• Journal of dental hygiene science
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• v.18 no.3
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• pp.188-193
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• 2018

The aim of the current study was to demonstrate the potential therapeutic efficacy of resveratrol in oral cancer patients. Lysophosphatidic acid (LPA) intensifies cancer cell invasion and metastasis, whereas resveratrol, a natural polyphenolic compound, possesses antitumor activity, suppressing cell proliferation and progression in various cancer cell lines (ovarian, gastric, oral, pancreatic, colon, and prostate cancer cells). In addition, resveratrol has been identified as an inhibitor of LPA-induced proteolytic enzyme expression and ovarian cancer invasion. Furthermore, resveratrol was shown to inhibit oral cancer cell invasion by downregulating hypoxia-inducible factor $1{\alpha}$ and vascular endothelial growth factor expression. Recently, we demonstrated that LPA is important for the expression of transcription factors TWIST and SLUG during epithelial-mesenchymal transition (EMT) in oral squamous carcinoma cells. In this study, we treated serum-starved cultures of oral squamous carcinoma cell line YD-10B with resveratrol for 24 hours prior to stimulation with LPA. To identify an optimal resveratrol concentration that does not induce apoptosis in oral squamous carcinoma cells, we determined the toxicity of resveratrol in YD-10B cells by assessing their viability using the MTT assay. Another assay was performed using Matrigel-coated cell culture inserts to detect oral cancer cell invasion activity. Immunoblotting was applied for analyzing protein expression of SLUG, TWIST1, E-cadherin, and GAPDH. We demonstrated that resveratrol efficiently inhibited LPA-induced oral cancer cell EMT and invasion by downregulating SLUG and TWIST1 expression. Therefore, resveratrol may potentially reduce oral squamous carcinoma cell invasion and metastasis in oral cancer patients, improving their survival outcomes. In summary, we identified new targets for the development of therapies against oral cancer progression and characterized the therapeutic potential of resveratrol for the treatment of oral cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.927-932
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• 2016

Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-${\beta}$ superfamily, regulate many cellular activities including cell migration, differentiation, adhesion, proliferation and apoptosis. Use of recombinant human bone morphogenic protein-2 (rhBMP-2) in oral and maxillofacial surgery has seen a tremendous increase. Due to its role in many cellular pathways, the influence of this protein on carcinogenesis in different organs has been intensively studied over the past decade. BMPs also have been detected to have a role in the development and progression of many tumors, particularly disease-specific bone metastasis. In oral squamous cell carcinoma - the tumor type accounting for more than 90% of head and neck malignancies- aberrations of both BMP expression and associated signaling pathways have a certain relation with the development and progression of the disease by regulating a range of biological functions in the altered cells. In the current review, we discuss the influence of BMPs -especially rhBMP-2- in the development and progression of oral squamous cell carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.1147-1150
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• 2013

Background: Cancer diagnostic biomarkers have a wide range of applications that include early detection of oral precancerous lesions and oral squamous cell carcinomas, and assessing the metastatic status of lesions. The interferon stimulated ISG15 gene encodes an ubiquitin-like protein, which conjugates to stabilize activation status of associated proteins. Hence a deregulated expression of ISG15 may promote carcinogenesis. Indeed overexpression of ISG15 has been observed in several cancers and hence it has been proposed as a strong candidate cancer diagnostic biomarker. Given the emerging relationship between malignant transformation and ISG15, we sought to examine the expression pattern of this gene in tumor biopsies of oral squamous cell carcinoma (OSCC) tissues collected from Indian patients. Materials and Methods: Total RNA isolated from thirty oral squamous cell carcinoma tissue biopsy samples were subjected to semi-quantitative RT-PCR with ISG15 specific primers to elucidate the expression level. Results: Of the thirty oral squamous cell carcinomas that were analyzed, ISG15 expression was found in twenty four samples (80%). Twelve samples expressed low level of ISG15, six of them expressed moderately, while the rest of them expressed very high level of ISG15. Conclusions: To the best of our knowledge, the results show for the first time an overexpression of ISG15 in up to 80% of oral squamous cell carcinoma tissues collected from Indian patients. Hence ISG15 may be explored for the possibility of use as a high confidence diagnostic biomarker in oral cancers.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.5027-5031
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• 2012

This study was conducted to investigate the expression of survivin and caspase 3 in oral squamous cell carcinoma and peritumoral tissue, and possible pathogenesis mechanisms. We used ELISA and western blotting to detect the protein expression levels of survivin and caspase 3 in tissue. In situ hybridization and real-time PCR were applied to assess mRNA expression levels. In this study, 13 tumor samples and 13 peritumoral tissue samples were collected from oral squamous cell carcinoma patients and 10 normal tissue samples obtained from patients without tumor. The result showed that the protein and mRNA expression of survivin in carcinoma was the highest among three types of tissue; following was that in peritumoral tissue. No difference in caspase 3 zymogen between peritumoral tissue and normal tissue could be found, while it was evidently decreased in carcinoma tissue. Activated caspase 3 was detected in normal tissue but could not be identified in peritumoral or carcinoma tissue. Our results indicate that the expression of survivin is apparently elevated in tumoral and peritumoral tissue. Expression of activated caspase 3 was not detected in tumoral tissue and the expression of caspase 3 zymogen was decreased in tumoral tissue. Our findings suggest that survivin may inhibit both synthesis and activation of caspase 3, hence inhibiting cell apoptosis and facililitating eventual development of oral squamous cell carcinoma.

• International Journal of Oral Biology
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• v.34 no.2
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• pp.73-79
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• 2009

Cytosolic $Ca^{2+}$ is an important regulator of tumor cell proliferation and metastasis. Recently, the strategy of blocking receptors and channels specific to certain cancer cell types has emerged as a potentially viable future treatment. Oral squamous cell carcinoma is an aggressive form of cancer with a high metastasis rate but the receptor-mechanisms involved in $Ca^{2+}$ signaling in these tumors have not yet been elucidated. In our present study, we report that bradykinin induces $Ca^{2+}$ signaling and its modulation in the human oral squamous carcinoma cell line, HSC-3. Bradykinin was found to increase the cytosolic $Ca^{2+}$ levels in a concentration-dependent manner. This increase was inhibited by pretreatment with the phospholipase C-${\beta}$ inhibitor, U73122, and also by 2-aminoethoxydiphenyl borate, an inhibitor of the inositol 1,4,5-trisphosphate receptor. Pretreatment with extracellular ATP also inhibited the peak bradykinin-induced $Ca^{2+}$ rise. In contrast, the ATP-induced rise in cytosolic $Ca^{2+}$ was not affected by pretreatment with bradykinin. Pretreatment of the cells with either forskolin or phorbol 12-myristate 13-acetate (activators of adenylyl cyclase and protein kinase C, respectively) prior to bradykinin application accelerated the recovery of cytosolic $Ca^{2+}$ to baseline levels. These data suggest that bradykinin receptors are functional in $Ca^{2+}$ signaling in HSC-3 cells and may therefore represent a future target in treatment strategies for human oral squamous cell carcinoma.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.30 no.4
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• pp.333-344
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• 2008

The objectives of this study was to explore the growth pattern of the oral squamous cell carcinoma when overexpressed COX was inhibited, explore the pathway that COX inhibitors suppressed the proliferation of cancer cells, and then hereafter investigate the potential of COX as chemopreventive target for oral squamous cell carcinoma. For confirming the COX-dependent effect and mechanisms on growth of the oral cancer cells, we treated the nonselective NSAID, Mefenamic acid and COX-2 selective inhibitor, Celecoxib in HN4 cell line. And then the cell line was evaluated with MTT assay and growth curve, the production of PGE2, total RNA extraction and RT-PCR analysis, and TEM The results were obtained as follows: 1. After administration of medication, in the result of MTT assay, Celecoxib inoculated group inhibit the cell growth rather than Mefenamic acid inoculated group. 2. The growth curve of cell line showed as time passes by there was a dramatic cell growth in the control group, and gradual growth inhibition was found in medication inoculated group and, in Celecoxib inoculated group there was more inhibition of cell growth. 3. After the administration of medication, Celecoxib tend to inhibit the synthesis of PGE2 more than Mefenamic acid. Mefenamic acid inhibit the synthesis of PGE2 more as the concentration gets high, but Celecoxib inhibited the synthesis of PGE2 even in low concentration. 4. After the administration of medication, the revelation of COX mRNA in cell line, there was a 50% decrease in COX-1, 60% decrease in COX-2 as in $50{\mu}M$ Mefenamic acid, and in Celecoxib $50{\mu}M$ there was not much difference in COX-1 and 90% decrease in COX-2 was found. 5. HN4 cell line showed broken nucleus and tangled cytoskeleton bundles in cytoplasm which meant apoptotic features after the treatment of Celecoxib in TEM view. Depending on the above results, we estimate that the inhibition of the expression of COX-2 cause the growth suppression of the oral squamous cell carcinoma, and it get achieved through pathway of reduced PGE2 production and increased apoptosis. In addition to, because COX-2 selective inhibitor specifically act to COX-2, it is considered that COX-2 selective inhibitor has the adequate potential as chemopreventive agent for oral squamous cell carcinoma.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.42 no.4
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• pp.221-226
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• 2016

Spindle cell carcinoma (SpCC) is referred to as a variant of oral squamous cell carcinoma. It is also known as "sarcomatoid squamous cell carcinoma" because it consists of normal squamous carcinoma cells with spindle-shaped cells that appear similar to a sarcoma. The term, "second primary tumor" (SPT) or "double primary tumor", is proposed for a second tumor that develops independently from the first. SPTs can present as either synchronous or metachronous lesions. Synchronous SPTs are defined as tumors occurring simultaneously or within 6 months after the first tumor. The patient in this case, whose primary tumor was in the tongue, was diagnosed with SpCC with metastases to both neck lymph nodes. This case also exhibited a second primary cancer as a synchronous lesion in the thyroid gland, which is uncommon. All carcinomas, both in the tongue and thyroid gland, were removed surgically, and especially in the tongue, an anterolateral thigh free flap was performed successfully to replace the defect.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.42 no.3
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• pp.133-138
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• 2016

Objectives: To assess the association between muscle invasion by oral squamous cell carcinoma of the posterior mandibular alveolar ridge and cervical lymph node metastasis on the basis of preoperative magnetic resonance imaging (MRI). Materials and Methods: Twenty-six patients with oral squamous cell carcinoma of the posterior mandibular alveolar ridge were evaluated by MRI. The associations between cervical lymph node metastasis and independent factors evaluated by MRI were analyzed. Overall survival was also analyzed in this manner. Representative biopsy specimens were stained with anti-podoplanin and anti-CD34 antibodies. Results: Mylohyoid muscle invasion was associated with cervical lymph node metastasis. A combinational factor of mylohyoid and/or buccinator muscle invasion was also associated with cervical lymph node metastasis. Cervical lymph node metastasis and masticator space invasion had a negative effect on overall survival. No lymphatic vessels were identified near the tumor invasion front within the mandible. In contrast, lymphatic vessels were identified near the front of tumor invasion in the muscles. Conclusion: This study demonstrates an association between muscular invasion by oral squamous cell carcinoma of the posterior mandibular alveolar ridge and cervical lymph node metastasis.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7497-7500
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• 2015

Background: Tumor markers, designated as a broad group of substances produced by malignancies, could be in the form of biochemical substances, immunological substances, cell surface changes and genetic alterations. Cancer, a disorder of cellular behavior is characterized by alteration of serum glycoproteins. L-fucose, a hexose, which is the terminal sugar in most of the plasma glycoproteins, may be useful as a tumor marker for the detection, monitoring and prognostic assessment of malignancies. The aim of the study was to ascertain the role of serum fucose as a biomarker for early detection of oral cancer and to compare serum fucose levels in healthy controls, leukoplakia and oral cancer patients. Materials and Methods: The study included 60 (100.0%) subjects, who were grouped as 20 (33.3%) control subjects, 20 (33.3%) squamous cell carcinoma patients and 20 (33.3%) leukoplakia patients. Fucose estimation was done using UV-visible spectrophotometry based on the method as adopted by Winzler using cysteine reagent. The results were analyzed statistically using ANOVA with Bonferroni post hoc tests. Results: Results showed a high significance in serum fucose in oral squamous cell carcinoma (OSCC) and leukoplakia subjects compared to normal controls. There was a gradual increase in the values noted from control to leukoplakia and to squamous cell carcinoma. Conclusions: Estimation of serum fucose may be a reliable marker and can be used as an effective diagnostic biomarker in oral squamous cell carcinoma patients.

• Journal of Oral Medicine and Pain
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• v.24 no.2
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• pp.145-161
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• 1999

The proto-oncogene bcl-2 confers a survival advantage to cells by blocking programmed cell death (apoptosis). Overexpression of bcl-2 probably plays a role in tumorigenesis, and the expression of the bcl-2 protein has been investigated in many kinds of tumors. An increased expression of nitric oxide synthetase(NOS) has been observed in human colon cancer cell lines as well as in human gynecological, breast, and CNS tumors. However there have been only a few reports on the expression of bcl-2 and $NOS_2$ in oral white lesions and cancer. The aim of this study was to investigate the relationship between the expression of Bcl-2 and $NOS_2$ and several pathological parameters such as histological types and layers. We reported desregulation of bcl-2 and $NOS_2$ expression during progression from oral white lesion, lichen planus and leukoplakia to squamous cell carcinoma. The obtained results were as follows: 1. Immunohistochemical analysis with monoclonal antibodies to bcl-2 oncoprotein and $NOS_2$ in formalin-fixed paraffin-embedded tissue sections revealed that bcl-2 expression is restricted to the basal cell layer and $NOS_2$ was mild expressed only in subepithelial inflammatory cells in normal human mucosa. There wasn't specific finding of those in lichen planus and leukoplakia. 2. Bcl-2 immunoreactivity in severe epithelial dysplasia or CIS occurs throughout the epithelium, $NOS_2$ reactivity in most superficial layer were noted. 3. In well-differentiated squamous cell carcinomas, mostly bcl-2 was overexpressed. In moderated and poor squamous cell carcinomas, the expression of $NOS_2$ was increased and that of bcl-2 was decreased. 4. The immunoreactivity of bcl-2 was 12.5% of normal mucosa, 30% of leukoplakia, 44% of lichen planus and 67% of carcinoma in situ. In carcinoma, those were 43%, 50% and 67% according to differentiation, respectively. 5. The immunoreactivity of $NOS_2$ was 25% of normal mucosa, 70% of leukoplakia, 78% of lichen planus and 100% of carcinoma in situ and epithelial dysplasia. In carcinoma, those were higher in moderated(100%) and poor(83%) squamous cell carcinomas than in well differentiated type(71%). 6. The expression of bcl-2 and $NOS_2$ by Western blot was increased highly in lichen planus and leukoplakia. Therefore, the expression of bcl-2 was increased in the white and precancerous lesions and that was decreased by differentiation of carcinoma. However, $NOS_2$ immunoreactivity in carcinoma in situ was lower than those in moderated and poor squamous cell. These findings suggest that the interaction of bcl-2 and $NOS_2$ may be roled importantly in growth and development of carcinoma.