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Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.

Hyperlipidemia is a major risk of atherosclerosis; however, systemic inflammatory diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus and systemic sclerosis are also known risks for the development of atherosclerosis. Periodontitis, a local and systemic inflammatory condition, has also been reported as a risk for atherosclerosis, but the specific link between periodontitis and atherosclerosis remains somewhat controversial. We previously reported that ligature‑induced periodontitis exacerbates atherosclerosis in hyperlipidemic Apolipoprotein E‑deficient (

Dentin hypersensitivity commonly occurs due to opened dentinal tubules for many reasons. In our previous study, copine 7 (CPNE7) could induce dentin formation for an indirect pulp-capping model in vivo. This study aims to investigate the formation of tertiary dentin when CPNE7 is applied to intentionally exposed dentin with nothing over it in vivo, whether it affects microleakage of the teeth, and the penetration ability of CPNE7 molecules through dentinal tubules in vitro. Cervical dentin areas of 6 maxillary incisors of 5 beagles were exposed to a class V–like lesion, and 1 side of 3 maxillary incisors was adapted with recombinant CPNE7 protein for 5 min as the experimental group. The other side was the control group, and there was no treatment of ethylenediaminetetraacetic acid (EDTA) and CPNE7 after preparation. The defects were exposed without any restorations, and all beagles were sacrificed after 4 wk. The fluid penetration of exposed dentin areas was investigated by a microleakage-testing device and confocal laser scanning microscope. Tertiary dentin formation was confirmed with histological scanning electronic microscopic analysis. Tertiary dentin formation reduces dentinal fluid flow due to occluded tubules or discontinuity with primary or secondary dentin. The in vivo hypersensitivity model with the anterior teeth of beagle dogs showed newly formed tertiary dentin at the dentin-pulp boundary in recombinant CPNE7–treated teeth when compared with the untreated control group in histologic analysis. Scanning electronic microscopic analysis revealed occluded sites with mineral deposition of intratubular dentin. In the permeability test, the mean microleakage value of the CPNE7-treated group was significantly lower than that of the control group ( P < 0.05). The tubular penetration of rhodamine B–combined CPNE7 was confirmed under confocal laser scanning microscope. CPNE7 induces formation of tertiary dentin through shallowly exposed dentinal tubules, which decreases dentin permeability.

ObjectiveBone grafts in patients with cleft lip and palate can undergo a significant amount of resorption. The aim of this study was to investigate the effects of bisphosphonates (BPs) on the success of bone grafts in rats.DesignThirty-five female 15-week-old Fischer F344 Inbred rats were divided into the following experimental groups, each receiving bone grafts to repair an intraoral CSD: (1) Graft/saline: systemic administration of saline and (2) systemic administration of zoledronic acid immediately following surgery (graft/BP/T0), (3) 1 week postoperatively (graft/BP/T1), and (4) 3 weeks postoperatively (graft/BP/T2). As an additional control, the defect was left empty without bone graft.Main Outcome MeasuresMicrocomputed tomography and histologic analyses were performed in addition to evaluation of osteoclasts through tartrate-resistant acid phosphatase staining.ResultsBone volume fraction (bone volume/tissue volume) for the delayed BP treatment groups (graft/BP/T1 = 45.4% ± 8.8%; graft/BP/T2 = 46.1% ± 12.4%) were significantly greater than that for the graft/saline group (31.0% ± 7.9%) and the graft/BP/T0 (27.6% ± 5.9%) 6 weeks postoperatively ( P < .05). Hematoxylin and eosin staining confirmed an evident increase in bone volume and fusion of defect margins with existing palatal bone in the graft/BP/T1 and graft/BP/T2 groups. The graft/BP/T0 group showed the lowest bone volume with signs of acute inflammation.ConclusionsDelayed BP administration following cleft bone graft surgery led to significant increase in bone volume and integration compared with saline controls. However, BP injection immediately after the surgery did not enhance bone volume, and rather, may negatively affect bone graft incorporation.

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis ( Pg)–induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides ( Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, β- proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter. After induction of Grhl2 KO, we confirmed the loss of GRHL2 and its target proteins, while Grhl2 KO strongly induced TGF-β signaling molecules. When exposed to 4-nitroquinoline 1-oxide (4-NQO), a strong chemical carcinogen, Grhl2 wild-type (WT) mice developed rampant oral tongue tumors, while Grhl2 KO mice completely abolished tumor development. In cultured oral squamous cell carcinoma (OSCC) cell lines, TGF-β signaling was notably induced by GRHL2 knockdown while being suppressed by GRHL2 overexpression. GRHL2 knockdown or KO in vitro and in vivo, respectively, led to loss of active p-Erk1/2 and p-JNK MAP kinase levels; moreover, ectopic overexpression of GRHL2 strongly induced the MAP kinase activation. Furthermore, the suppressive effect of GRHL2 on TGF-β signaling was diminished in cells exposed to Erk and JNK inhibitors. These data indicate that GRHL2 activates the Erk and JNK MAP kinases, which in turn suppresses the TGF -β signaling. This novel signaling represents an alternative pathway by which GRHL2 regulates carcinogenesis, and is distinct from the direct transcriptional regulation by GRHL2 binding at its target gene promoters, e.g., E-cadherin, hTERT, p63, and miR-200 family genes. Taken together, the current study provides the first genetic evidence to support the role of GRHL2 in carcinogenesis and the underlying novel mechanism that involves the functional interaction between GRHL2 and TGF-β signaling through the MAPK pathways.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Dental pulp is a vital organ of a tooth fully protected by enamel and dentin. When the pulp is exposed due to cariogenic or iatrogenic injuries, it is often capped with biocompatible materials in order to expedite pulpal wound healing. The ultimate goal is to regenerate reparative dentin, a physical barrier that functions as a "biological seal" and protects the underlying pulp tissue. Although this direct pulp-capping procedure has long been used in dentistry, the underlying molecular mechanism of pulpal wound healing and reparative dentin formation is still poorly understood. To induce reparative dentin, pulp capping has been performed experimentally in large animals, but less so in mice, presumably due to their small sizes and the ensuing technical difficulties. Here, we present a detailed, step-by-step method of performing a pulp-capping procedure in mice, including the preparation of a Class-I-like cavity, the placement of pulp-capping materials, and the restoration procedure using dental composite. Our pulp-capping mouse model will be instrumental in investigating the fundamental molecular mechanisms of pulpal wound healing in the context of reparative dentin in vivo by enabling the use of transgenic or knockout mice that are widely available in the research community.

High-risk human papillomaviruses (e.g., HPV-16 and HPV-18) are closely associated with the development of human head and neck squamous cell carcinomas (HNSCC), including malignant lesions in the oral cavity. However, less is known about the possible role and the underlying mechanisms of HPV in enhancing cancer progression and promoting the virulence of cancer, including oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play crucial role in cancer progression, metastasis and recurrence, and are epigenetically regulated by microRNAs (miRNAs). Recent studies demonstrated that miRNA expression is affected by HPV status in HNSCC, suggesting a possible role of HPV in epigenetic regulation of CSCs. In this study, we investigated the role of high-risk HPV on malignant and CSC phenotypes as well as epigenetic regulation in OSCC. Incorporation of HPV-16 whole genome into HPV-negative OSCCs resulted in enhancement of malignant phenotypes (e.g., increased anchorage independent growth, proliferation in organotypic epithelial raft culture, and tumorigenicity in nude mice) and CSC phenotypes (e.g., increased CSC-related markers, self-renewal, and migration/invasion). High-throughput miRNA expression analysis revealed that miRNA-181 family members were significantly underexpressed in the HPV16-harboring OSCCs. HPV-16 downregulated the promoter activity of miR-181a. Furthermore, restoration of miR-181 in the presence of HPV-16 suppressed CSC-like phenotype. Taken together our data indicate that high-risk HPV enhances stemness phenotypes in OSCC by epigenetic regulation of miR-181 expression. Citation Format: Sung Hee Hee Lee, Nicole Rigas, Chang-Ryul Lee, Jiho Han, Reuben Kim, Mo Kang, No-Hee Park, Ki-Hyuk Shin. Human papillomavirus enhances oral cancer stem cell phenotype by regulating microRNA-181. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1948. doi:10.1158/1538-7445.AM2014-1948

In view of the resemblance of exercise-induced plethysmographic changes with those obtained by direct venous pressure measurement, we decided to use a combination of photo-plethysmography (PPG) and hydrostatic pressure calibration to determine the PPG/pressure relationship. A standard foot dorsiflexion exercise involving stepwise position changing was performed which induced hydrostatic pressure changes that were recorded as the heart-probe distance. A logarithmic PPG/pressure relationship was identified and the resulting ambulatory venous pressure (AVP) was obtained from the PPG/pressure curve. Simultaneous direct AVP was recorded in 14 patients scheduled for venous surgery. `Non-invasive AVP only' was determined in 24 normal control subjects with a mean value of 19.24 mmHg (±8.79 SD). In the patient group, the direct AVP values were 40.00 mmHg (±10.83 SD) compared with the PPG values of 33.07 mmHg (±12.94 SD). The resulting correlation was r = 0.8850. By utilizing stepwise leg elevation, a reliable PPG/pressure curve can be established which, in turn, permits AVP determination. It is suggested that this non-invasive AVP determination may serve as a screening test to evaluate non-invasively venous hemodynamics.

Purpose : The purpose of this study was to develop a physiologic method to measure outflow and inflow from the lower extremities and thus to quantify the degree of venous valvular insufficiency and venous obstructive disease. Methods : Calibrated photoplethysmography was used in combination with passive changes in hydrostatic pressure, by leg elevation followed by repositioning of the leg to the original sitting position. With the principle of venous occlusion plethysmography, timed volume changes were then used to calculate the outflow and inflow. The inflow and outflow units were the percentage of optical reflectance (%OR) per minute. The respective resistances were calculated by identifying the hydrostatic pressure distance from the third intercostal space to the probe site that is inducing these site changes. The resistance units were millimeters of Mercury × minutes per %OR. Results : Four groups of subjects were examined: normal individuals, patients with venous valvular insufficiency, deep venous thrombosis, and a combination of both. The most significant differences in outflow values were found between the control group (81.77% OR/min) and the deep venous thrombosis group (28.47% OR/min). In contrast, the most significant differences in inflow values were found between the control group (9.67% OR/min) and the venous valvular insufficiency group (108.61% OR/min). The resistances changed correspondingly. Conclusion : The application of calibrated photoplethysmography in conjunction with induced changes in leg hydrostatic pressure proved to be an effective physiologic method to noninvasively quantify venous hemodynamics in normal control subjects, patients with venous valvular insufficiency, venous obstructive disease, or both. (J Vasc Surg 2000;31:472-6.)

Zoledronic acid (ZA), a third generation of bisphosphonates, is known to have both anti-osteolytic and anti-tumor activities. It exerts anti-osteolytic function by interfering with mevalonate pathway and preventing protein prenylation required for growth and survival in osteoclast cells. Also, similar function has been found to induce cancer apoptosis and inhibit cancer growth in bone-related cancer, but its effect on other cancer types, including head and neck squamous cell carcinoma (HNSCC) is still unclear. In this study, we first monitored the effect of ZA on cancer growth in HNSCC cell lines in vitro. ZA significantly suppressed cancer growth, shown by decreased anchorage independent growth in soft agar assay and diminished cell growth in organotypic raft culture. Because cancer stem cell (CSC; also called tumor-initiating cell) plays a significant role in cancer growth, we further investigated the effect of ZA on CSC in HNSCC. ZA-treated HNSCC cells significantly decreased CSC phenotypes such as sphere forming ability and migratory ability. In SCC4, a tongue squamous cell carcinoma cell line, side population and expression of pluripotency marker genes were significantly decreased by ZA. Also, ZA inhibited the CSC-related Sonic Hedgehog pathway in SCC4 as demonstrated by decreased mRNA expression of transcriptional factor, Gli-1. Taken together, our data suggest that ZA targets CSC and hence inhibits cancer growth in HNSCC. Citation Format: Sung Hee Lee, Reuben Kim, Mo Kang, No-Hee Park, Ki-Hyuk Shin. Zoledronic acid inhibits cancer growth and cancer stem cell phenotypes in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3715. doi:10.1158/1538-7445.AM2013-3715

p63 is a p53 family protein required for morphogenesis and postnatal regeneration of epithelial tissues. Here we demonstrate that ΔNp63α, a p63 isoform lacking N-terminal transactivation domain, induces epithelial-mesenchymal transition (EMT) in primary human keratinocytes in TGF-β-dependent manner. Rapidly proliferating normal human epidermal keratinocytes (NHEK) were infected with retroviral vector expressing ΔNp63α, ΔNp63α, ΔNp63α, or empty vector, and serially subcultured until replicative senescence. No phenotypic changes were observed until the culture reached senescence. Then, cells transduced with ΔNp63α and ΔNp63α demonostrated morphological changes resembling mesenchymal cells, while ΔNp63α did not trigger such change in phenotype. Treatment with exogenous TGF-β accelerated EMT in pre-senescent ΔNp63α-transduced cells, and inhibition of TGF-β signaling reversed the EMT phenotype. Molecular markers of EMT, such as loss of E-Cadherin and cytokeratin 14 expression, were observed in cells expressing ΔNp63α but not those expressing ΔNp63α. TGF-β treatment alone led to growth arrest in control NHEK with no evidence of EMT, indicating that ΔNp63α altered the cellular response to TGF-β treatment. ΔNp63α-transduced cells acquiring EMT gained ability to be differentiated to osteo/odontogenic and adipogenic pathways, resembling mesenchymal stem cells (MSCs). Furthermore, these cells expressed enhanced levels of Nanog and Lin28, which are transcription factors associated with pluripotency. These data indicate that ΔNp63α triggered EMT in TGF-β-dependent manner, while ΔNp63α only caused morphologically changes resembling mesenchymal cells. The current study suggests that mesenchymal transition of normal skin keratinocytes might be a novel approach to generate induced MSCs (iMSCs), which may be useful for regenerative therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3326. doi:1538-7445.AM2012-3326

Although there is an increasing evidence of chronic inflammation-associated tumorigenesis, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis have not yet been fully understood. Recent studies have uncovered and validated the pathophysiological role of self-renewing cells, named cancer stem cells (CSC; also called tumor-initiating cells), in long-term sustenance of cancers. In this study, we investigated the effect of chronic inflammation on CSC phenotype of oral squamous cell carcinoma cells (OSCC). We treated OSCC cell lines with tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, for extended periods and examined the effect of chronic TNFα on CSC characteristics, i.e., undifferentiated tumor sphere forming ability, stem cell-associated genes expression and chemo-radioresistance. Chronic treatment of OSCC with TNFα enhanced CSC phenotype, which is shown by increased tumor sphere forming ability, greatly increased tumorigenicity and chemo-radioresistance, and increased expression of stemness-related genes. Moreover, activation of Notch1 signaling was detected in the TNFα treated cell, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of Hes-1, the downstream target of Notch1, led to suppression of CSC phenotype. Taken together, the data suggest that proinflammatory cytokine exposure can generate or/and enrich OSCC CSC population, in part, by activation of the Notch1 signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3341. doi:1538-7445.AM2012-3341

While acute inflammation is a part of the defense response, there have been emerging lines of evidence that suggest a strong link between chronic inflammation and cancer. Human papillomaviruses (HPV) infection is one of key factors in cervical cancer development, and possible link between HPV and oral carcinogenesis have been proposed. However, mechanisms by which HPV and chronic inflammation contribute to oral carcinogenesis have not been fully understood. The objective of this study was to determine the effect of chronic inflammation on malignant progression of HPV-associated oral carcinogenesis. We treated HPV-immortalized oral keratinocytes (HOK-16B) with a major pro-inflammatory cytokine, TNF-α for 4 months and examined the effect of chronic TNF-α treatment on malignant behavior of HOK-16B. Chronic treatment of TNF-α resulted in reduction in differentiation potential, and induction in proliferation potential and in migration ability of the HPV-immortalized oral keratinocytes. cDNA microarray analysis revealed that a subset of genes was significantly downregulated in long-term TNF-α treated cells, and the genes that were involved in differentiation, tumor suppression, and cell-cell junction functions supported the three increased malignant phenotypes, respectively. Our results indicate that chronic inflammation promotes malignant behavior of HPV-immortalized oral keratinocytes, suggesting that chronic inflammation is an important co-carcinogenic factor for HPV-associated oral carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5542. doi:10.1158/1538-7445.AM2011-5542

MicroRNAs (miRNAs) are novel epigenetic regulators of eukaryotic gene expression and play key roles in many cellular processes. However, the contribution of miRNAs to replicative senescence remains largely unexplored. To understand the role of miRNA in replicative senescence of normal human epithelial cells, we examined the expression profiles of 847 miRNAs in non-senescent (young) and senescent (old) normal human oral keratinocytes (NHOKs). We identified 126 senescence-associated miRNAs (SA-miRs) whose expression was altered greater than 2-fold with senescence. Among SA-miRs, 117 miRNAs (93%) were up-regulated and 9 miRNAs (7%) were down-regulated in senescent NHOKs compared to non-senescent NHOKs. miR-137 and miR-668 were consistently up-regulated with senescence of three independent NHOK cultures and with ionizing irradiation, a premature senescence inducer of NHOKs. Overexpression of miR-137 and miR-668 significantly increased senescence-associated β-galactosidase (SA β-gal) activity and senescence markers, p16INK4A and p53 in non-senescing NHOKs, indicating that they are senescence-inducing miRNAs. Furthermore, we found that these senescence-inducing miRNAs were frequently downregulated in human head and neck squamous cell carcinoma cell lines. Since senescence is considered as a tumor suppressor mechanism, the newly identified senescence-inducing miRNAs need to be considered for therapeutic application for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3205.

It has been reported that nicotine/alcohol alters epigenetic control and leads to abrogated DNA methylation and histone modifications, which could subsequently perturb transcriptional regulation critically important in cellular transformation. The aim of this study is to determine the molecular mechanisms of nicotine/alcohol-induced epigenetic alterations and their mechanistic roles in transcriptional regulation in human adult stem cells. We hypothesized that nicotine/alcohol induces deregulation of epigenetic machinery and leads to epigenetic alterations, which subsequently affect transcriptional regulation in oral epithelial stem cells. As an initiating step we have profiled transcriptomic alterations induced by the combinatory administration of EtOH and nicotine in primary normal human oral keratinocytes. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE57634. Our data provide comprehensive transcriptomic map describing molecular changes induced by EtOH and nicotine on normal human oral keratinocytes.