextraction bleeding among patients who received DOAC and vitamin K antagonists (VKAs), such as warfarin. DESIGN: This study was a retrospective cohort analysis. Incidence rates and propensity score-matched regression models were used to compare the risks of bleeding after tooth extractions involving DOACs and VKAs. SETTING: The study took place in a single university hospital in Japan. PARTICIPANTS: Between April 2013 and April 2015, 543 patients underwent a total of 1196 simple tooth extractions. PRIMARY OUTCOME MEASURE: The primary outcome measure was the occurrence of postextraction bleeding, which was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 min and 7 days after the extraction. RESULTS: A total of 1196 tooth extractions (634 procedures) in 541 patients fulfilled the study criteria, with 72 extractions (41 procedures) involving DOACs, 100 extractions (50 procedures) involving VKAs and 1024 extractions (543 procedures) involving no anticoagulants. The incidences of postextraction bleeding per tooth for the DOAC, VKA and no anticoagulant extractions were 10.4%, 12.0% and 0.9%, respectively. The incidences of postextraction bleeding per procedure for DOACs, VKAs and no anticoagulants were 9.7%, 10.0% and 1.1%, respectively. In comparison to the VKA extractions, the DOAC extractions did not significantly increase the risk of postextraction bleeding (OR 0.69, 95% CIs 0.24 to 1.97; p=0.49). CONCLUSIONS: The risk of postextraction bleeding was similar for DOAC and VKA extractions.

Programmed death ligand 1 (PD-L1) expression and tumor microenvironment: Implications for patients with oral precancerous lesions.

OBJECTIVES: Cancer immunoediting represents a relatively novel concept attempting to explain the process of tumor escape from the host immune system response. Here, we attempted to elucidate the role of programmed death ligand 1 (PD-L1), the tumor microenvironment, and tumor escape mechanisms that allow malignant transformation of oral precancerous lesions. MATERIALS AND METHODS: Patients with oral precancerous lesions managed at the Nara Medical University Hospital, Japan, (n=120) were enrolled in this study. Epithelial dysplasias were graded by experienced pathologists, and subepithelial PD-L1-, CD163-, and CD8-positive cells were counted in the superficial lamina propria of oral mucosa. Epithelial PD-L1 expression was evaluated according to the staining intensity. The association of clinicopathological factors with epithelial dysplasia, malignant-free survival time, and significance of risk factors for malignant transformation were determined. RESULTS: Multivariate analysis showed that the subepithelial CD163-positive cell count was the only significant risk factor for high-grade epithelial dysplasia (P<0.001), while subepithelial CD163- and PD-L1-positive cell counts, and epithelial PD-L1 positivity were significantly associated with malignant-free survival (P=0.004, 0.04, and <0.001, respectively). Subepithelial PD-L1-positive cell count and epithelial PD-L1 positivity were significantly associated with malignant transformation (P=0.01 and 0.04, respectively). CONCLUSION: Our results indicate that PD-L1-expressing dysplastic epithelial and recruited subepithelial cells in oral precancerous legions may evade the host immune system, and that the inhibition of PD-1/PD-L1 pathway may potentially prevent malignant transformation of oral precancerous legions as well as can treat advanced cancers.

NEDD 4 binding protein 2-like 1 promotes cancer cell invasion in oral squamous cell carcinoma.

Head and neck cancer, including oral squamous cell carcinoma, is the sixth most common cancer worldwide. Although cancer cell invasion and metastasis are crucial for tumor progression, detailed molecular mechanisms underlying the invasion and metastasis of oral squamous cell carcinoma are unclear. Comparison of transcriptional profiles using a cDNA microarray demonstrated that N4BP2L1, a novel oncogene expressed by neural precursor cells, is involved in oral squamous cell carcinoma. Expression of N4BP2L1 in oral squamous cell carcinoma is regulated by activation of miR-448 and is higher than in normal oral mucosa. Knockdown of N4BP2L1 and upregulation of miR-448 significantly reduced the invasive potential of oral squamous cell carcinoma cells. We studied N4BP2L1 expression in 187 cases of oral squamous cell carcinoma and found its overexpression to be significantly associated with nodal metastasis (P = 0.0155) and poor prognosis (P = 0.0136). Expression of miR-448 was found to be inversely associated with that of N4BP2L1 (P = 0.0019). Cox proportional hazards analysis identified N4BP2L1 expression as an independent predictor of disease-free survival (P = 0.0349). Our results suggest that N4BP2L1 plays an important role in tumor cell invasion in oral squamous cell carcinoma. Further studies on expression of N4BP2L1 may provide new insight into its function and clarify its potential as biomarker in human oral cancer.

Storkhead box 2 and melanoma inhibitory activity promote oral squamous cell carcinoma progression.

BACKGROUND: Storkhead box protein 2 (STOX2) is a transcriptional factor associated with pre-eclampsia with fetal growth restriction. We recently reported that melanoma inhibitory activity (MIA) promotes oral squamous cell carcinoma (OSCC) progression. However, the relationship between STOX2 and MIA remains unknown in malignancies. METHODS: We used immunohistochemistry and PCR to investigate MIA and STOX2 expression in OSCC. We also performed functional analysis in human OSCC cells. RESULTS: MIA and STOX2 mRNA levels were higher in OSCCs than in normal oral epithelial cells, and upregulation of STOX2 was significantly correlated with overexpression of MIA. Immunostaining for STOX2 was associated with nodal metastasis (P = 0.0002) and MIA expression (P < 0.0001). Furthermore, MIA expression (P = 0.0035) and STOX2 expression (P = 0.0061) were associated with poor outcome in OSCCs. In vitro analysis using OSCC cells revealed that MIA increased expression of STOX2 by paracrine manner. Moreover, STOX2 accelerated OSCC cell growth, invasion, suppressed apoptosis, and enhanced resistance to paclitaxel, cisplatin, and 5-FU. CONCLUSIONS: Our results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in OSCCs.

A comprehensive expression analysis of the MIA gene family in malignancies: MIA gene family members are novel, useful markers of esophageal, lung, and cervical squamous cell carcinoma.

Melanoma inhibitory activity (MIA) gene family members include MIA, MIA2, and Transport and Golgi organization protein 1 (TANGO). Although MIA gene family members have several tumor-related functions, their detailed roles in malignancies remain poorly elucidated. In this study, 477 tumor specimens were subjected to immunohistochemical screening to evaluate MIA gene family expression. For a validation analysis, we also examined the association between MIA gene family expression and clinicopathological factors in 66 cases of esophageal cancer, 145 cases of lung cancer, and 126 cases of cervical cancer. The frequency of MIA gene family expression was higher among squamous cell carcinomas than among other tumor types subjected to screening. In the validation analysis, MIA gene family staining was observed frequently in esophageal and lung cancers associated with nodal and/or distant metastasis. In cervical cancers, MIA and TANGO immunostaining also correlated with tumor progression and metastasis. Furthermore, MIA2 expression levels in invasive cervical cancer were upregulated relative to those in cervical intraepithelial neoplasia 3. A disease-free survival analysis revealed that MIA-, MIA2, or TANGO-positive patients had a significantly shorter disease-free survival than did those patients who were negative. Our results suggest that MIA, MIA2, and TANGO may be useful diagnostic and therapeutic molecular targets in human malignancies.

Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells.

Epithelial-mesenchymal transition (EMT) is a key process involved in the invasion and metastasis of cancer cells. Furthermore, EMT can induce a cancer stem cell (CSC)-like phenotype in a number of tumor types. We demonstrated that Snail is one of the master regulators that promotes EMT and mediates cancer cell migration and invasion in many types of malignancies including head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated the role of Snail in inducing and maintaining CSC-like properties through EMT in HNSCC. We established HNSCC cell lines transfected with Snail. Stem cell markers were evaluated with real-time RT-PCR and western blot analysis. CSC properties were assessed using sphere formation and WST-8 assays as well as chemosensitivity and chick chorioallantoic membrane in vivo invasion assays. Introduction of Snail induced EMT properties in HNSCC cells. Moreover, Snail-induced EMT maintained the CSC-like phenotype, and enhanced sphere formation capability, chemoresistance and invasive ability. These data suggest that Snail could be one of the critical molecular targets for the development of therapeutic strategies for HNSCC.

Prox1 and FOXC2 act as regulators of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma.

Prospero homeobox 1 (Prox1) and forkhead box (FOX) C2 regulate angiogenesis and/or lymphangiogenesis. However, the detailed role and function of Prox1 and FOXC2 in cancer remains controversial. In the present study, we examined the expression of Prox1 and FOXC2 proteins in specimens from 163 cases with oral squamous cell carcinoma (OSCC). Furthermore, the role of Prox1 and FOXC2 in cancer cell growth and invasion was evaluated in cultured OSCC cells. Prox1 expression was significantly associated with local progression of the tumor (P = 0.0023), clinical stage (P<0.0001), lymphovessel density (LVD) (P<0.0001), nodal metastasis (P<0.0001), and worse prognosis (P<0.0001). Immunoreactivity of FOXC2 was strongly correlated with microvessel density (MVD) (P<0.0001) and poor prognosis (P = 0.0076). In vitro analysis demonstrated that Prox1 regulates cell growth, proliferation, invasion, and lymphangiogenesis by activating vascular endothelial growth factor (VEGF)-C expression. Furthermore, FOXC2 enhanced the expression level of Prox1 and promoted angiogenesis by enhancement of VEGF-A expression. Our results suggested that Prox1 and FOXC2 play key roles in OSCC progression and that further studies focusing on these proteins may yield useful insights for diagnosis and therapy of OSCC.

Transport and Golgi organisation protein 1 is a novel tumour progressive factor in oral squamous cell carcinoma.

Transport and Golgi organisation protein 1 (TANGO), also known as MIA3, belongs to the melanoma inhibitory activity (MIA) gene family. Although MIA acts as an oncogene, MIA2 and TANGO have a tumour-suppressive function in several malignancies; accordingly, the role and function of the MIA gene family in tumours remain controversial. Here the roles of TANGO were investigated in oral squamous cell carcinoma (OSCC). We analysed expression and function of TANGO in human OSCC cell lines. TANGO expression was also examined in 171 cases of primary OSCC by immunohistochemistry and statistically assessed the correlation between TANGO positivity and the clinicopathological parameters including vessel density. By TANGO knockdown in OSCC cells, the growth and invasion were repressed and apoptosis was induced. Activities of platelet-derived growth factor beta polypeptide (PDGFB) and Neuropilin2 were inhibited by TANGO knockdown. TANGO immunoreactivity was detected in 35.1% (60/171) cases of OSCC. TANGO expression was strongly associated with tumour progression, nodal metastasis, clinical stage and number of blood or lymph vessels in OSCC. Patients showing TANGO-expression fared significantly worse disease-free survival than cases without TANGO expression. These findings suggest that TANGO might promote angiogenesis and lymphangiogenesis by upregulation of PDGFB and Neuropilin2 in OSCC.

A keratocyst in the buccal mucosa with the features of keratocystic odontogenic tumor.

A 74-year-old male patient consulted us for an elastic firm mass in the right buccal mucosa. CT examination revealed a well-circumscribed oval cystic lesion in the anterior region of the masseter muscle. On MRI, the lesion showed a low signal on T1-weighted image and a high signal on T2-weighted image. Aspiration biopsy demonstrated the presence of squamous cells in whitish liquid. Under the diagnosis of epidermoid cyst, the lesion was intraorally extirpated under general anesthesia. The lesion was cystic at the size of 30 × 25mm. Histologically, the cyst wall was lined with parakeratinized squamous epithelium corrugated on its surface, the basal layer of which consisted of cuboidal cells showing palisading of the nuclei. Immunohistochemically, the lining epithelium was positive for CK17 and negative for CK10. The basal and suprabasal cells were labeled for Ki-67 at a relatively high rate. These features are compatible with those of keratocystic odontogenic tumor.

Trks are novel oncogenes involved in the induction of neovascularization, tumor progression, and nodal metastasis in oral squamous cell carcinoma.

The function of tropomyosin receptor kinase (Trk) family including TrkA, TrkB, and TrkC in cancer remains unknown. The role of Trks in oral squamous cell carcinoma (OSCC) was examined. Knockdown of Trks provided inhibition of growth or invasion and decrease of apoptosis in OSCC cells, which expressed Trks at high levels. VEGF expression was associated with TrkA and TrkB expression; a decrease of VEGF-C and VEGF-D was observed in OSCC cells with TrkB knockdown. TrkC did not affect the expression of VEGF family. An immunohistochemical analysis of 102 OSCCs showed that TrkB expression was related to microvessel density (MVD), lymph vessel density (LVD), and poor prognosis. TrkC expression was correlated with clinical stage, lymph node metastasis, MVD, LVD, and poor prognosis. TrkA expression was associated with VEGF expression, whereas TrkB expression was associated with the expressions of VEGF, VEGF-C and VEGF-D. No significant association was found between the expression of TrkC and genes of the VEGF family. Expression of Trks was not associated with RUNX3 silencing by methylation in OSCC cells. Trks expression was inversely correlated with RUNX3 expression in the OSCC cases. These results suggested that Trks enhances progression of OSCC through angiogenesis and lymphangiogenesis.