Chi Mei Foundation Medical Center

Tainan, Taiwan

Chi Mei Foundation Medical Center

Tainan, Taiwan
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Huang C.-W.,National Cheng Kung University | Chow J.C.,Chi Mei Foundation Medical Center | Tsai J.-J.,National Cheng Kung University | Wu S.-N.,National Cheng Kung University
Psychopharmacology | Year: 2012

Rationale: Eugenol (EUG, 4-allyl-2-methoxyphenol), the main component of essential oil extracted from cloves, has various uses in medicine because of its potential to modulate neuronal excitability. However, its effects on the ionic mechanisms remains incompletely understood. Objectives: We aimed to investigate EUG's effects on neuronal ionic currents and excitability, especially on voltage-gated ion currents, and to verify the effects on a hyperexcitability- temporal lobe seizure model. Methods: With the aid of patch-clamp technology, we first investigated the effects of EUG on ionic currents in NG108-15 neuronal cells differentiated with cyclic AMP. We then used modified Pinsky-Rinzel simulation modeling to evaluate its effects on spontaneous action potentials (APs). Finally, we investigated its effects on pilocarpine-induced seizures in rats. Results: EUG depressed the transient and late components of I Na in the neurons. It not only increased the degree of I Na inactivation, but specifically suppressed the non-inactivating I Na (I Na(NI)). Its inhibition of I Na(NI) was reversed by tefluthrin. In addition, EUG diminished L-type Ca 2+ current and delayed rectifier K + current only at higher concentrations. EUG's effects on APs frequency reduction was verified by the simulation modeling. In pilocarpine-induced seizures, the EUG-treated rats showed no shorter seizure latency but a lower seizure severity and mortality than the control rats. The EUG's effect on seizure severity was occluded by the I Na(NI) antagonist riluzole. Conclusion: The synergistic blocking effects of I Na and I Na(NI) contributes to the main mechanism through which EUG affects the firing of neuronal APs and modulate neuronal hyperexcitability such as pilocarpine-induced temporal lobe seizures. © 2011 Springer-Verlag.


Hsueh Y.-S.,National Cheng Kung University | Hsueh Y.-S.,National Institute of Cancer Research | Yen C.-C.,Taipei Veterans General Hospital | Yen C.-C.,National Yang Ming University | And 8 more authors.
Autophagy | Year: 2013

Gastrointestinal stromal tumor (GIST) is a prototype of mutant KIT oncogene-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Heat shock protein 90 (HSP90AA1) is a chaperone protein responsible for protein maturation and stability, and KIT is a known client protein of HSP90AA1. Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway. In this study, we demonstrated that NVP-AUY922 (AUY922), a new class of HSP90AA1 inhibitor, is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the imatinibsensitive GIST882 and imatinib-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922- induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange- or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. Therefore, the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitorinduced KIT degradation. © 2013 Landes Bioscience.


Chen J.-Y.,National Health Research Institute | Li C.-F.,Chi Mei Foundation Medical Center | Kuo C.-C.,National Health Research Institute | Tsai K.K.,National Health Research Institute | And 4 more authors.
Breast Cancer Research | Year: 2014

Introduction: Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear.Methods: Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.Results: Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.Conclusion: Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival. © 2014 Chen et al.; licensee BioMed Central; licensee BioMed Central Ltd.


Fang F.-M.,Chang Gung University | Li C.-F.,Chi Mei Foundation Medical Center | Huang H.-Y.,Chang Gung University | Lai M.-T.,Chung Shan Medical University | And 6 more authors.
American Journal of Pathology | Year: 2011

RSF-1, also known as hepatitis B X-antigen associated protein (HBXAP), is a subunit of an ISWI chromatin remodeling complex, remodeling and spacing factor (RSF). Recent studies have provided new evidence that chromatin remodeling participates in the pathogenesis of neoplastic diseases by altering cell cycle regulation and gene expression. In this report, we studied the biological roles of RSF-1 in oral squamous cell carcinoma (OSCC), a highly invasive neoplastic disease. Based on IHC and quantitative real-time PCR, we demonstrated that RSF-1 expression could be detected in the majority of OSCC cases, and the levels were significantly higher in OSCC cells than in their normal counterparts. Moreover, expression levels of RSF-1 significantly correlated with the presence of angiolymphatic invasion, abnormal mitoses, metastasis, tumor recurrence, and advanced stage disease at presentation. Univariate and multivariate analyses showed a significant association of RSF-1 overexpression and worse overall survival in OSCC patients. RSF-1 knockdown remarkably decreased cellular proliferation and induced apoptosis in OSCC cells with high RSF-1 expression levels, but not in those without. Taken together, our results suggest that RSF-1 up-regulation is associated with several clinicopathological features of disease aggressiveness in OSCC patients, and RSF-1 plays an important role in maintaining cellular growth and survival in OSCC.


Huang H.-Y.,Chang Gung University | Li C.-F.,Chi Mei Foundation Medical Center | Li C.-F.,National Sun Yat - sen University | Fang F.-M.,Chang Gung University | And 4 more authors.
Annals of Surgical Oncology | Year: 2010

Background: The bases of tumorigenesis, progression, and metastasis remain obscure in myxofibrosarcoma. As a member of ezrin-radixin-moesin family, ezrin acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It is implicated in tumor progression and metastatic dissemination, and it is associated with adverse outcomes in several cancer types, including pediatric sarcomas. Methods: Ezrin immunostain could be assessed from tissue microarrays of 78 cases of primary localized myxofibrosarcomas and correlated with clinicopathological factors and patient survival. In two myxofibrosarcoma cell lines, ezrin mRNA expression was measured by real-time reverse transcriptase-polymerase chain reaction and the endogenous expression and activating phosphorylation of ezrin protein analyzed by Western blot test. Results: Ezrin overexpression was significantly associated with remarkable tumor necrosis (P = 0.025), increased histological grades (P = 0.037), advanced American Joint Committee on Cancer stages (P = 0.034), and higher mitotic rate (P < 0.001). Importantly, ezrin overexpression independently predicted inferior metastasis-free survival (P = 0.012, risk ratio = 4.083) and disease-specific survival (P = 0.0337, risk ratio = 4.537). The mRNA and total protein of ezrin in various cells were comparable in the expression level. Despite variation in abundance, phosphorylated ezrin at threonine567 was detectable in myxofibrosarcoma cell lines but not in fibroblasts. Conclusions: In primary myxofibrosarcomas, ezrin overexpression correlates with important prognostic elements and independently portends worse outcomes, highlighting the potential prognostic usefulness of ezrin in predicting tumor aggressiveness. © 2010 Society of Surgical Oncology.


Chen T.-J.,Chang Gung University | Huang S.-C.,Chang Gung University | Huang H.-Y.,Chang Gung University | Wei Y.-C.,Chang Gung University | And 2 more authors.
APMIS | Year: 2011

Dysregulated chromatin remodeling often leads to abnormal gene expression or silencing in cells, thereby implicating tumor development and progression. As a subunit of remodeling and spacing factor (RSF) complex, Rsf-1, a novel nuclear protein with histone chaperon function, mediates ATPase-dependent chromatin remodeling and confer tumor aggressiveness in common carcinomas. We aimed, for the first time, to evaluate the Rsf-1 expression status and its associations with clinicopathological features and patient survival in a well characterized cohort of gallbladder carcinomas. Using tissue microarray-based immunohistochemistry, we assessed Rsf-1 expression in gallbladder carcinomas, yielding 88 cases undergoing surgical intervention with interpretable results. The Rsf-1 overexpression, present in 61 cases (69.3%), was significantly associated with higher histological grades (p=0.002) and vascular invasion (p=0.037) and marginally with non-papillary histotypes (p=0.058). In univariate log-rank analysis, Rsf-1 overexpression was significantly predictive of disease-specific survival (p=0.0015), which remained prognostically independent [p=0.0191, risk ratio (RR)=2.683], along with American Joint Committee on Cancer stages II-IV (p=0.0265, RR=2.102). Our findings indicate that Rsf-1 overexpression is common and associated with adverse prognosticators in gallbladder carcinomas. It may confer tumor aggressiveness through chromatin remodeling and represents a potential prognostic biomarker of gallbladder carcinomas. © 2011 The Authors. APMIS © 2011 APMIS.


Lin K.-T.,National Health Research Institute | Gong J.,Columbia University | Li C.-F.,Chi Mei Foundation Medical Center | Jang T.-H.,National Health Research Institute | And 4 more authors.
Cancer Research | Year: 2012

Prostate cancer remains the second leading cause of cancer death in men in the Western world. Yet current therapies do not significantly improve the long-term survival of patients with distant metastasis. In this study, we investigated the role of the guanine nucleotide exchange factor Vav3 in prostate cancer progression and metastasis and found that Vav3 expression correlated positively with prostate cancer cell migration and invasion. Stimulation of the receptor tyrosine kinase EphA2 by ephrinA1 resulted in recruitment and tyrosine phosphorylation of Vav3, leading to Rac1 activation as well as increased migration and invasion in vitro. Reduction of Vav3 resulted in fewer para-aortic lymph nodes and bone metastasis in vivo. Clinically, expression of Vav3 and EphA2 was elevated in late-stage and metastatic prostate cancers. Among patients with stage IIB or earlier prostate cancer, higher Vav3 expression correlated with lower cumulative biochemical failure-free survival, suggesting that Vav3 may represent a prognostic marker for posttreatment recurrence of prostate cancer. Together, our findings provide evidence that the Vav3-mediated signaling pathway may serve as a therapeutic target for prostate cancer metastasis. ©2012 AACR.


Cheng H.-C.,National Cheng Kung University | Liu Y.-P.,National Cheng Kung University | Shan Y.-S.,National Cheng Kung University | Huang C.-Y.,National Yang Ming University | And 6 more authors.
Carcinogenesis | Year: 2013

Loss of RUNX3 expression is frequently observed in gastric cancer and is highly associated with lymph node metastasis and poor prognosis. However, the underlying molecular mechanisms of gastric cancer remain unknown. In this study, we found that the protein levels of RUNX3 and osteopontin (OPN) are inversely correlated in gastric cancer clinical specimens and cell lines. Furthermore, similar inverse trends between RUNX3 and OPN messenger RNA (mRNA) expression were demonstrated in six out of seven normal-tumor-paired gastric cancer clinical specimens. In addition, low RUNX3 and high OPN expression were associated with poor prognosis in gastric cancer patients. Ectopic expression of green fluorescent protein-RUNX3 reduced OPN protein and mRNA expression in the AGS and SCM-1 gastric cancer cell lines. In contrast, knockdown of RUNX3 in GES-1, a normal gastric epithelial cell line, increased OPN expression. Although three RUNX3-binding sequences have been identified in the OPN promoter region, direct binding of RUNX3 to the specific binding site, -142 to -137bp, was demonstrated by chromatin immunoprecipitation assay. The binding of RUNX3 to the OPN promoter significantly decreased OPN promoter activity. The knockdown of OPN or overexpression of RUNX3 inhibited cell migration in AGS and SCM-1 cells; however, the coexpression of RUNX3 and OPN reversed the RUNX3-reduced migration ability in AGS and SCM-1 cells. In contrast, the knockdown of both RUNX3 and OPN inhibited RUNX3-knockdown-induced migration of GES-1 cells. Together, our data demonstrated that RUNX3 is a transcriptional repressor of OPN and that loss of RUNX3 upregulates OPN, which promotes migration in gastric cancer cells. © The Author 2013. Published by Oxford University Press. All rights reserved.


Lin Y.-S.,Chi Mei Foundation Medical Center | Lin Y.-S.,Taipei Medical University | Tsai S.-J.,National Cheng Kung University | Lin M.-W.,National Yang Ming University | And 3 more authors.
American Journal of Reproductive Immunology | Year: 2011

Problem Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder. This study was to evaluate whether insulin receptor substrate (IRS)-2 Gly1057Asp polymorphism influences chronic inflammatory parameters in Taiwanese patients with PCOS. Method of study DNA was extracted from whole blood samples for genotyping and detection of IRS-2 Gly1057Asp polymorphism in 129 PCOS women and 109 control women. Ninety-seven PCOS women accepted metformin treatment for 3months, and low-grade chronic inflammatory markers were assessed. Results The levels of IL-6 were significantly elevated in PCOS women compared with normal women. Among allelic variant of IRS-2, concentrations of IL-6 were greater in IRS-2 homozygous Asp population. Treatment with metformin significantly reduced IL-6, especially in PCOS patients with IRS-2 homozygous Asp variant. Conclusion The results showed that IL-6 may be an early low-grade chronic inflammatory marker among PCOS patients with IRS-2 polymorphism in Taiwanese population. This pharmacologic study in IRS-2 polymorphism may provide more information for preventing long-term complications in PCOS. © 2011 John Wiley & Sons A/S.


Yang C.-S.,National Cheng Kung University | Chow J.C.,Chi Mei Foundation Medical Center | Tsai J.-J.,National Cheng Kung University | Huang C.-W.,National Cheng Kung University
Epilepsy and Behavior | Year: 2011

Hyperventilation is a traditional seizure-provoking procedure used mainly in idiopathic generalized epilepsy and with a relatively limited role in partial epilepsy. Ictal fear is a rare seizure semiology seen in temporal lobe epilepsy. It has been suggested that the amygdala and anterior hippocampus are involved in generating ictal fear. We describe a rare patient with nonlesional temporal epilepsy who, while hyperventilating during an electroencephalography recording, developed complex partial seizures presenting as ictal fear. The particular sensitivity of the anterior hippocampus (probably the amygdala) to hypocapnia might be an important factor contributing to seizures. To avoid misdiagnosing this unusual condition as a pseudo-seizure, a detailed history and seizure semiology, as well as a concurrent electroencephalography recording, are mandatory. © 2011 Elsevier Inc.

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