Kyubo Kim

Expression of hepatocyte growth factor and c-Met in hypopharyngeal squamous cell carcinoma

Conclusion. Our results suggest that hepatocyte growth factor (HGF) may play an important role in the progression of hypopharyngeal cancer. Objective. HGF, a potent stimulator of hepatocyte growth, stimulates the motility, invasiveness, proliferation and morphogenesis of epithelium and may be involved in physiologic and pathologic processes such as embryogenesis, wound healing, organ regeneration, inflammation and tumor invasion. We therefore examined the role of HGF and c-Met in the invasion and metastasis of hypopharyngeal squamous cell carcinoma (SCC). Material and methods. We performed immunohistochemical staining of 40 specimens each of normal mucosa and SCC of the hypopharynx with HGF and c-Met antibodies. For reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting, fresh normal and cancer tissue from the hypopharynx obtained from five patients were used. Results. Positive rates of HGF and c-Met expression in hypopharyngeal SCC were 77.5% and 70%, respectively. HGF staining was significantly correlated with lymph node metastasis and pathologic stage (p < 0.05). c-Met staining was only significantly correlated with lymph node metastasis (p < 0.05). Increased expression of c-Met mRNA (RT-PCR) and protein (Western blotting) was detected in hypopharyngeal cancer tissue.

Impact of pretreatment thrombocytosis on blood-borne metastasis and prognosis of gastric cancer

BACKGROUND Thrombocytosis has been associated with malignancies and poor prognostic implications in cancer patients. In the present study the prognostic significance of pretreatment platelet (PLT) level was assessed with regard to recurrence and survival in patients with primary gastric adenocarcinoma. METHODS The authors reviewed the prospective data of 1593 gastric cancer patients who received curative gastrectomy with extended lymphadenectomy. The correlations of PLT level with recurrence and overall survival were evaluated by both univariate and multivariate analyses. RESULTS Thrombocytosis (≥ 40 × 10(4)/ μL), present in 6.4% of the patients prior to curative surgery, was more frequently associated with advanced T and N classification, larger tumor size, anemia, and leukocytosis (p < 0.05). In patients with pretreatment thrombocytosis compared to those without it, five-year survival rate was worse (56.9% vs. 65.5%; p = 0.043), and recurrence rate was higher mainly due to the frequent hematogenous spread (51.0% vs. 34.5%; p < 0.001). Furthermore, risk of blood-borne metastasis was almost three-fold higher in patients with pretreatment thrombocytosis (Odds ratio 2.83 [95% CI 1.67-4.77], p < 0.001). CONCLUSIONS Pretreatment thrombocytosis correlated significantly with poor prognosis and can be used as an independent predictor of recurrence by blood-borne metastasis in gastric cancer.

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

ABSTRACT Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces “mitochondrial priming” by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

Regulator of G-Protein Signaling 4 Suppresses LPS-Induced MUC5AC Overproduction in the Airway

Mucus overproduction and airway obstruction are common features in airway mucosal inflammation. The mechanism by which LPS induces MUC5AC overexpression, however, has not been fully explored. The aims of this study were twofold: first, to examine the ATP-dependent mechanism by which LPS induces MUC5AC gene expression, and second, to identify specific molecules that could suppress LPS-induced MUC5AC expression at a G-protein-coupled receptor level. Here, we suggest that LPS from Pseudomonas aeruginosa induces MUC5AC overproduction by both an ATP-dependent pathway and an ATP-independent pathway. In addition, we showed that Regulator of G-protein signaling (RGS) 4 plays as a suppressor for ATP-induced MUC5AC expression by interacting with G alpha q in a GTP-dependent manner in vivo. These results give additional insights into the molecular mechanism of negative regulation of mucin overproduction and enhance our understanding of mucus hypersecretion during airway mucosal inflammation.

cAMP-responding Element-binding Protein and c-Ets1 Interact in the Regulation of ATP-dependent MUC5AC Gene Expression

Exogenous ATP activates purinoreceptors on the cell surface that regulate diverse cellular functions, including mucous cell secretion in the respiratory epithelium. In this study, ATP increased MUC5AC mRNA in primary human nasal epithelial cells and in NCI-H292 pulmonary adenocarcinoma cells in vitro. ATP-induced MUC5AC mRNA was mediated by phospholipase Cβ3. A dominant-negative mutation in the PDZ binding domain of PLCβ3 inhibited ATP-induced MUC5AC gene expression. ATP sequentially activated the phosphorylation of Akt, ERK1/2, p38, RSK1, and cAMP-responding element-binding protein (CREB) in a protein kinase C-independent manner. ATP-induced MUC5AC mRNA levels were regulated by CREB via direct interaction with c-Ets1 on the MUC5AC gene promoter (located –938 to –930). Effects of CREB and c-Ets1 were additive. Inhibition of either CREB or c-Ets1 inhibited ATP-induced MUC5AC gene expression. Stimulation with ATP caused the direct binding of CREB and c-Ets1 to the MUC5AC promoter, increasing the phosphorylation of c-Ets1. Chromatin immunoprecipitation assays demonstrated that in the presence of ATP, both c-Ets1 and CREB bound to the MUC5AC promoter. The effects of exogenous ATP on MUC5AC gene expression are mediated by a complex regulatory cascade controlling interactions between CREB and c-Ets1 that bind to a promoter element in the MUC5AC gene enhancing MUC5AC gene transcription. ATP-dependent activation of MUC5AC gene expression via CREB-c-Ets1 may contribute to mucous cell hypersecretion associated with common respiratory disorders.

Early development of the nose in human embryos: a stereomicroscopic and histologic analysis.

Objectives/Hypothesis: To analyze the morphologic features of the nose in the human embryo from the 4th to 8th developmental week according to Carnegie stage.

Paranasal sinus mucoceles with ophthalmologic manifestations: a 17-year review of 96 cases.

Background The purpose of this study was to assess the characteristics of paranasal sinus mucoceles with ophthalmologic manifestations with a focus on optic neuropathy. Methods From January 1993 to May 2010, 96 consecutive patients diagnosed with paranasal sinus mucoceles with ophthalmologic manifestations were investigated. Clinical and therapeutic factors and demographics were reviewed from medical records. Statistical associations between clinical and therapeutic factors and visual outcomes after surgery were also analyzed. Results A total of 352 patients were diagnosed with paranasal sinus mucoceles and underwent surgical treatment. Ninety-six of them presented with ophthalmologic symptoms, and periorbital swelling and pain were the most common symptoms (36.4%) in those patients. Among the 96 patients with ophthalmologic manifestations, 18 (18.8%) were diagnosed with optic neuropathy based on the deterioration of their visual acuity and unilateral relative afferent papillary defect. Ten of these 18 patients showed improvements in their vision after surgical intervention. The statistical analysis of the association between clinical and therapeutic factors and visual outcomes showed that the presence of infection was the only significant factor (p = 0.023). Conclusion Paranasal sinus mucoceles present various ophthalmologic manifestations. Among them, optic neuropathy may be one of the most devastating conditions. In treating optic neuropathy caused by mucoceles, the presence of infection was the only factor that had any influence on postoperative visual outcomes. Therefore, we conclude that not only surgical drainage and ventilation of the sinus are necessary, but infection control is also a vital factor in treating mucoceles with optic neuropathy.

Interaction of SOCS3 with NonO attenuates IL-1β-dependent MUC8 gene expression

The intracellular negatively regulatory mechanism which affects IL-1beta-induced MUC8 gene expression remains unclear. We found that SOCS3 overexpression suppressed IL-1beta-induced MUC8 gene expression in NCI-H292 cells, whereas silencing of SOCS3 restored IL-1beta-induced MUC8 gene expression. Sequentially activated ERK1/2, RSK1, and CREB by IL-1beta were not affected by SOCS3, indicating that SOCS3 has an independent mechanism of action. Using immunoprecipitaion and nano LC mass analysis, we found that SOCS3 bound NonO (non-POU-domain containing, octamer-binding domain protein) in the absence of IL-1beta, whereas IL-1beta treatment dissociated the direct binding of SOCS3 and NonO. A dominant-negative SOCS3 mutant (Y204F/Y221F) did not bind to NonO. Interestingly, SOCS3 overexpression dramatically suppressed MUC8 gene expression in cells transfected with wild-type or siRNA of NonO. Moreover, silencing of SOCS3 dramatically increased NonO-mediated MUC8 gene expression caused by IL-1beta compared to NonO overexpression alone, suggesting that SOCS3 acts as a suppressor by regulating the action of NonO.

Expression and regulation of PLUNC in human nasal epithelium

Conclusions. We demonstrated that PLUNC (palate, lung, and nasal epithelium clone) is secreted from nasal epithelial cells and is not influenced by differentiation or proinflammatory mediators. The functional role of PLUNC in the human airway has yet to be elucidated. Objectives. The localization and regulation of PLUNC protein in human nasal epithelium was investigated. First, we located epithelial cells expressing PLUNC protein in human nasal mucosa. Secondly, we sought to identify PLUNC protein in either human nasal secretions from healthy volunteers or apical secretions from cultured human nasal epithelial cells. Lastly, we investigated whether epithelial differentiation and proinflammatory cytokines influence the expression of PLUNC in human nasal epithelial cells. Materials and methods. Immunohistochemical staining for PLUNC was conducted on nasal turbinate specimens. Western blot analysis was conducted on nasal secretions from healthy volunteers, apical secretion from cultured human nasal epithelium, and on normal-appearing posterior ethmoid mucosa, inferior turbinate, and nasal polyp specimens. Reverse transcription-PCR (RT-PCR) of PLUNC was performed with mRNA from cultured human nasal epithelium cells treated with either interleukin-1β or tumor necrosis factor-α. Results. PLUNC was expressed in ciliated cells of surface epithelium and serous cells of the submucosal gland in the human nasal mucosa, and was also found in the nasal secretions of healthy volunteers and apical secretions of cultured human nasal epithelial cells. The degree of mucociliary differentiation and proinflammatory mediators did not influence the expression of PLUNC gene and protein in nasal epithelium.

Sinonasal carcinoma associated with inverted papilloma: a report of 16 cases

OBJECTIVES To analyse the characteristics and outcome of patients with carcinoma associated with inverted papilloma, and find predictors of associated malignancy. METHODS The medical records of 228 patients who were diagnosed with IP between January 1990 and December 2010 were retrospectively reviewed. Out of 228 patients, 16 were also diagnosed with carcinoma. We evaluated their clinical characteristics, treatment modalities, and survival outcomes. RESULTS The incidence of carcinoma associated with IP was 7.0%. Fourteen were synchronous carcinomas and two were metachronous. Tumours arising inside the frontal sinus or the frontoethmoidal recess were more likely to be associated with carcinoma. Patients who had a stage of T2 or less had a much better outcome than those who had a stage of T3 or greater (disease-free period, 84.8 months vs. 5.7 months, p<0.001). CONCLUSION Tumours originating in the frontal sinus or frontoethmoidal recess have a tendency to be associated with carcinoma. As most (87.5%) of the carcinomas were diagnosed at the same time as the inverted papilloma, complete histological examination of the whole excised tumour is warranted because early diagnosis and treatment is essential as T2 and lower stage carcinomas had a strikingly better prognosis than T3 and higher stage carcinomas.