Virucidal effect of mouthwash on acyclovir-resistant herpes simplex virus.

OBJECTIVES: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains. MATERIALS AND METHODS: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system. RESULTS: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine. CONCLUSION: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients.

IL-10 and TGF-ß1 gene polymorphisms in Greek patients with recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of the oral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly in normal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptive immunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines may predispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-ß1 gene polymorphisms with RAS. MATERIAL AND METHODS: Study's cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patients with minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched control subjects were included in this study. DNA was extracted from whole blood samples of all patients and sequence-specific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms for cytokines IL-10 at loci -592 and -819 and for TGF-ß1 at codon 10 were detected. RESULTS: Significant differences between patients with minor RAS and healthy controls were recorded for IL-10 genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygous TGF-ß1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively). CONCLUSIONS: These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-ß1, which, in turn, may vary according to geographic origin and genetic background.

A randomized clinical trial of topical dexamethasone vs. cyclosporine treatment for oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a common, frequently symptomatic, immune-mediated disease. Various treatments have been used for symptomatic OLP, including corticosteroids and immunosuppressants administered topically or systemically. The aim of this study was to compare the effectiveness of topical dexamethasone vs. topical cyclosporine in treatment of symptomatic OLP. MATERIAL AND METHODS: Thirty-two patients with biopsy-proven symptomatic OLP were randomly assigned to two therapeutic groups: dexamethasone 2mg/5ml or cyclosporine 100mg/ml, both administered topically in a swish and spit method three times a day for 4 weeks. The patients were followed up for a total of 6 months. Assessed parameters included clinical scoring (according to Thongprasom's scale, 0-5), pain (VAS scale, 0-10), dysphagia and speech difficulties (none, mild or severe). Possible side effects, including fungal overgrowth, were also recorded. RESULTS: At the end of the 4-week treatment period, both dexamethasone and cyclosporine showed a statistically significant improvement in clinical scoring (p<0.025 and p=0.034, respectively), which was better with dexamethasone (p=0.001). In addition, both dexamethasone and cyclosporine induced statistical significant improvement in pain and dysphagia (and speech difficulties for dexamethasone), without significant differences between the two groups. Regarding side effects, patients in the dexamethasone group developed candidiasis more frequently compared to cyclosporine (p=0.031). At the end of the 6-month follow-up period, the difference in response between the two groups was not statistically significant. Interestingly, a trend for further improvement compared with the end of the 4-week treatment period was noticed only for patients treated with cyclosporine. CONCLUSIONS: Despite the small number of enrolled patients, topical cyclosporine treatment induces a significant clinical improvement in symptomatic OLP patients, which, compared to topical dexamethasone, appears to be less pronounced during initial administration, but capable to induce further improvement after discontinuation with a satisfactory long-term remission in the absence of significant side effects. This study may contribute to a better understanding of the differences in effectiveness of OLP topical treatments and guide future larger scale clinical trials.

Tumors of the labial mucosa: a retrospective study of 1045 biopsies.

BACKGROUND: To investigate the relative frequency of localized mucosal swellings of the upper and lower labial mucosa, the clinical-pathological diagnosis agreement and whether patient's age and gender and tumor's site and size may raise the suspicion of neoplasm. MATERIAL AND METHODS: Retrospective analysis was performed on upper or lower labial mucosal tumors, histopathologically diagnosed between 2009-2018. The diagnostic categories developmental/reactive tumors, benign and malignant neoplasms were associated with patient's age and gender and tumor's site and size; clinical-pathological diagnosis agreement was, also, evaluated. RESULTS: Overall, 1000 (95.7%) developmental/reactive tumors, 35 (3.3%) benign and 10 (1%) malignant neoplasms were found. Upper/lower lip tumor ratio was 0.14:1. The diagnostic category was significantly associated with age (p<0.0001), site (p<0.0001) and diameter (p<0.0001). Age ≥60 years, tumor's location on the upper lip and diameter >1cm were independent predictors for neoplasms. Patients presenting 2 or 3 of these variables were 20.2 times (p < 0.0001) or 33.6 times (p < 0.0001), respectively, more likely to have a neoplasm. Complete/partial agreement between clinical and pathological diagnosis was seen in 96.3% of the cases. CONCLUSIONS: Most lip tumors involve the lower lip and are reactive, but upper lip tumors measuring >1cm in patients≥60 years have significantly higher probability to be neoplasms.

p38 Expression and Modulation of STAT3 Signaling in Oral Cancer.

p38 protein belongs to Mitogen-activated protein kinases family that link extracellular stimuli with intracellular responses participating in numerous of fundamental cell processes. Persistent activation of STAT3 has been associated with cell proliferation, differentiation and apoptosis in oral squamous cell carcinoma (OSCC). This study examines the effects of p38 modulation on STAT3 signaling and cellular activities in OSCC cells and investigates possible correlation of p38 expression with tumor degree of differentiation. Phospho-p38 immunostaining was performed in 60 OSCC including well, moderately and poorly differentiated tumors. Semiquantitative analysis was used, by calculating intensity, percentage and combined scores. Protein expression levels of STAT3 (total, tyrosine and serine phosphorylated), p38 and cyclin D1 were assessed in two OSCC cell lines. p38 inhibition was achieved by pharmacological agent(SB2023580). Cell proliferation and viability rates were also evaluated. Phospho-p38 immunoexpression was intense in almost all tumor specimens, nevertheless did not correlate with tumor differentiation. Inhibition of p38 with SB203580 did not appear to affect tyrosine or serine phosphorylated STAT3 as well as cyclin D1 levels in both cell lines. Moreover, p38 inhibition resulted in mild dose-dependent decreases in cell growth and viability in both cell lines. p38 is highly expressed in OSCC but does not seem to mediate the oncogenic STAT3 pathway. However, changes found in proliferation and viability may suggest that p38 functions as potent regulator of HNSCC. Understanding the complexity of p38 signaling and cross-talk between other major molecules, may guide the development of novel pharmacologic therapies for cancer treatment and prevention.

Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

Osteonecrosis of the jaws (ONJ) is a rare but severe complication of antiresorptive medications, such as bisphosphonates, used in the treatment of bone malignancy or osteoporosis. Tooth extraction and dental disease have been strongly associated with ONJ development. Here, we investigated molecular and cellular markers of socket healing after extraction of healthy or teeth with experimental periodontitis (EP) in Wistar-Han rats treated with zoledronic acid (ZA). We included 4 experimental groups: vehicle-treated animals with extraction of healthy teeth or teeth with ligature-induced EP and ZA-treated animals with extraction of healthy teeth or teeth with EP. Animals were pretreated with vehicle or ZA for a week, and EP was induced. Four weeks later, the second maxillary molars were extracted; sockets were allowed to heal for 4 wk; animals were euthanized; and maxillae were isolated. Radiographically, extraction sockets in groups 1, 2, and 3 demonstrated normal healing. Contrary incomplete socket healing was noted after extraction of teeth with EP in ZA-treated rats of group 4. Histologically, persistent inflammation and extensive osteonecrosis were seen in group 4. Disorganization of the collagen network, collagen type III predominance, and lack of collagen fiber insertion in the necrotic bone were associated with impaired socket healing. Cells positive for MMP-9, MMP-13, and α-SMA expression were present at the areas of epithelial invagination and adjacent to osteonecrotic bone. Importantly, human biopsies from patients with ONJ showed similar findings. Our data emphasize the importance of dental disease and tooth extraction in ONJ pathogenesis and help delineate an altered profile in wound-healing markers during ONJ development.

Epidural abscess imitating recurrent pilonidal sinus: a case report.

Pilonidal sinus or pilonidal cyst is a common benign disease, affecting mostly young working men. We present the first case of an epidural abscess imitating pilonidal sinus. A 33-year old male, suffering from previously undiagnosed and untreated diabetes mellitus (DM), presented to our emergency department (ER), one month after open surgical treatment of pilonidal sinus, due to weakness and fever. After re-operation of the pilonidal cyst and due to post-operative pus production and continuation of fever a computer tomogr aphy (CT )scan was performed revealing an epidural abscess extending from the thoracic vertebrae 12 (T-12) to the sacrococcygeal area. At that point he underwent new surgery for drainage of the epidural abscess. The patient received intravenous antimicrobial treatment and was discharged on the 23rd postoperative day without signs or symptoms of infection. At follow up for a whole year no signs of recurrence have been observed.

Spontaneous splenic artery aneurysm rupture in a 38-year old female: a case report.

Splenic artery aneurysm (SAA) is a rare and extremely difficult diagnosis. A rare case of a ruptured SAA in a 38-year old female, firstly treated with endovascular embolization and then with splenectomy, is presented. A 38-year old female presented to the emergency department with epigastric pain and fainting episodes. Direct catheter angiography revealed a ruptured SAA and distal, as well as proximal coil embolization was performed. Due to abdominal compartment syndrome the patient underwent open surgery with splenic artery ligation and splenectomy. Postoperative she showed signs of sepsis and was treated with i.v. fluids, steroids, packed red blood cells, platelets, fresh frozen plasma and antimicrobial treatment. Additionally, a multidrug resistant Acinetobacter baumanni was yielded from the urine culture. She had a satisfactory recovery. She is followed up a total of 5 years with no signs of overwhelming post-splenectomy infection syndrome. Direct catheter angiography is a very helpful option in diagnosis, as well as treatment, but a close monitoring after embolization is essential. Furthermore, post-splenectomy sepsis is a severe disease with high mortality rates that requires immediate appropriate treatment.

ERK1/2, JNK and STAT3 activation and correlation with tumor differentiation in oral SCC.

Signal transducer and activator of transcription 3 (STAT3) and mitogen activated protein kinases (MAPKs), including ERK and JNK, have been implicated in oral squamous cell carcinoma (OSCC) development and progression. Our purpose was to evaluate the levels of activated STAT3, ERK1/2 and JNK by immunohistochemistry in OSCC and to investigate possible correlations of these molecules with each other as well as with the degree of tumor differentiation. Immunohistochemical assessment of the phosphorylated levels of STAT3(tyrosine/ serine), ERK1/2 and JNK was performed in 60 OSCC, including well, moderately and poorly differentiated tumors. Semiquantitative scoring system was used, by calculating intensity of immunostaining, percentage of positive cells and combined scores. Statistics included Fisher's test, Student's T-Test and Kruskal-Wallis analysis, Spearman's correlation coefficient and multivariate logistic regression analyses. Immunohistochemical levels of both pSTAT3(tyr) and pERK1/2 showed statistically significant differences between well and poorly differentiated tumors with the latter receiving higher mean percentage, intensity and total scores. On the other hand, pJNK showed statistically significantly higher intensity levels in moderately compared to poorly differentiated tumors. pSTAT3(ser) immunoexpression did not appear to correlate with tumor differentiation. Between different molecules, more pronounced, pERK1/2 levels exhibited statistically significant positive correlation with pSTAT3(ser), pSTAT3(tyr) and pJNK expression. ERK1/2 and STAT3 activation (as assessed by tyrosine but not serine phosphorylation) could contribute to a less differentiated phenotype in OSCC, while JNK activation may have an opposite, although possibly less pronounced, effect. Positive correlations between MAPK and STAT3 levels may indicate a direct crosstalk and/or regulation by common upstream pathways.

The autoimmunity-oral microbiome connection.

To date, there is a major effort in deciphering the role of complex microbial communities, especially the oral and gut microbiomes, in the pathogenesis of various diseases. Increasing evidence indicates a key role for the oral microbiome in autoimmune diseases. In this review article, we discuss links of the oral microbiota to a group of autoimmune diseases, that is, Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), Crohn's disease (CD), and rheumatoid arthritis (RA). We particularly focus on factors that affect the balance between the immune system and the composition of microbiota leading to dysbiosis, loss of tolerance and subsequent autoimmune disease progression and maintenance.

Immunohistochemical evaluation of the mTOR pathway in intra-oral minor salivary gland neoplasms.

OBJECTIVES: The aim of this study was to investigate the expression of upstream and downstream molecules of the oncogenic mTOR signaling pathway in intra-oral minor salivary gland tumors (SGTs). MATERIALS AND METHODS: Tissue samples consisted of 39 malignant and 13 benign minor SGTs, and 8 controls of normal minor salivary glands (NMSG). An immunohistochemical analysis for phosphorylated Akt, 4EBP1 and S6 (total and phosphorylated), and eIF4E was performed. RESULTS: Expression of pAkt and 4EBP1 was observed in all SGTs and in most NMSG. p4EBP1 was detected in almost all SGT cases, NMSG being negative. S6 immunoreactivity was observed in 37.5% of NMSG, 92.3% of benign and 100% of malignant SGTs, while pS6 expression was observed in 77% of benign and 95% of malignant SGTs, but not in NMSG. Finally, eIF4E was expressed in 12.5% of NMSG, 69.2% of benign, and 76.9% of malignant tumors. All molecules studied had statistically significantly lower expression in NMSG compared with SGTs. Moreover, malignant neoplasms received higher scores compared with benign tumors for all molecules with the exception of eIF4E. CONCLUSION: The mTOR signaling pathway is activated in SGTs, especially in malignancies. Therefore, the possible therapeutic role of targeting the mTOR pathway by rapamycin analogs in SGTs needs further investigation.

Orofacial granulomatosis as early manifestation of Crohn's disease: report of a case in a paediatric patient.

BACKGROUND: Orofacial granulomatosis (OFG) is a controversial entity mainly characterised by recurrent or permanent soft tissue swelling of sudden onset in the orofacial area with a histologic appearance of granulomatous inflammation. Differential diagnosis includes local diseases and systemic conditions, such as Crohn's disease (CD). A case of OFG in a paediatric patient is reported here, focusing on the clinical features, diagnostic procedures, treatment and long-term outcome. CASE REPORT: A 7 year-old boy presented with persistent and prominent lip swelling and painful oral mucosa lesions of six months duration. A biopsy of the lower labial mucosa revealed granulomatous inflammation consistent with OFG. The oral manifestations were managed with topical and intralesional corticosteroids. His medical history included gastrointestinal disturbances, perianal skin folds and bloody stools that raised the suspicion of CD. Colonoscopy showed inflammation without clear evidence of CD. One year later, repeated bowel investigation provided evidence suggestive of CD and the patient was placed under systemic treatment. Two years after the initial diagnosis the patient is free of oral or other pathological findings. CONCLUSION: The differential diagnosis in cases of orofacial swellings with histological granulomatous inflammation includes a variety of local and systemic diseases, diagnosis and management of which require full investigation and cooperation by a team of healthcare providers.

The role of mTOR signaling pathway in premalignant and malignant cervical lesions.

PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium. MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6. RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated. CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.

How can we treat a patient with liver cirrhosis (hepatitis C virus), hepatocellular carcinoma, and synchronous colon cancer?

INTRODUCTION: The coexistence of liver cirrhosis with hepatocellular carcinoma (HCC) and colon cancer (Ca), which is a rare clinical condition, was treated in a liver transplant recipient. PATIENTS AND METHODS: A 46-year-old man, diagnosed incidentally during an ultrasound (US) examination with a 3.5-cm HCC in segment VII related to chronic hepatitis C virus (HCV), was referred for liver resection. He underwent a laparoscopic protocol evaluation for liver cirrhosis. Liver appearance and biopsy of the left lobe showed Child B/C liver cirrhosis. Because he fulfilled the Milan criteria, we suggested an orthotopic liver transplantation (OLT). During protocol colonoscopy, we discovered an ulcerative sigmoid colon Ca. Three weeks after completing the pre-OLT assessment he underwent an OLT and was discharged home on day 9 on an immunosuppressive regimen of Everolimus, Myfortic, and Prezolone. Two months after transplantation, the patient underwent a sigmoidectomy and for nearly 1 month thereafter received chemotherapy for colon Ca (6 cycles of FOLFOX:Folinic Acid+Fluorouracil+Oxaliplatin). One and a half years after OLT, patient was in good condition but presented with an increased alpha fetoprotein (a-FP) without other findings. A couple of months later we discovered a colon Ca recurrence and 3 small liver metastases. Patient underwent a bowel resection with Hartmann's procedure. Almost immediately after the last operation, he was found to suffer multiple myeloma. He underwent chemotherapy for both malignancies with good responses, but a few months later died of severe sepsis. DISCUSSION: The relevant literature regarding treatment of liver cirrhosis complicated with HCC and synchronous colon Ca reveals poor and controversial outcomes. Our patient underwent chemotherapy immediately after colon resection in the presence of with a good functioning liver. Although his condition was satisfactory after OLT, the optimal treatment of such complicated patients is as yet uncertain.

Expression and alterations of the PTEN / AKT / mTOR pathway in ameloblastomas.

OBJECTIVES: Recently, an allelic loss of phosphatase and tensin homologue (PTEN) was shown to occur in ameloblastomas. In carcinogenesis, loss of PTEN allows for overactivity of the phosphatidylinositol-3-kinase/protein kinase B (PI3K / AKT) pathway inducing an upregulation of mammalian-target of rapamycin (mTOR) and its downstream effector ribosomal-subunit-6 kinase (S6K); allowing for uncontrolled cell proliferation, apoptosis inhibition and cell cycle deregulation. METHODS: Thirty ameloblastomas and five dental follicles were studied, looking at the immunohistochemical expression of total PTEN and AKT, as well as their phosphorylated (p) active forms, and the downstream effector and indicator of mTOR activity p70 ribosomal-subunit-6 kinase (pS6K). Also assessed was the expression of extracellular-signal-regulated kinase (ERK), which cross talks with AKT. RESULTS: Total PTEN was absent in 33.3% of ameloblastomas, while its stabilized, phosphorylated(ser380 / thr382 / thr383) form was absent in 83.3% of tumors. In contrast, AKT was expressed in 83.3% of ameloblastomas, showing high expression of the p-thr(308)AKT and p-ser(473) AKT forms in 93.3% and 56.6% of cases, respectively. Further, the mTOR activated pS6K(ser240 / 244) was detected in 86.7% of ameloblastomas, while ERK was overexpressed in 70.0% of the cases. CONCLUSION: Immunohistochemical analysis of aberrant signaling in the PI3K/AKT/mTOR pathway in ameloblastomas may represent a valuable tool for elucidating pathogenesis, aggressiveness and selecting optimal therapeutics.

Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer.

Sulindac exerts its antitumorigenic effects in oral squamous cell carcinoma (SCC) cells by modulating survivin in a Stat3-dependent manner. Immunohistochemistry was used to detect the protein levels of phosphorylated-tyrosine Stat3 (p-tyr Stat3) and survivin in SCC tissues. Western blot, reverse transcriptase polymerase chain reaction, Annexin-V and cell proliferation assays were used to determine p-tyr Stat3 and survivin protein and mRNA expression, and cell viability following treatment with cyclooxygenase (COX) inhibitors, Stat3 siRNA, or the forced expression of Stat3 or survivin. Immunohistochemical analysis revealed an overexpression of p-tyr Stat3 in T1 SCCs. The importance of constitutive Stat3 activation in tumourigenesis was confirmed by siRNA inhibition of Stat3, resulting in cell growth inhibition and apoptosis, via a downregulation of survivin mRNA and protein expression. The forced expression of survivin partially reversed these effects of Stat3 inhibition. Sulindac, but not other COX inhibitors, downregulated Stat3, which correlated to an inhibition of cell proliferation, survival and survivin expression. Transfection of constitutively active Stat3 restored survivin expression and partially rescued SCC cells from sulindac-induced antitumorigenic effects. These data indicate that survivin is a downstream target and effector of oncogenic Stat3 signalling in SCC, which is targeted by sulindac in a COX-2-independent manner.

Targeting the STAT pathway in head and neck cancer: recent advances and future prospects.

Head and neck cancer, the sixth most common type of cancer worldwide, is associated with a dismal prognosis that has minimally improved during the last few decades. Future advances in the treatment and prognosis of this fatal disease largely rely upon a better understanding of the molecular events that underlie tumor development and progression, allowing specific targeting of the involved molecules and pathways. In this context, recent efforts have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins comprise a family of latent cytoplasmic transcription factors that become transiently activated in response to extracellular signals, leading to regulation of diverse physiological responses. There is compelling evidence that persistent activation of specific STAT molecules, especially Stat3 and Stat5, possesses oncogenic properties in a number of human cancers, including head and neck cancer. The presence of constitutively activated STAT molecules in cancer cells is mainly attributed to the dysregulation of upstream activating pathways and the aberration of negative regulatory mechanisms. The end result is induction of specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion. Therefore, targeting and disruption of oncogenic STAT signaling may theoretically be accomplished through various approaches, involving direct (e.g. interference with the various facets of STAT expression, activation or function) and indirect strategies (e.g. inhibition of upstream signaling events and enhancement or restoration of negative regulatory mechanisms). The availability of multiple potential targets for interruption of aberrant STAT signaling in cancer and the thus-far promising results have generated optimism for the clinical applicability of STAT targeting in head and neck cancer, which is the focus of this review.

Signal transducers and activators of transcription: insights into the molecular basis of oral cancer.

Recent efforts on developing more direct and effective targets for cancer therapy have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins are latent cytoplasmic transcription factors that become activated in response to extracellular signaling proteins. STAT proteins have been convincingly reported to possess oncogenic properties in a plethora of human cancers, including oral and oropharyngeal cancer. Signal transduction pathways mediated by these oncogenic transcription factors and their regulation in oral cancer are the focus of this review.

Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ(2) in oral squamous carcinoma cells.

Cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exerts antineoplastic effects on various types of human cancer. We recently showed that treatment with 15d-PGJ(2) induces apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signalling in human oral squamous cell carcinoma (SCC) cells. The current study examines the effects of 15d-PGJ(2) on the epidermal growth factor receptor (EGFR) and Janus Kinase (JAK)-mediated signalling pathways. Inhibition of Stat3 by 15d-PGJ(2) was abolished by exogenous stimulation with transforming growth factor alpha (TGF-alpha), but not interleukin 6 (IL-6), supporting a selective effect of 15d-PGJ(2) on IL-6-mediated signalling. Importantly, 15d-PGJ(2) selectively abrogated constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR-activated levels. Moreover, the inhibitory effect of 15d-PGJ(2) on JAK signalling required the reactive alpha,beta-unsaturated carbon within the cyclopentenone ring. Targeting of JAK signalling using a specific JAK inhibitor also abolished Stat3 phosphorylation and resulted in apoptosis in oral SCC cells. Our findings provide the first evidence for 15d-PGJ(2)-mediated downregulation of constitutive and IL-6-induced JAK signalling in cancer and support that JAK inhibition and suppression of EGFR-independent Stat3 activation by 15d-PGJ(2) represent a promising approach for induction of apoptosis in oral SCC cells.