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Background/aim: The expression of tumor-associated programmed death-ligand 1 (PD-L1) predicts clinical responses to PD-1-directed immunotherapy. The expression levels of PD-L2, another PD-1 ligand, and its relationship with responses to PD-1-targeting therapy in oral squamous cell carcinoma (OSCC) remain unclear. Furthermore, the clinicopathological characteristics and prognostic effects of the expression of PD-L1 and PD-L2 in OSCC have not yet been elucidated., Materials and Methods: The expression of PD-L1 and PD-L2 was immunohistochemically examined in 98 tongue carcinomas. Furthermore, the expression levels of PD-L1 and PD-L2 in OSCC cell lines and their relationships with those of MMP2 and MMP9 were assessed., Results: The expression levels of PD-L1 and PD-L2 correlated with those of MMP2 and MMP9. The expression of PD-L1 and/or PD-L2 was detected in OSCC cells, and their levels correlated with those of MMP9. The prognosis of patients with PD-L1- and PD-L2-positive tumors was significantly worse., Conclusion: PD-L1 and PD-L2 status is potentially a novel predictor of the prognosis of OSCC and provides a rationale for the development of novel immunotherapies., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Toxins such as polychlorinated biphenyls (PCBs) and dioxins dramatically affect patients even decades after exposure. Patients with Yusho, a condition caused by exposure to PCBs and dioxins, have diverse mental and physical complaints, even though it is almost 50 years since the Yusho incident. Oral pigmentation is one of the major symptoms in Yusho patients., Patients and Methods: A total of 183 participants in the Yusho health study were examined. Oral examinations, including recording the prevalence of oral pigmentation, were performed by two oral surgeons. Demographic and clinical characteristics, including blood concentration of PCB and 2,3,4,7,8-pentachlorodibezofuran (2,3,4,7,8-PeCDF), which are the major causes of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group., Results: The mean serum PCB and 2,3,4,7,8-PeCDF levels of the 183 Yusho patients were 1.59 ± 1.25 ppb and 29.0 ± 42.9 pg/g lipid, respectively. There was a significant correlation between the levels of PCB and 2,3,4,7,8-PeCDF (r = 0.64, p < 0.01). The rate of oral pigmentation in Yusho patients (25.7%) was significant higher than among potential victims of Yusho (13 of 183, 7.1%) (p < 0.05)., Conclusion: The prevalence of oral pigmentation was still significantly higher in Yusho patients, even 50 years after exposure, although blood PCB levels have decreased in that time., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background/aim: Postresective mandibular reconstruction is common in cases of oral and mandibular tumors. However, complications such as plate fracture and/or plate exposure can occur. The purpose of this study was to analyze complications and survival of reconstructive plates used to correct mandibular defects caused by oral cancer., Patients and Methods: Clinical and radiological data from 34 patients were analyzed. Only discontinuous mandibular defect cases were included in this study. All cases were classified using the Hashikawa's CAT and Eichner's classification methods. Then, we determined whether these classifications and clinical treatment methods were significantly related to complications., Results: Complications after mandibular reconstruction occurred in 10 of 34 patients, specifically, two plate fractures, one screw fracture, and seven plate exposures occurred. The plate fractures occurred 5 and 6 months after operation, and the screw fracture occurred 39 months after operation. Using the Hashikawa's CAT classification, the two cases of plate fracture were one of AT type and the other of T type, and the screw fracture was AT type. Using Eichner's classification, all three cases of plate and screw fractures were B2 type., Conclusion: We suggest that plate and screw fractures were caused by the type of mandibular defect and bite force., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Low pre-operative lymphocyte-to-monocyte ratio (LMR) is associated with worse outcomes in several malignancies. The aim of this study was to determine the prognostic value of LMR in tongue cancer., Materials and Methods: A total of 103 patients with pathologically-proven tongue cancer were retrospectively analyzed. The peripheral LMR and the ratio of CD8-positive to CD14-positive (CD8 + /CD14 + ) tumor-infiltrating cells were determined by immunohistochemical staining. Receiver operating characteristic curve analysis, log-rank test, and Cox proportional hazards regression models were used for statistical analysis., Results: There was a significant difference in overall survival (OS) between low LMR and high LMR, and low CD8 + /CD14 + tumor-infiltrating cells and high CD8 + /CD14 + tumor infiltrating cells. For the clinical analysis, multivariate analysis showed that clinical ocular inspection type and low LMR were independent predictors for poor OS. Concerning the immunohistochemical analysis, monocyte count was independent predictor of poor OS., Conclusion: Pre-operative LMR and CD8 + /CD14 + tumor-infiltrating cells serve as independent prognostic biomarkers., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2., Materials and Methods: We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC)., Results: mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa. mTORC1 expression was correlated with T classification, N classification, and survival rate (p<0.05), whereas mTORC2 expression was only correlated with T classification (p<0.05). Histologically, the expression levels of mTORC1 and mTORC2 correlated with cancer cell invasion and the expression of proliferating cell nuclear antigen (p<0.05), respectively. Expression levels of vascular endothelial growth factors and hypoxia-inducible factor 1 in the mTORC1 (-)/ mTORC2 (+) group were significantly lower than those in other groups., Conclusion: These findings suggested that mTORC1 and mTORC2 could be promising anti-tumor targets in OSCC, and mTORC1 (-)/mTORC2 (+) may have a correlation with the malignant potential of OSCC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The mammalian target of rapamycin (mTOR) has recently emerged as a promising target for therapeutic anti-cancer interventions in several human tumors. In present study, we investigated the expression of mTOR, and subsequently examined its relationship with clinicopathological factors and the anti-tumor effect of everolimus (also known as RAD001) in oral squamous cell carcinoma (OSCC). The expression of phosphorylated mTOR (p-mTOR) was immunohistochemically evaluated in specimens obtained from 70 OSCC patients who underwent radical surgery. The relationships between the expression of p-mTOR and clinicopathological factors and survival were determined. We also investigated the effect of everolimus on the OSCC cell lines, SAS, HSC-2, HSC-3, HSC-4, OSC-20, SCC25 and Ca9-22 by the MTT assay. We further evaluated whether mTOR contributed to cell functions by blocking its activity with everolimus, and confirmed the direct target by the Matrigel invasion assay, wound healing assay and Western blotting. p-mTOR was overexpressed in 37 tumors (52.8 %), and correlated with the T classification, N classification, and survival rate (P < 0.05). The treatment with everolimus significantly inhibited cell growth, and significantly reduced the expression of p-mTOR, downstream signaling proteins, and hypoxic related proteins as well as invasion and migration potentials (P < 0.05). The results of the present study suggest that everolimus may represent an attractive approach for the future treatment of OSCC.

Yusho patients had many symptoms, and mouth dryness was one of the important oral symptoms. Presently, some Yusho patients complain of mouth dryness. In the present study, we measured mouth dryness by using an oral moisture checking device and examined metabolites of saliva by using metabolome analysis. We found no difference between Yusho patients and controls in terms of mouth dryness. Concerning metabolomes of saliva, there were some metabolites in Yusho patients that were not in controls.

Although lipomas are common soft tissue tumors, few cases of lipoma or its variants have been reported in the oral cavity. We here described the clinical, histological, and immunohistochemical features of 24 cases of oral lipoma obtained from medical records at Nagasaki University Hospital between 1977 and 2010, and also retrospectively reviewed 603 cases of oral lipoma reported in the English literatures. The patients examined comprised 11 men and 13 women with a mean age of 59 years, ranging from 31 to 90 years. The main sites involved were the buccal mucosa (n = 9), followed by the tongue (n = 4), lip and retromolar area (n = 3), floor of the mouth (n = 2), and gingiva (n = 1). The mean tumor size was 2.0 cm, ranging from 0.2 to 5 cm. Histological analysis revealed 20 cases of lipoma, 2 cases of fibrolipoma, and one case each of intramuscular lipoma and spindle cell lipoma. Twenty-three cases were treated surgically while one case underwent biopsy and follow-up. Recurrence was not observed in any case. We reviewed the English literatures, and similar results were obtained. In immunohistochemical analysis, PCNA and ki-67 expression indices were higher in intramuscular lipoma cases than in its variants. Especially, it showed that a long time follow-up may be necessary in ki-67 positive cases.

Granular cell ameloblastoma is classified as a histological subtype of solid/multicystic ameloblastoma. Usual granular cell ameloblastoma is histologically characterized by granular changes of stellate-like cells located in the inner portion of the epithelial follicles. Here we report a case of another type of granular cell ameloblastoma, showing predominant anastomosing double-stranded trabeculae of granular cells. This type of granular cell ameloblastoma is extremely rare, and the World Health Organization classification does not contain the entity. We tentatively termed it 'anastomosing granular cell ameloblastoma' in this report. The present case suggests the importance of differential diagnosis because the histology of 'anastomosing granular cell ameloblastoma' resembles that of salivary gland oncocytoma rather than that of usual granular cell ameloblastoma. The trabeculae observed in our case continued to the peripheral cells of a small amount of epithelial sheets of plexiform ameloblastoma, and the tumor cells were positive for CK19, which is regarded as an immunohistochemical marker of odontogenic epithelium. Similar to usual granular cell ameloblastoma, the tumor cells had CD68-positive granules. For precise diagnosis of this condition, immunohistochemistry using CK19 and CD68, as well as detailed histological observation, are recommended., (© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

MicroRNA-21 (miR-21) is overexpressed in a wide variety of cancers and has been related to cellular proliferation, apoptosis, and invasion; however, the function of miR-21 is unknown in oral tongue squamous cell carcinoma (OTSCC). The purpose of this study was to examine miR-21 expression in OTSCC, correlate it with clinicopathological factors, and investigate its contribution to OTSCC cell invasion. MiR-21 expression in 79 primary OTSCCs was evaluated using locked nucleic acid in situ hybridization, and correlation was examined with the clinicopathological factors. To determine the miR-21 target, we searched for molecular genes involved in tumor invasion using the commonly cited prediction program miRanda. In an OTSCC cell line, SCC25 cells, we further evaluated whether miR-21 contributes to cell invasiveness by blocking its expression with a specific knockdown LNA probe and confirmed the direct target by Matrigel invasion assay and Western blotting. MiR-21 overexpression was detected in 60 of 79 cases (75.9 %) and correlated with the pattern of invasion (P = 0.016). We selected DKK2 as a Wnt/antagonist involved in tumor invasion. MiR-21 overexpression was significantly correlated with the DKK2-/β-catenin- immunohistochemical phenotype. Knockdown of miR-21 significantly decreased the invasion potential of SCC25 cells with up-regulated DKK2. It was found that miR-21 is overexpressed and associated with tumor invasion in OTSCC, and that miR-21 promotes OTSCC cell invasion via the Wnt/β-catenin pathway by targeting DKK2 in vitro. These results suggest that miR-21 may be a potential therapeutic target for OTSCC treatment.

Locoregional recurrence of oral tongue squamous cell carcinoma (OTSCC) has been considered a poor prognostic entity in terms of survival rate. The purpose of this study was to evaluate the incidence of locoregional recurrence and to identify significant risk factors for locoregional recurrence in early-stage OTSCC. We retrospectively reviewed the records of 58 patients who underwent radical surgery for T1-2N0 OTSCC. The local recurrence and regional recurrence rates were 10.3 % (6/58 patients) and 15.5 % (9/58 patients) in this study, respectively. The survival rate of patients with local recurrence was 66.7 %, which was significantly lower than that (96.2 %) of patients without local recurrence, whereas the survival rates of patients with or without regional recurrence were not significantly difference. Pattern of invasion (POI), neoadjuvant chemotherapy (NAC) and the status of the surgical margin were identified as factors influencing local recurrence. In particular, the status of the deep surgical margin was a high potential independent risk factor. The deep surgical margin was resected closely in many NAC-treated cases, suggesting that NAC may lead to local recurrence and a poor outcome. No efficacy of NAC was observed, suggesting that the standard treatment for early OTSCC is surgery alone.

Objectives: Toxins, such as PCBs, dramatically affect patients even decades after exposure. Although 40 years have passed since the accidental poisoning with polychlorinated biphenyl (PCB) in Western Japan in 1968, high concentrations of PCBs are still detected in the serum of the "Yusho" (oil disease) patients. In this study, an epidemiological examination was carried out to reveal the prevalence of the oral pigmentation and blood concentrations of PCBs and polychlorinated quaterphenyl (PCQ) in Yusho victims., Design: We performed a group examination of patients (Yusho victims) from 2004 to 2006, including 72 Yusho victims and 15 control subjects. The oral examination was performed by two oral and maxillofacial surgeons. The serum concentrations of PCB and PCQ were determined using gas chromatography; blood samples from Yusho victims were analyzed for PCB and PCQ by saponification in 1M NaOH ethanol solution, extraction with n-hexane column chromatography on silica gel, and then gas chromatography with electron capture detection., Results: The mean Yusho victim's serum PCB and PCQ concentrations were 3.3ppb and 0.9ppb, respectively. In controls, these were 0.7ppb and 0ppb, respectively. Oral pigmentation was observed in 24 out of 72 Yusho patients. In controls, oral pigmentation was observed in one out of 15 persons. Oral pigmentation was most frequently observed in the buccal mucosa, followed by gingival mucosa. The blood concentration of PCB in Yusho patients with oral pigmentations was significantly higher than that in Yusho patients without oral pigmentation., Conclusion: These results indicated that PCB-related compounds may be responsible for the higher prevalence of oral pigmentation in Yusho victims, even though a long time has passed since the Yusho poisoning accident., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In the present study, we clarified the TMJ symptoms of Yusho patients. An epidemiologic examination was carried out to identify TMJ arthrosis in patients with Yusho. The patients were collected during annual Yusho examinations in 2012. Nine of 187 patients had TMJ symptoms. The symptoms were pain, trismus, and a clicking sound of the TMJ. We diagnosed these patients with TMJ arthrosis. The rate of TMJ arthrosis in Yusho patients was 4.8%, being similar to the rate of TMJ arthrosis in general. The PCB concentration in the blood of these 9 patients was 2.76 ppb, and the average blood PCB concentration of all patients was 2.98 ppb. We identified no relationship between the blood PCB concentration and TMJ arthrosis.

The aim of this study was to examine the effectiveness of covering wounds to the tongue with a polyglycolic acid (PGA) sheet and fibrin glue. Eighteen mature male Japanese white rabbits had a unilateral glossectomy involving an area 10mm×10mm×2mm. After glossectomy the tongues were covered with PGA sheets 8mm×8mm in size and fibrin glue (mucosal defect covered with fibrin glue and polyglycolic acid sheet=MCFP) 1 week after the operation (n=3), after 2 weeks (n=3), and after 4 weeks (n=3). In control groups, after 1, 2, and 4 weeks (n=3 in each group), the partially resected tongues were closed with absorbable sutures (polyglactin 910). One week (experimental and control groups 1), 2 weeks (experimental and control groups 2) and 4 weeks (experimental and control groups 3) after operation the tongues were harvested and stained for microscopic examination. Histological examination showed that the covered wound surface had not epithelialised and the basal layer had yet to form in experimental group 1, but had formed in experimental group 2. However, in control group 1, epithelialisation of the sutured wound had begun. Immunohistochemical examination showed that, in experimental group 1, the non-uniform epithelial layer of the covered wound surface expressed cytokeratin AE1/AE3, and the epithelial and connective tissue layers stained strongly for FGF-2. Similar results were obtained in experimental group 2, whereas in experimental group 3, FGF-2 was expressed only in the connective tissue layer, and epithelialisation was complete. However, in control group 1, AE1/AE3 was expressed in the epithelial layer, and FGF was expressed in the connective tissue layer beneath the basal layer. In control groups 2 and 3, AE1/AE3 and FGF-2 were expressed in patterns similar to those in experimental groups 2 and 3. We suggest that this method is useful and the operation is simple. However, further testing of the method is needed and it should be widely used clinically before it is recommended., (Copyright © 2011 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Distant metastasis of malignant neoplasm to the oral soft tissue is extremely rare. We report a case of renal cell carcinoma (RCC) metastasizing to the tongue. A 47-year-old man visited our hospital with chief complaint of a lump on the middle third of the dorsum of his tongue and the lesion fell off from the tongue. Although histopathological diagnosis of the mass was granuloma teleangiectaticum, similar nodule reappeared in the same area 2 weeks later. The second lesion was composed of granuloma teleangiectaticum and aggregation of neoplastic clear cells in ductal arrangement. The clear cells were immunohistochemically positive for EMA and CD10. The abdominal CT scan revealed a 5.5 cm mass in the left kidney, suggesting RCC. Thus, the lingual lesion was consistent with metastatic RCC. There has been no recurrence for 2 years after the radical nephrectomy and local excision of the tongue.

The aim of this study was to clarify the relationship between vascular endothelial growth factor (VEGF) expression and clinicopathological factors in oral squamous cell carcinoma (OSCC). We also examined the correlation between the VEGF expression and the mammalian target of rapamycin (mTOR)-hypoxia inducible factor-1α (HIF-1α) pathway. Formalin-fixed paraffin-embedded tissues from 120 OSCC cases and 10 samples of normal mucosa were stained immunohistochemically for VEGF-A, VEGF-C, p-mTOR and HIF-1α proteins. VEGF-A and VEGF-C protein expression was detected in 76 out of 120 (63%) and 81 of 120 (67.5%) OSCCs, respectively, and their expression was significantly higher in primary OSCC than in normal oral mucosa. VEGF-A expression was significantly associated with the tumor stage and age. VEGF-C expression was significantly associated with the cancer cell invasion. The cases with combined p-mTOR+/HIF-1α(+)/VEGF-A(+) expression had a significantly higher tumor stage and invasion grade, and combined p-mTOR+/HIF-1α(+)/VEGF-C(+) expression was significantly associated with tumor stage, regional lymph node metastasis and invasion grade. In a survival analysis, no obvious correlation was observed with any of the immunohistochemical results. This study indicated that the mTOR-HIF-1α-VEGF pathway affects the progression of OSCC, and inhibition of this pathway may be useful for the treatment of OSCC.

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are 5-fluorouracil (5-FU) metabolizing enzymes and are involved in the sensitivity of carcinoma patients to 5-FU. Although 5-FU is often used for the treatment of oral carcinoma, there has not been any investigation into the expression of these enzymes in metastatic lymph nodes or of their roles in the effectiveness of 5-FU in treating lymph node-metastatic cancer. Oral squamous cell carcinoma (OSCC) often metastasizes to the lymph nodes, and these enzymes may be significant in the survival of patients with this disease. This study investigated the expression of TS and DPD in cervical lymph node metastases and its relationship with primary OSCC, as well as the interaction between these enzymes and Kangai 1(KAI1/CD82) which is a metastasis suppressor protein. Surgical specimens from 20 cases of OSCC with lymph node metastasis, 20 cases of OSCC without lymph node metastasis, and 10 cases of normal mucosa were examined by immunohistochemistry. The relationship between TS and DPD expression and clinicopathological data was analyzed. TS and DPD proteins were overexpressed in primary OSCC compared to that in normal mucosa. TS expression of the primary oral cancer cells in the group with lymph node metastasis was higher than that of those without. DPD expression did not significantly correlate with the occurrence of lymph node metastasis, nor was it different between primary oral cancer cells and cervical metastases. CD82 expression was significantly reduced in lymph node metastases. These findings indicate that TS and CD82 may be of great value in assessing lymph node metastasis of OSCC, and could be taken as new targets for therapy of metastatic OSCC.

Recent studies suggest that cancer stem cells may be responsible for tumorigenesis and contribute to some individuals' resistance to cancer therapy. Some studies demonstrate that side population (SP) cells isolated from diverse cancer cell lines harbor stem cell-like properties; however, there are few reports examining the role of SP cells in human oral cancer. To determine whether human oral cancer cell lines contain a SP cell fraction, we first isolated SP cells by fluorescence activated cell sorting, followed by culturing in serum-free medium (SFM) using the SCC25 tongue cancer cell line, so that SP cells were able to be propagated to maintain the CSC property. Differential expression profile of stem cell markers (ABCG2, Oct-4 and EpCAM) was examined by RT-PCR in either SP cells or non-SP cells. Growth inhibition by 5-FU was determined by the MTT assay. Clonogenic ability was evaluated by colony formation assay. SCC25 cells contained 0.23% SP cells. The fraction of SP cells was available to grow in SFM cultures. SP cells showed higher mRNA expression of stem cell markers (ABCG2, Oct-4 and EpCAM) as compared with non-SP cells. Moreover, SP cells demonstrated more drug resistance to 5-FU, as compared with non-SP cells. The clone formation efficiency of SP cells was significantly higher than non-SP cells at an equal cell number (P<0.01). We isolated cancer stem-like SP cells from an oral cancer cell line. SP cells possessed the characteristics of cancer stem cells, chemoresistance, and high proliferation ability. Further characterization of cancer stem-like SP cells may provide new insights for novel therapeutic targets., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of various carcinomas. This study was performed to assess the efficacy and safety profile of the combination of S-1 and cisplatin(S-1/CDDP)in patients with oral cancer as neo-adjuvant chemotherapy. We reviewed our experience of 12 patients diagnosed with oral carcinoma, who were treated with S-1/CDDP. S-1 was administered orally at a dose of 50mg twice a day for 21 consecutive days, followed by a 14-day rest period. CDDP(60mg/m2)in 500 mL physiological saline was administered by intravenous drip as a 120-min infusion on day 8, together with standard premedications and hydration. Seven partial responders were obtained. The median follow-up duration was 54. 8 months, and all patients were alive excluding one case. This regimen was well tolerated, with only one case of grade 3 thrombocytopenia, and no grade 4 patient. No treatment-related death was observed. Moreover, we evaluated immunohistochemical expressions of thymidylate synthase (TS), dihydropyrimidine dehydrogenase(DPD), and orotate phosphoribosyl transferase(OPRT)which are associated with chemosensitivity to 5-FU-based therapies. We investigated the relation between the immunohistochemical score and clinicopathological factors, however we could not clarify the relationship between the efficacy of chemotherapy and results of immunohistochemistry.

CT10 regulator of kinase (CRK) was originally identified as an oncogene product of v-CRK in a CT10 chicken retrovirus system. Overexpression of CRKII has been reported in several human cancers. CRKII regulates cell migration, morphogenesis, invasion, phagocytosis, and survival; however, the underlying mechanisms are not well understood. In the present study, we evaluated the possibility of CRKII as an appropriate molecular target for cancer gene therapy. The expression of CRKII in 71 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens was determined immunohistochemically, and the correlation of CRKII overexpression with clinicopathological factors was evaluated. Overexpression of CRKII was detected in 41 of 70 oral squamous cell carcinomas, the frequency being more significant than in normal oral mucosa. In addition, CRKII overexpression was more frequent in higher-grade cancers according to the T classification, N classification, and invasive pattern. Moreover, RNAi-mediated suppression of CRKII expression reduced the migration and invasion potential of an oral squamous cell carcinoma cell line, OSC20. Downregulation of CRKII expression also reduced the expression of Dock180, p130Cas, and Rac1, and the actin-associated scaffolding protein cortactin. These results indicate that the overexpression of CRKII is tightly associated with an aggressive phenotype of oral squamous cell carcinoma. Therefore, we propose that CRKII could be a potential molecular target of gene therapy by RNAi-targeting in oral squamous cell carcinoma., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Cortactin, an F-actin binding protein, stabilizes F-actin networks and promotes actin polymerization by activating the Arp2/3 complex. Overexpression of cortactin has been reported in several human cancers. Cortactin stimulates cell migration, invasion, and experimental metastasis. However, the underlying mechanism is not still understood. In the present study, we therefore evaluated the possibility that cortactin could be appropriate as a molecular target for cancer gene therapy. In 70 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens, cortactin expression was evaluated by immunological analyses, and the correlations of the overexpression of cortactin with clinicopathologic factors were evaluated. Overexpression of cortactin was detected in 32 of 70 oral squamous cell carcinomas; significantly more frequently than in normal oral mucosa. Cortactin overexpression was more frequent in higher grade cancers according to T classification, N classifications, and invasive pattern. Moreover, RNAi-mediated decrease in cortactin expression reduced invasion. Downregulation of cortactin expression increased the expression levels of E-cadherin, β-catenin, and EpCAM. The siRNA of cortactin also reduced PTHrP expression via EGF signaling. These results consistently indicate that the overexpression of cortactin is strongly associated with an aggressive phenotype of oral squamous cell carcinoma. In conclusion, we propose that cortactin could be a potential molecular target of gene therapy by RNAi targeting in oral squamous cell carcinoma.