Cheng-Ming Hsu

Altered expression of SIRT gene family in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) include a group of malignant neoplasms that arise from the upper aerodigestive tract and represent the seventh most common cause of cancer-related death. The overall 5-year survival rates have not significantly improved for decades in spite of the advances in the field of oncology and surgery, encouraging further research on factors that might modify disease prognosis. The silent information regulator (SIR) genes (Sirtuins) play key roles in cellular stress and are associated with aging-related diseases including cancer. Currently, seven human sirtuin (SIRT1–7) genes have been identified, but the roles of SIRT genes in HNSCC are still uncertain. Therefore, in this study, we used real-time quantitative reverse transcription-polymerase chain reaction to investigate the expressions of the seven SIRT genes in human HNSCC tissues to assess the changes in cancerous and noncancerous parts and the correlation with different tumor behaviors. Our results demonstrated that the expression levels of SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly downregulated in cancerous tissues compared with noncancerous tissues (all p < 0.01). The expression levels of SIRT1, SIRT2, SIRT3, SIRT5, and SIRT7 showed downregulation in advanced stages in respect to early stages (p < 0.05). These results indicate that the downregulation of SIRT genes expression may contribute to the development of cancer and trigger the neoplastic disease to more advanced stages. Our study indicates that SIRT genes expression could help in the diagnosis and represent a prognostic biomarker in HNSCC.

Circulating miRNA is a novel marker for head and neck squamous cell carcinoma

The aim of the study is to investigate the alteration of plasma miRNA in head and neck squamous cell carcinoma (HNSCC). Altered microRNAs (miRNAs) expression has been found in many cancers, including lung cancer, breast cancer, prostate cancer, bladder cancer and colorectal cancer. Many recent studies have demonstrated that aberrant plasma miRNAs were also found in various types of cancers. However the alteration of plasma expression in HNSCC remains unclear. In this present study, the expression profiles of ten miRNAs, let-7a, miR-21, miR26b, miR-34c, miR-99a, miR-133a, miR-137, miR-184, miR-194a, and miR-375, in plasma from 50 patients and 36 healthy subjects were evaluated using real-time quantitative polymerase chain reaction (PCR). Our results demonstrated that the expression level of miR-21 was significantly up-regulated in plasma samples obtained from HNSCC patients (p < 0.01) than those from healthy subjects, which were in consistent with our finding in HNSCC tissues. A 7.7-fold increase of miR-21 in cancerous parts when compared to their non-cancerous counterparts (p < 0.0001) was observed in HNSCC tissues. In addition, the expression levels of miR-21 and miR-26b were both reduced in post-operative HNSCC patients with good prognosis. In contrast, the concentration of plasma miR-21 and miR-26b stayed high after tumor removal in the expired cases. Our study suggests that detecting circulating miR-21 and miR-26b pre- and post-operatively might provide a novel tumor marker for HNSCC.

Altered expression of circadian clock genes in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) means a group of cancers developed from the upper aerodigestive tract, and 90% of them are squamous cell carcinomas. HNSCC is the tenth most commonly diagnosed form of cancer in males worldwide, but it is the seventh most common cause of cancer-related death. The circadian clock regulates daily rhythmic variations in various physiologic processes including sleep and activity, appetite, hormone levels, metabolism, and gene expression. Many recent studies have demonstrated that the disruption of circadian rhythm is associated with cancer development and tumor progression, such as chronic myeloid leukemia, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However the direct links between aberrant circadian clock gene expression and human malignancies, including HNSCC, remain largely unknown. In this study, the expression profiles of nine circadian clock genes of cancer tissue and noncancerous part from 40 patients of HNSCC were investigated. The expression of PER1, PER2, PER3, CRY1, CRY2, CKIε, and BMAL1 showed significant downregulation in the cancer tissues (p < 0.005). Downregulated PER3, CRY2, and BMAL1 expression was correlated with more advanced cancer stages (p < 0.05). Downregulated PER3 and upregulated TIM expression correlated with larger tumor size (p < 0.05), and lower expression of PER3 correlated with deeper tumor invasion (p < 0.05). Poor survival was related to lower expression of PER1 (p < 0.05) and PER3 (p < 0.01). These results indicate a possible association of circadian clock gene, especially PER3, expression with the pathogenesis of HNSCC.

Deregulated expression of circadian clock genes in gastric cancer

BackgroundGastric cancer (GC), an aggressive malignant tumor of the alimentary tract, is a leading cause of cancer-related death. Circadian rhythm exhibits a 24-hour variation in physiological processes and behavior, such as hormone levels, metabolism, gene expression, sleep and wakefulness, and appetite. Disruption of circadian rhythm has been associated with various cancers, including chronic myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However, the expression of circadian clock genes in GC remains unexplored.MethodsIn this study, the expression profiles of eight circadian clock genes (PER1, PER2, PER3, CRY1, CRY2, CKIϵ, CLOCK, and BMAL1) of cancerous and noncancerous tissues from 29 GC patients were investigated using real-time quantitative reverse-transcriptase polymerase chain reaction and validated through immunohistochemical analysis.ResultsWe found that PER2 was significantly up-regulated in cancer tissues (p < 0.005). Up-regulated CRY1 expression was significantly correlated with more advanced stages (stage III and IV) (p < 0.05).ConclusionsOur results suggest deregulated expressions of circadian clock genes exist in GC and circadian rhythm disturbance may be associated with the development of GC.

Induction of Cellular Senescence by Doxorubicin Is Associated with Upregulated miR-375 and Induction of Autophagy in K562 Cells

Background Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging. Methodology/Principal Findings An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted. Conclusions/Significance This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.

Clinical predictors of effective continuous positive airway pressure in patients with obstructive sleep apnea/hypopnea syndrome.

To identify standard clinical parameters that may predict the optimal level of continuous positive airway pressure (CPAP) in adult patients with obstructive sleep apnea/hypopnea syndrome (OSAHS).

Sleep Disturbance and Altered Expression of Circadian Clock Genes in Patients With Sudden Sensorineural Hearing Loss

AbstractThe cause of sudden sensorineural hearing loss (SSNHL) remains unclear and therefore it is often considered as idiopathic. Sleep disturbance has been linked to SSNHL and circadian rhythm disruption, but the link between circadian rhythm disruption and SSNHL has never been investigated.In this study, we surveyed the sleep quality of 38 patients with SSNHL using a simple insomnia sleep questionnaire. The expression of circadian clock genes in peripheral blood (PB) leukocytes from 38 patients with SSNHL and 71 healthy subjects was accessed using real-time quantitative reverse transcriptase-polymerase chain reaction and validated using immunocytochemical staining.We found that 61.8% of patients with SSNHL suffered from insomnia before the insult of hearing loss. Besides, significantly decreased expression of PER1, CRY1, CRY2, CLOCK, BMAL1, and CKl&egr; was found in PB leukocytes of patients with SSNHL when compared with healthy subjects. SSNHL patients with vertigo had significantly lower expression of CRY1 and CKl&egr; than patients without vertigo symptoms. Our results imply the association of sleep disturbance and disrupted circadian rhythm in SSNHL.

PER1 and CLOCK: potential circulating biomarkers for head and neck squamous cell carcinoma.

Circadian clock regulates daily rhythms in various physiologic processes and deregulated circadian clock are linked to cancers. We have previously demonstrated the association between altered circadian clock genes (CCGs) and head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to investigate whether the CCGs were also altered in peripheral blood (PB) of patients with HNSCC.

Risk of acute epiglottitis in patients with preexisting diabetes mellitus: A population-based case–control study

Objective Studies have revealed that 3.5%–26.6% of patients with epiglottitis have comorbid diabetes mellitus (DM). However, whether preexisting DM is a risk factor for acute epiglottitis remains unclear. In this study, our aim was to explore the relationship between preexisting DM and acute epiglottitis in different age and sex groups by using population-based data in Taiwan. Methods We analyzed data between January 2000 and December 2013 obtained from the Taiwan National Health Insurance Research Database. The case group consisted of 2,393 patients with acute epiglottitis. The control group comprised 9,572 individuals without epiglottitis, frequency matched by sex, age, urbanization level, and income. Underlying DM was retrospectively assessed in the cases and controls. Univariate and multivariate logistic regression analyses were used to investigate the associations between underlying DM and acute epiglottitis. Results Of the 2,393 patients, 180 (7.5%) had preexisting DM, whereas only 530 (5.5%) of the 9,572 controls had preexisting DM. Multivariate logistic regression analyses indicated that preexisting DM was significantly associated with acute epiglottitis (adjusted odds ratio [aOR] = 1.42, 95% confidence interval [CI] = 1.15–1.75, P = 0.004). Subgroup analysis showed that the association between DM and epiglottitis remained significant for men (aOR = 1.57, 95% CI: 1.19–2.08, p = 0.002) but not for women. Age-stratified analysis revealed a significant association between DM and acute epiglottitis in patients aged 35–64 years. Use of anti-diabetic agents was not significantly associated with the development of acute epiglottitis among diabetic patients, including oral hypoglycemic agents (OHA) alone (aOR = 0.88, 95% CI = 0.53–1.46, p = 0.616), and OHA combined with insulin/ insulin alone (aOR = 1.30, 95% CI = 0.76–2.22, p = 0.339). The association between presence of diabetes complications and the occurrence of acute epiglottitis was also not significant among diabetic patients in this study setting (aOR = 0.86, 95% CI = 0.59–1.26, p = 0.439). Conclusions The results of our large-scale population-based case–control study indicate that preexisting DM is one of the possible factors associated with the development of acute epiglottitis. Physicians should pay attention to the symptoms and signs of acute epiglottitis in DM patients, particularly in men aged 35–64 years.

NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin

NVP-BEZ235 is a dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor. A dual approach targeting more than one downstream effector is a promising strategy for treating cancers. The aim of this study was to evaluate the effect of NVP-BEZ235 in treating FaDu hypopharyngeal squamous cell carcinoma (HSCC), either alone or in combination with cisplatin. We found mTOR expression was higher in patients with HSCC. In the in vitro study, treatment with NVP-BEZ235 alone attenuated cell proliferation and suppressed p-p70S6K and p-4E-BP1 expression in FaDu cells. When NVP-BEZ235 was combined with Cisplatin, apoptosis was induced more effectively than with either drug alone. In mice with a FaDu xenograft, cotreatment with NVP-BEZ235 and Cisplatin engendered synergistic effects and produced a greater antitumor response than did treatment with either drug alone. Resected tumor samples also showed decreased p-p70S6K expression. Collectively, these data demonstrate that NVP-BEZ235 inhibits HSCC growth through phospho-p70S6K suppression and has a synergistic effect with Cisplatin in treating HSCC. The data also provide a strategy for more effective HSCC treatment.