Purpose: Even today, cancer remains a challenge to overcome. The purpose of this study is to understand the current status of lip-oral-pharyngeal cancer in Koreans by identifying the survival rate of lip-oral-pharyngeal cancer in Koreans through long-term big data. Material and Method: This study utilized 2023 KOSIS (Cancer Registration Statistics, Ministry of Health and Welfare) academically. The 5-year relative survival rates of lip-oral-pharyngeal cancer from 1996 to 2020 were compared and analyzed at 5-year intervals. Results: The 5-year relative survival rate for lip-oral-pharyngeal cancer was 47.4% from 1996 to 2000, 54.5% from 2001 to 2005, 61.1% from 2006 to 2010, 65.5% from 2011 to 2015, and 69.7% from 2016 to 2020. From 1996 to 2005, the 5-year relative survival rate for lip-oral-pharyngeal cancer was higher than the 5-year relative survival rate for all cancers. However, in the recent 15 years from 2006 to 2020, the 5-year relative survival rate for lip-oral-pharyngeal cancer was lower than for all cancers. Conclusions: In conclusion, this long-term big data showed that the 5-year relative survival rate of lip-oral-pharyngeal cancer in Koreans has increased further in modern times. However, in order to increase the overall survival rate of all human cancers, continuous efforts to improve the survival rate of lip-oral-pharyngeal cancer are needed in the future.

SOCS3, a suppressor of cytokine signaling 3, is known as a negative regulator of various cytokines and a tumor suppressor gene in human tumors. This study aimed to investigate the role of SOCS3 in oral squamous cell carcinoma (OSCC) and its impact on epithelial-mesenchymal transition (EMT) in OSCC cells. Although SOCS3 is recognized as a negative regulator of various cytokines and a tumor suppressor gene in human tumors, its specific effects on OSCC remain poorly understood. For the assessment of SOCS3 expression in OSCC, the UALCAN website and TCGA data were used to evaluate its expression in head and neck cancer. Additionally, immunohistochemical staining was conducted to determine the SOCS3 expression specifically in OSCC. The findings indicated a significant decrease in SOCS3 expression in tumor tissue compared to that in normal tissues. To investigate the enhancement of SOCS3 expression in OSCC cancer cell lines, IL6 treatment was administered to MC3 cells. However, no significant differences were observed in cell viability, wound healing assay, and invasion assay. Conversely, the transfection of SOCS3 siRNA into OSCC cells led to a notable increase in cell viability and statistically significant increases in wound healing and invasion assays. These results suggest that SOCS3 plays a crucial role in cell viability and EMT in OSCC, thereby contributing to oral carcinogenesis. Further research is necessary to elucidate the precise role of SOCS3 in OSCC.

Porphyromonas gingivalis, a major pathogen of chronic periodontitis, colonizes in subgingival crevice and affects surrounding oral tissues, especially in periodontitis patients. Oral cancer mainly occurs in old-aged persons, and are exposed to the P. gingivalis, released from periodontitis, one of the most common inflammatory disease of oral cavity. Thus oral cancer cells may be infected with P. gingivalis, and its biologic behavior are autologously and/or heterogeneously modulated by altering gene expression. Exosomes which are derived from cells contain not only coding genes but also non-coding RNAs such as long non-coding RNAs, miRNA, and piRNAs. Here, to investigate the effect of P. gingivalis on oral cancer cells and to gain insight into the crosstalk between inflammatory signal from tumor microenvironment and oral cancer, we observed miRNA profiles of exosomes from P. gingivalis–infected oral cancer cells. Upregulation of 6 miRNAs, miR-203-3p, miR-6516-3p, miR-483-5p, miR-1275, miR-8485, and miR-19a-3p, were observed whereas 14 miRNAs including let-7a-3p, miR-106a-5p were downregulated. In addition, KEGG pathway analysis using the upregulated- and downregulated- miRNAs showed association with cell adhesion molecules pathway and ECM-receptor interaction pathway, respectively. These findings suggest that P. gingivalis could modulate biologic behavior of oral cancer cells through changes of exosomal miRNAs.

Purpose: The purpose of this study is to determine how the incidence of oral cancer has changed over the past few years. Material and Method: In this study, the number of total cancers and lip-oral-pharyngeal cancers by year was compared using public big data from the National Cancer Center. The incidence rate of lip-oral cavity-pharyngeal cancer from 2000 to 2015 was analyzed. Results: In 2000, there were 101,772 cases of all cancers in all men and women. In 2015, there were 202,266 cancer cases in both men and women. In 2000, there were 2,183 cases of lip-oral-pharyngeal cancers for both men and women. In 2015, lip-oral-pharyngeal cancer were 3337 in both men and women. Conclusions: It is possible that oral cancer also increased along with the increase in total cancer, and it is thought that we should focus on preventing cancer in the future.

Ficus carica L. (fig ) is one of the first cultivated crops and is as old as humans. This plant has been extensively used as a traditional medicine for treating diseases, such as cough, indigestion, nutritional anemia, and tuberculosis. However, the physiological activity of fig leaves on oral cancer is as yet unknown. In this study, we investigated the anticancer effect of methanol extracts of Ficus carica (MeFC) and the mechanism of cell death in human FaDu hypopharyngeal squamous carcinoma cells. MeFC decreased the viability of oral cancer (FaDu) cells but did not affect the viability of normal (L929) cells, as determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay and Live and Dead assay. In addition, MeFC induced apoptosis through the proteolytic cleavage of procaspase-3, -9, poly (ADP-ribose) polymerase (PARP), downregulation of Bcl-2, and upregulation of Bax, as determined by 4′,6-diamidino-2-phenylindole dihydrochloride staining and western blot analysis. Moreover, a concentration of MeFC without cytotoxicity (0.25 mg/mL) significantly suppressed colony formation, a hallmark of cancer development, and completely inhibited the colony formation at 1 mg/mL. Collectively, these results suggest that MeFC exhibits a potent anticancer effect by suppressing the growth of oral cancer cells and colony formation via caspase- and mitochondrial-dependent apoptotic pathways in FaDu human hypopharyngeal squamous carcinoma cells. Therefore, the methanol extract of Ficus carcica leaves provide a natural chemotherapeutic drug for human oral cancer.

Hypoxia is one of the most common features of cancer. It is also associated with cancer progression and the acquisition of aggressiveness, which includes invasion and metastasis. Oral squamous cell carcinoma accounts for 90% of all oral cancers, and its 5-year survival rate is about 50%. Despite various attempts and trials, its prognosis has not improved. Among numerous adverse prognostic factors, hypoxia is suspected as one of the most important factors, as it increases the aggressiveness of oral cancer cells. We attempted to observe the effect of hypoxia on the expression of epithelial-mesenchymal transition markers in oral cancer cells. We analyzed and compared both the mRNA and protein expression levels of epithelial-mesenchymal markers using qRT-PCR and western blotting in both normoxic and hypoxic YD10B oral squamous cell carcinoma cells. Eighty-six genes were analyzed through real-time PCR using commercial microarray plates, performed in triplicate. Among the 86 genes, the expression of 24 were increased (≥ 2 fold) by hypoxia, while that of three genes was decreased (≥ 2 fold). Hypoxia significantly affects epithelial-mesenchymal transition-related genes. Further studies on the regulation of these genes may help to develop more efficient therapeutic modalities for oral cancer and to improve prognosis of oral cancer patients.

In the present study, rutile phase titanium dioxide nanoparticles (R-TiO2 NPs) were prepared by hydrolysis of titanium tetrachloride in an aqueous solution followed by calcination at 900℃. The composition of R-TiO2 NPs was determined by the analysis of X-ray diffraction data, and the characteristic features of R-TiO2 NPs such as the surface functional group, particle size, shape, surface topography, and morphological behavior were analyzed by Fourier-transform infrared spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy, transmission electron microscopy, dynamic light scattering, and zeta potential measurements. The average size of the prepared R-TiO2 NPs was 76 nm, the surface area was 19 m2/g, zeta potential was −20.8 mV, and average hydrodynamic diameter in dimethyl sulfoxide (DMSO)–H2O solution was 550 nm. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and morphological observations revealed that R-TiO2 NPs were cytocompatible with oral cancer cells, with no inhibition of cell growth and proliferation. This suggests the efficacy of R-TiO2 NPs for the aesthetic white pigmentation of teeth.

Trifolium pratense leaves (red clover) has been used in Oriental and European folk medicine for the treatment of whooping cough, asthma, and eczema, and is now being used to treat and alleviate the symptoms, such as hot flushes, cardiovascular health effects that occur in postmenopausal women. However, relatively little scientific data is available on the physiological activity of this plant. Therefore, in this study, we investigated the anti-cancer activity of T. pratense leaves using methanol extract of T. pratense leaves (MeTP) on human FaDu hypopharyngeal squamous carcinoma cells. MeTP inhibited the viability of FaDu cells by inducing apoptosis through the cleavage of procaspase- 3, -7, and -9 and poly (adenosine diphosphate ribose-ribose) polymerase (PARP), downregulation of Bcl- 2, and upregulation of Bax, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Live & dead assay, 4’6-diamidino-2-phenylindole stain, fluorescence-activated cell sorting analysis, and Western blot analysis. In addition, colony formation was slightly inhibited when FaDu cells were treated with a non-cytotoxic concentration (0.125 mg/mL) of MeTP and almost completely inhibited when cells were treated with 0.25 mg/mL MeTP. Collectively, these results indicate that MeTP induced cell apoptosis via caspase- and mitochondrial-dependent apoptotic pathways, and inhibited colony formation of cancer cells in FaDu human hypopharyngeal squamous carcinoma cells. These findings suggest MeTP should be considered for clinical development as a chemotherapeutic option in oral cancer.

MicroRNAs (miRNAs) are a group of small non-coding RNAs consisting of 18~24 nucleotides in length. Each miRNA is expected to bind a few hundreds of putative target mRNAs, thus inhibiting their translation into protein products mostly by degradation of targets. With its biogenesis extensively deciphered, miRNAs have been implicated in a variety of biological processes, including early development and cellular metabolism. In addition, dysregulation of miRNAs and subsequent alterations in the expression of its target molecules are thought to be linked to the pathophysiology of multiple human illnesses, including cancer. To establish the miRNA-target relationships important for developing a specific disease, it is critical to validate the putative targets of each miRNA suggested by computational methods in vivo. In this review, we will first discuss oncogenic and tumor-suppressive roles of miRNAs in human cancer and introduce computational methods to predict putative targets of miRNAs. Then, the value of Drosophila melanogaster as an alternative model system will be further discussed in studying human cancer and in validating the miRNA-target relationships in vivo. Finally, we will present a possibility of applying the mammals-to-Drosophila-to-mammals approach to study the roles of miRNAs and their targets in the pathophysiology of oral cancer, an intractable type of cancer with poor prognosis and survival rate.

Recently chronic inflammation is focused on the association with cancer progression and acquisition of aggressive biologic behaviors, such as invasion, metastasis, and resistance to chemotherapeutic reagents. Due to the close vicinity within oral cavity, oral cancer may be intimately associated with chronic periodontitis. The present study was done to observe the effect of chronic periodontitis on oral cancer cells by utilizing P. gingivalis infection, a major pathogen in chronic periodontitis. We analyzed and compared the mRNA expression levels of epithelial-mesenchymal transition (EMT) markers in non-infected and P. gingivalis-infected oral cancer cells. Eighty-six genes, which are well known as EMT markers, were analyzed using commercially available EMT microarray plates, performed in triplicate. Among the 86 genes, the expression of 26 was increased (≥ 2 fold) by P. gingivalis, whereas that of 7 genes was decreased (≥ 2 fold). Our study suggests that P. gingivalis infection evokes significant changes in EMT-related genes. Further observations on molecular mechanisms underlying these changes may help to clarify the role of chronic periodontitis on cancer progression and to develop more efficient preventive and therapeutic modalities for oral cancer. (182 words)

Codium fragile (Suringar) Hariot is an edible green seaweed that belong to the Codiaceae family and has been used in Oriental medicine for the treatment of enterobiasis, dropsy, and dysuria. Methanol extract of codium fragile has anti-oxidant, anti-inflammatory and anti-cancer properties, although the anti-cancer effect on oral cancer has not yet been reported. In this study, we investigated the anti-cancer activity and the mechanism of cell death by methanol extracts of Codium fragile (MeCF) on human FaDu hypopharyngeal squamous carcinoma cells. Our data showed that MeCF inhibits cell viability in a dose-dependent manner, and markedly induced apoptosis, as determined by the MTT assay, Live/Dead assay, and DAPI stain. In addition, MeCF induced the proteolytic cleavage of procaspase -3, -7, -9 and poly(ADP-ribose) polymerase(PARP), and upregulated or downregulated the expression of mitochondrial-apoptosis factor, Bax(pro-apoptotic factor), and Bcl-2(anti-apoptotic factor), . Futhermore, MeCF induced a cell cycle arrest at the G1/S phase through suppressing the expression of the cell cycle cascade proteins, p21, CDK4, CyclinD1, and phospho-Rb. Taken together, these results indicated that MeCF inhibits cell growth, and this inhibition is mediated by caspase- and mitochondrial-dependent apoptotic pathways through cell cycle arrest at the G1/S phase in human FaDu hypopharyngeal squamous carcinoma cells. Therefore, methanol extracts of Codium fragile can be provided as a novel chemotherapeutic drug due to its growth inhibition effects and induction of apoptosis in human oral cancer cells.

5-fluorouracil (5-FU) is a pyrimidine analog which can work as antineoplastic antimetabolite by blocking thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid in DNA synthesis. This study is aimed to know the anticancer effect of 5-FU on the expressions of important signaling proteins in KB cells through immunoprecipitation high performance liquid chromatography (IP-HPLC). KB cells were treated with 5 μM 5-FU and cultured for 12, 24, 48, 72, and 96 hours, and followed by IP-HPLC analysis using 32 antisera. 5-FU suppressed the proliferation of KB cells by decreases in the expressions of proliferation-related proteins, Ki-67, PCNA, CDK4, and MPM2 to 82.6%, 92.4%, 95.2%, and 95.9%, respectively, but increases of antiproliferation-related proteins, p16 and p21 to 106.7% and 125.5%, respectively, during 96 hours of experiment. This proliferation reduction was also negatively regulated by cMyc/MAX/MAD network signaling. The cellular protection and survival were consistently arrested by 5-FU treatment in KB cells. The expressions of NFkB, MDR, p-mTOR, and TNFα were decreased to 95.1%, 92.8%, 93.4%, and 90.3% in 48-72 hours, respectively, while cellular stress was increased by upregulation of p38 to 111.3% in 48 hours. And the expressions of pAKT1/2/3, hTERT, and AMPK were also decreased to 93.3%, 97.4%, and 89.3% in 24-48 hours, respectively, while the cellular transformation might be undergone by upregulation of TGF-β1 to 117% until 96 hours. Particularly, 5-FU treatment greatly induced the cellular apoptosis in KB cells by increased expressions of PARP, cPARP, caspase 9, c-caspase 9, caspase 8, and caspase 3 in the lack of p53/BAX and FASL/FAS signaling. The expressions of PARP and c-PARP were increased maximum to 119.2% in 24 hours, and followed by increases of caspase 9, c-caspase 9, caspase 8, and caspase 3 to 111.2%, 125.9%, 108.6%, and 116.3% in 72-96 hours. Therefore, it is presumed that 5-FU induced cellular apoptosis in KB cells may be derived from the overexpression of PARP due to the increased DNA defect caused by 5-FU, which can lead to ATP depletion and subsequent cellular apoptosis.

Porphyromonas gingivalis is a gram-negative bacteria of rod shape, and grown in an anerobic condition. It colonizes in subgingival crevice and is known as a major pathogen causing chronic periodontitis. It possesses an invasive property and replicative potential within various cell types, presumably playing an important role in modulating biological behaviors of oral cancer. However, the pathophysiology of P. gingivalis in the malignant transformation of oral cancer has not been fully understood. In this study, we aimed to investigate molecular changes of oral squamous cell carcinoma cells induced by repetitive P. gingivalis infection that clinically resembles chronic periodontitis.

Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, was reported to various physiological and pharmacological effects including anti-cancer activity. Nevertheless, there is no report of the anticancer effect of lycorine in oral cancer cells. The effects of lycorine on cell proliferation and apoptosis were examined through trypan blue exclusion assay, 4’-6-diamidino-2-phenylindole (DAPI) stain, Live/Dead assay, Western blot analysis and RT-PCR. Lycorine suppressed cell viability and induced apoptosis in MC3 and HSC-3 cell lines. Lycorine decreased survivin protein but did not affect its mRNA. It regulated survivin through accelerating protein degradation in a time-dependent manner although neither proteasome nor lysosome was not associated with lycorine-mediated protein degradation. Collectively, our results suggest that lycorine may be a potential therapeutic anti-cancer drug candidate for the treatment of human oral cancer.

Tyrosol, a phenylethanoid and a derivative of phenethyl alcohol, possesses various biological properties, such as anti-oxidative and cardioprotective activity. Olive oil is the principal source of tyrosol in the human diet. However, so far the anti-cancer activity of tyrosol has not yet been well defined. This study therefore undertakes to examine the cytotoxic activity and the mechanism of cell death exhibited by tyrosol in KB human oral cancer cells. Treatment of KB cells with tyrosol induced the cell growth inhibition in a concentration- and a time-dependent manner. Furthermore, the treatment of tyrosol induced nuclear condensation and fragmentation of KB cells. Tyrosol also promoted proteolytic cleavage of procaspase-3, -7, -8 and –9, increasing the amounts of cleaved caspase-3, -7, -8 and –9. In addition, tyrosol increased the levels of cleaved PARP in KB cells. These results suggest that tyrosol induces the suppression of cell growth and cell apoptosis in KB human oral cancer cells, and is therefore a potential candidate for anti-cancer drug discovery.

Recently, the importance of inflammation in carcinogenesis has been recognized and studied extensively. As a result, a clear correlation between inflammation and carcinogenesis has been well established in some types of cancers. Despite a high prevalence of chronic periodontitis, one of the most common inflammatory diseases in the general population, there are only a few reports on the role of chronic periodontitis in oral cancer progression. In this study, we aimed to investigate genetic changes in oral cancer cells induced by repetitive Porphryomonas gingivalis infections to mimic chronic periodontitis in a clinical setting. Cells of oral squamous cell carcinoma (OSCC), the most common type of oral cancer, and P. gingivalis 381 were used for the present study. ID1 and ID3 were mRNAs of higher expression in the P. gingivalis-infected group compared to the uninfected control. These mRNAs have been regarded as important modulators participating in cancer progression. Future studies will provide an insight into the roles of the molecules we identified in oral cancer progression. Outcomes from these studies will also shed light on the significance of chronic periodontitis induced by bacterial pathogen, such as P. gingivalis, in progression of oral cancer and relevant molecular mechanisms underlying altered cancer cell behaviors.

β-carotene is present in carrots, pumpkins, and sweet potatoes. It suppresses many types of cancers by regulating cellular proliferation and apoptosis through a variety of mechanisms. However, the effects of β -carotene on oral cancer cells have not been clearly established. The main goal of this study was to investigate the effects of β-carotene on cell growth and apoptosis in oral cancer cells. Our results demonstrate that treatment with β-carotene induced inhibition of cell growth, and that the effect was dependent on β-carotene treatment time and concentration in KB cells. Furthermore, treatment with β-carotene induced nuclear condensation and fragmentation in KB cells. β-carotene promoted proteolytic cleavage of procaspase-3, -7, -8 and –9 with associated increases in the concentration of cleaved caspase-3, -7, -8 and –9. In addition, the level of cleaved PARP was increased by β-carotene treatment in KB cells. These results suggest that β-carotene can suppress cell growth and induce apoptosis in KB human oral cancer cells, and that it may have potential usefulness in anti-cancer drug discovery efforts.

Immunoprecipitation-based high performance liquid chromatography (IP-HPLC) is a type of modified enzyme-linked immunosorbent assay (ELISA) that uses protein A/G (or antibody)-conjugated beads instead of the antibody-conjugated wells used in ELISA. In order to determine the fidelity of IP-HPLC, the author used 83 antisera to identify protein expression changes caused by cisplatin treatment in KB human oral cancer cells. KB cells were cultured for 12 or 24 hours with 10 ug/mL cisplatin. The results obtained by IP-HPLC were comparable with published cisplatin data, although ELISA was not conducted in the present study. Cisplatin dominantly reduced the levels of proteins associated with cell proliferation, transcription factors, growth factors, cytoskeletal proteins, and cellular differentiating factors, but on the other hand, apoptosis-related factors, oncogenes, and protective proteins were usually up-regulated, presumably to address cisplatin-induced DNA damage. In particular, cisplatin directly inactivated genomic DNA by down-regulating histone H1 and demethylase and by up-regulating deacetylase. Cisplatin also rapidly induced p53 overexpression and mitochondria-mediated endogenous apoptosis occurred after 12 hours of cisplatin treatment, although this was almost completely replaced by FASL/FAS-mediated exogenous apoptosis after 24 hours. This preliminary study was conducted to investigate the anticancer effect of cisplatin on the KB human oral cancer cells and to determine the fidelity of IP-HPLC data. It was concluded that IP-HPLC is useful for identifying profile changes of genome wide essential proteins and signaling changes of major molecular pathways.

Terfenadine (TFN) was a second generation histamine receptor antagonist. Although several studies have reported the regulatory effect of H1-histamine receptor antagonists in human cancer cell lines, its effect in oral cancer remains unclear. In this study, we focused on addressing the anti-cancer activity of TFN in human oral cancer cell lines. The anti-cancer activities of TFN were performed by tryphan blue exclusion assay, 4'-6-diamidino-2-phenylindole (DAPI) staining, live/dead assay and Western blot analysis. TFN induced a significant reduction of the growth in three different human oral cancer cell lines (MC3, HSC4 and Ca9.22). TFN markedly induced apoptosis through DNA damage and increase in cytotoxicity. It also accumulated cleaved PARP and caspase 3. This process was due to cleavage of caspase 8 and Bid protein. The results from this study strongly demonstrated that the cleavages of caspase 8 and Bid are required for the apoptotic activity of TFN in human oral cancer cells. Taken together, these findings suggest TFN as a potent anticancer drug candidate for the treatment of oral cancer.

Oral squamous cell carcinoma (OSCC), is the most common malignancy of oral cavity, and the sixth most frequently diagnosed cancer worldwide. This tumor type is associated with poor prognosis, and most OSCC patients are diagnosed after the cancer has reached an advanced stage. The over expression of NF-κB p65 has been associated with OSCC progression and lymph node metastasis. Hence, the present study analyzed the expression of NF-κB p65 in OSCC from Korean patients. Immunohistochemistry for NF-κB p65 was performed using 12 normal oral mucosas (NOM), 16 oral leukoplakia (with/without dysplasia), and 58 OSCC patients samples. Immunoreactivity was semi-quantitatively scored and the correlation between the expression of NF-κB p65 and clinicopathological parameters of OSCC patients was analyzed. Immunohistochemical staining revealed that NF-κB p65 expression level increased in oral leukoplakia with dysplasia and OSCC. Moreover, the immunoexpression of NF-κB p65 appeared to be associated with age, recurrence, TNM stage, and lymph node metastasis in OSCC patients (p<0.05). These results indicated that NF-κB p65 can play a role as oncogene in OSCC. Moreover, NF-κB p65 may play an important role in both oral carcinogenesis and OSCC patient outcome. It may be considered as another new malignant biomarker of OSCC.