• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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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.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제33권3호
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• pp.191-198
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• 2007

The p53 which is well known as tumor suppressor gene is located at 17p13. p53 is a sequence-specific DNA binding transcription factor that responds to certain cytotoxic stresses, such as DNA damage, by enhancing the transcription of genes that regulate cell-cycle progression as well as programmed cell death. The p63 gene that is located at 3q27-29, is recognized members of the p53 family, and responsible for the transcription of 6 isoforms. Three isoforms ($TAp63{\alpha}$, $TAp63{\beta}$, $TAp63{\gamma}$) contain an N-terminal transactivation (TA) domain and can induce apoptosis. The other 3 isoforms (${\Delta}Np63{\alpha}$, ${\Delta}Np63{\beta}$, ${\Delta}Np63{\gamma}$) lack the TA domain and may function in a dominant-negative fashion by inhibiting the transactivation functions of p53 and TAp63 proteins, and thus act as oncoproteins. A number of studies have investigated the role of p63 in human squamous cell carcinomas from different organs. Only a few studies have examined ${\Delta}Np63$ isoform in oral squamous cell carcinoma including normal epithelium. This study aimed to evaluate expression of ${\Delta}Np63$ isoform in human oral squamous cell carcinoma tissue and normal mucosa. The 3 cases of well differenciated oral squamous cell carcinoma specimen including adjacent normal mucosa were examined, and immunohistochemical study with monoclonal antibody(4A4) and tumor cell apoptosis analysis with Transmission Electon Microscopy were studied. And, RT-PCR analysis was done for expression of ${\Delta}Np63$ isoform. The results were as followed. 1. Normal gingiva showed the restricted p63 expression in basal cell layer. 2. Well differentiated squamous cell carcinoma showed mainly p63 expression in overall area of malignancy, especially in basal cell layer to adjacent stromal tissue. 3. Tumor cells around keratinized area with no p63 expression disclosed less micro-organelle in decreased size cytoplasm and severe chromatin margination with nuclear destruction that means apoptosis. 4. Comparison of mRNA expression of ${\Delta}Np63$ isoform by RT-PCR showed variable expression of ${\Delta}Np63$ isoform, but ${\Delta}Np63{\alpha}$ was most highly expressed in all 3 tumor specimen. From theses results, it should be suggested that ${\Delta}Np63$ isoform expression in well differentiated squamous cell carcinoma was closely related to tumor oncogenesis, expecially overexpression of ${\Delta}Np63{\alpha}$ is a most important factor in tumor genesis of oral squamous cell carcinoma.

• International Journal of Oral Biology
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• 제35권2호
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• pp.51-60
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• 2010

Few studies have evaluated the apoptosis-inducing efficacy of NaF on cancer cells in vitro but there has been no previous investigation of the apoptotic effects of NaF on human oral squamous cell carcinoma cells. In this study, we have investigated the mechanisms underlying the apoptotic response to NaF treatment in the YD9 human squamous cell carcinoma cell line. The viability of YD9 cells and their growth inhibition were assessed by MTT and clonogenic assays, respectively. Hoechst staining, DNA electrophoresis and TUNEL staining were conducted to detect apoptosis. YD9 cells were treated with NaF, and western blotting, immunocytochemistry, confocal microscopy, FACScan flow cytometry, and MMP and proteasome activity assays were performed sequentially. The NaF treatment resulted in a time- and dose-dependent decrease in YD9 cell viability, a dose-dependent inhibition of cell growth, and the induction of apoptotic cell death. The apoptotic response of these cells was manifested by nuclear condensation, DNA fragmentation, the reduction of MMP and proteasome activity, a decreased DNA content, the release of cytochrome c into the cytosol, the translocation of AIF and DFF40 (CAD) into the nucleus, a significant shift of the Bax/Bcl-2 ratio, and the activation of caspase-9, caspase-3, PARP, Lamin A/C and DFF45 (ICAD). Furthermore, NaF treatment resulted in the downregulation of G1 cell cyclerelated proteins, and upregulation of p53 and the Cdk inhibitor $p27^{KIP1}$. Taken collectively, our present findings demonstrate that NaF strongly inhibits YD9 cell proliferation by modulating the expression of G1 cell cycle-related proteins and inducing apoptosis via mitochondrial and caspase pathways.

• International Journal of Oral Biology
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• 제46권2호
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• pp.74-80
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• 2021

Autophagy is an evolutionarily well-conserved cellular homeostasis program that responds to various cellular stresses and degrades unnecessary or harmful intracellular materials in lysosomes. Accumulating evidence has shown that autophagy dysfunction often results in various human pathophysiological conditions, including metabolic disorders, cancers, and neurodegenerative diseases. The discovery of an autophagy machinery protein network has revealed underlying molecular mechanisms of autophagy, and advances in the understanding of its regulatory mechanism have provided novel therapeutic targets for treating human diseases. Recently, reports have emerged on the involvement of autophagy in oral squamous cell carcinoma (OSCC). Although the role of autophagy in cancer therapy is controversial, the beneficial use of the induction of autophagic cell death in OSCC has drawn significant attention. In this review, the types of autophagy, mechanism of autophagosome biogenesis, and modulating molecules and therapeutic candidates affecting the induction of autophagic cell death in OSCC are briefly described.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6193-6200
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• 2015

Head and neck cancer, including oral cancer, is the sixth most common cancer in humans worldwide. More than 90% of oral cancers are of squamous cell carcinoma type. Recent studies have shown a strong relationship between human papillomavirus (HPV) infection and head and neck cancer, especially oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Moreover, the incidence of HPV-related OSCC appears to be on the rise while HPV-unrelated OSCC tends to have stabilized in the past decades. p16, a tumor suppressor gene, normally functions as a regulator of the cell cycle. Upon infection with high-risk types of HPV (HR-HPV), particularly types 16, 18, 31, 33, 34, 35, 39, 51, 52, 56, 58, 59, 66, 68, and 70, the expression of p16 is aberrantly overexpressed. Therefore, the expression of p16 is widely used as a surrogate marker for HPV infection in head and neck cancer.

• International Journal of Oral Biology
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• 제34권2호
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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.

• 한방안이비인후피부과학회지
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• 제22권2호
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• pp.50-59
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• 2009

Objectives : The aim of this study was conducted that CRE (Coptidis Rhizoma Extract) induces apoptosis in YD-10B cells, human oral squamous carcinoma cell line. Methods : In this study, YD-10B cells were exposed to CRE (0.03-0.30 mg/ml), for 6-24 hours. We measured the effects of CRE on the changes of cell viability and cell membrane, TUNEL assay of CRE-treated YD-10B cell. Results : In this study, CRE caused a decrease of viability in YD-10B cells, human oral squamous carcinoma cell line. When YD-10B cells were treated with CRE, cells showed dose-dependent manner apoptotic cell death. Conclusions : These results suggest that CRE may be potential therapeutic approach in the clinical management of oral squamous cell carcinoma.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제35권2호
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• pp.66-73
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• 2009

Tumor angiogenesis is a process leading to formation of blood vessels within tumors and is crucial for maintaining a supply of oxygen and nutrients to support tumor growth and metastasis. Vascular endothelial growth factor(VEGF) plays a key role in tumor angiogenesis including induction of endothelial cell proliferation, migration, survival and capillary tube formation. VEGF binds to two distinct receptors on endothelial cells. VEGFR-2 is considered to be the dominant signaling receptor for endothelial cell permeability, proliferation, and differentiation. Bevacizumab(Avastin, Genetech, USA) is a monoclonal antibody against vascular endothelial growth factor. It is used in the treatment of cancer, where it inhibits tumor growth by blocking the formation of new blood vessels. The goal of this study is to identify the anti-tumor effect of Bevacizumab(Avastin) for oral squamous cell carcinoma cell lines. Human squamous cell carcinoma cell line(HN4) was used in this study. We examined the sensitivity of HN4 cell line to Bevacizumab(Avastin) by using in vitro proliferation assays. The results were as follows. 1. In the result of MTT assay according to concentration of Bevacizumab(Avastin), antiproliferative effect for oral squamous cell carcinoma cell lines was observed. 2. The growth curve of cell line showed the gradual growth inhibition of oral squamous cell carcinoma cell lines after exposure of Bevacizumab(Avastin). 3. In the apoptotic index, groups inoculated Bevacizumab(Avastin) were higher than control groups. 4. In condition of serum starvation, VEGFR-2 did not show any detectable autophosphorylation, whereas the addition of VEGF activated the receptor. Suppression of phosphorylated VEGFR-2 and phosphorylated MAPK was observed following treatment with Bevacizumab(Avastin) in a dose-dependent manner. 5. In TEM view, dispersed nuclear membrane, scattered many cytoplasmic vacuoles and localized chromosomal margination after Bevacizumab(Avastin) treatment were observed. These findings suggest that Bevacizumab(Avastin) has the potential to inhibit MAPK pathway in proliferation of oral squamous cell carcinoma cell lines via inhibition of VEGF-dependent tumor growth.

• Journal of Oral Medicine and Pain
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• 제24권2호
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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.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제27권4호
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• pp.330-336
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• 2001

Angiogenesis is an essential process for the growth, invasion and metastasis of cancer. However, it is uncertain that antiangiogenic effects can be a major treatment strategy of oral cancer. The aim of this study was to investigate whether thalidomide, which is known to be a potent inhibitor of angiogenesis, have inhibitory effect on the growth and antiangiogenic effects of oral squamous cell carcinoma(OSCC) xenografted in nude mice and whether antiangiogenesis of thalidomide can be included as a major treatment strategy of oral cancer. After human oral squamous cell carcinoma strain KB was subcutaneously implanted in 20 nude mice, the volume of tumor was measured every three days. When the tumor mass reached $75{\sim}100mm^3$, thalidomide(200mg/kg/d) was administered into 10 experimental nude mice and the same volume of distilled water was administered into 10 control nude mice and the tumor volume was measured every three days. The excised tumor masses on the 30th day after administration were frozen and processed for immunohistochemistry using vascular endothelial growth factor(VEGF) and CD31. We evaluated microvessel density and VEGF expression. The results were as follows ; 1. Thalidomide retarded the growth of human OSCC as compared with the control group, but it was not statistically significant. 2. A statistically significant lower microvessel density was observed in the thalidomide-treated group than in the control group(p<0.01) and thalidomide significantly reduced VEGF expression (p<0.01). Thalidomide exhibited significantly antiangiogenic effect, but did not inhibit the growth of human OSCC effectively. Antiangiogenic therapy of thalidomide alone is not likely to be effective in the treatment of human OSCC, but might be regarded as adjuvant chemotherapeutic strategy.