Hsin An Chen

Survivin-Mediated Cancer Cell Migration Through GRP78 and Epithelial-Mesenchymal Transition (EMT) Marker Expression in Mahlavu Cells

BackgroundSurvivin has multiple functions during the progression of cancer. However, the role of survivin in the progression and metastasis of hepatocellular carcinoma (HCC) remains unknown.Materials and MethodsSurvivin expression in HCC cells (Mahlavu and Hep3B) was assessed using reverse transcription real-time PCR and Western blot analyses. In addition, survivin expression in HCC cells was manipulated using small interfering RNA (siRNA) or overexpression and proliferation and transwell migration assays were performed to monitor the effect of manipulated survivin expression on the growth rate and migratory ability of the transfected cells.ResultsAmong the HCC cell lines tested, we found high endogenous expression of survivin mRNA and protein in Mahlavu cells. After silencing survivin expression in Mahlavu cells, there was a dramatic decrease in the cell growth rate and an increase in the metastatic potential of the cells. Overexpression of survivin in Hep3B cells suppressed the ability of the cell to migrate. The mechanism of enhanced cell migration caused by decreased survivin expression is mediated through the downregulation of glucose-regulated protein 78 (GRP78) and the upregulation of the epithelial-mesenchymal transition (EMT) marker, vimentin.ConclusionsSurvivin may mediate metastasis in HCC. The knockdown of survivin expression may enhance cancer metastasis through the downregulation of GRP78 and upregulation of vimentin expression.

Increased risk of atrial fibrillation in end-stage renal disease patients on dialysis: A nationwide, population-based study in Taiwan

AbstractEnd-stage renal disease (ESRD) patients commonly have a higher risk of developing cardiovascular diseases than general population. Chronic kidney disease is an independent risk factor for atrial fibrillation (AF); however, little is known about the AF risk among ESRD patients with various modalities of renal replacement therapy. We used the Taiwan National Health Insurance Research Database to determine the incident AF among peritoneal dialysis (PD) and hemodialysis (HD) patients in Taiwan.Our ESRD cohort include Taiwan National Health Insurance Research Database, we identified 15,947 patients, who started renal replacement therapy between January 1, 2002 and December 31, 2003. From the same data source, 47,841 controls without ESRD (3 subjects for each patient) were identified randomly and frequency matched by gender, age (±1 year), and the year of the study patients index date for ESRD between January 1, 2002 and December 31, 2003.During the follow-up period (mean duration: 8–10 years), 3428 individuals developed the new-onset AF. The incidence rate ratios for AF were 2.07 (95% confidence interval [CI] = 1.93–2.23) and 1.78 (95% CI = 1.30–2.44) in HD and PD groups, respectively. After we adjusted for age, gender, and comorbidities, the hazard ratios for the AF risk were 1.46 (95% CI = 1.32–1.61) and 1.32 (95% CI = 1.00–1.83) in HD and PD groups, respectively. ESRD patients with a history of certain comorbidities including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, heart failure, valvular heart disease, and chronic obstructive pulmonary disease (COPD) have significantly increased risks of AF.This nationwide, population-based study suggests that incidence of AF is increased among dialysis ESRD patients. Furthermore, we have to pay more attention in clinical practice and long-term care for those ESRD patients with a history of certain comorbidities.

Suppression of dicer increases sensitivity to gefitinib in human lung cancer cells

BackgroundAccumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear.MethodsIn this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes.ResultsDicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis.ConclusionsDicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.

Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL

Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR.

Clinical significance of survivin expression in patients with urothelial carcinoma

Background. Survivin is a member of the inhibitors of apoptosis protein family that plays an important role in carcinogenesis. Here, we examined the association between survivin expression and clinical outcome in urothelial carcinoma of the bladder (UCB). Methods. A total of 56 histopathologically confirmed UCB patients were recruited from the Department of Urology of Chiayi Christian Hospital from August 2007 to May 2009. Immunohistochemistry (IHC) was used to detect the survivin expression in tumor tissues. The –31 C/G polymorphism in survivin promoter region was determined by polymerase chain reaction-restricted fragment length polymorphism. Results. The frequency of high survivin expression was significantly higher in muscle-invasive tumors (66.6%) than in non-muscle-invasive tumors (34.2%) (P = 0.042) and in poorly differentiated (85.7%) tumors than in moderately differentiated tumors (30.8%) (P = 0.0014). The higher frequency of risk genotypes (C/C and C/G) was found in the median (72.7%) and high (68.0%) survivin expression groups. The multivariate analysis showed that a high survivin expression level was a potential predictive biomarker of poor overall survival (P = 0.02). Conclusion. Our results suggest that the high survivin expression was associated with tumor stage and grade and may present a predictive marker of overall survival in UCB.