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Dive into the research topics where Jeng-Jer Shieh is active.

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Featured researches published by Jeng-Jer Shieh.


Gut | 2012

Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies

Hsiao-Ping Chen; Jeng-Jer Shieh; Chia-Che Chang; Tzu-Ting Chen; Jaw-Town Lin; Ming-Shiang Wu; Jeng-Horng Lin; Chun-Ying Wu

Objective Type 2 diabetes mellitus is associated with a higher risk of hepatocellular carcinoma (HCC), which is attenuated by the use of metformin. However, there are no studies addressing the effect of metformin on hepatocarcinoma cells from the antitumoural perspective. Design In the nationwide case-control study, the authors recruited 97 430 HCC patients and 194 860 age-, gender- and physician visit date-matched controls. The chemopreventive effects of metformin were examined by multivariate analysis and stratified analysis. The in vitro effects of metformin on cell proliferation and cell cycle were studied in HepG2 and Hep3B hepatoma cell lines. Results The OR of diabetes in HCC patients was 2.29 (95% CI 2.25 to 2.35, p<0.001). Each incremental year increase in metformin use resulted in 7% reduction in the risk of HCC in diabetic patients (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001). In the multivariate stratified analysis, metformin use was associated with a reduced risk of HCC in diabetic patients in nearly all subgroups. Cell line studies showed that metformin inhibits hepatocyte proliferation and induces cell cycle arrest at G0/G1 phase via AMP-activated protein kinase and its upstream kinase LKB1 to upregulate p21/Cip1 and p27/Kip1 and downregulate cyclin D1 in a dose-dependent manner, but independent of p53. Combined treatment of oral metformin with doxorubicin functioned more efficiently than either agent alone, in vivo. Conclusions Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dose-dependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.


Journal of Investigative Dermatology | 2009

Modification of Alternative Splicing of Mcl-1 Pre-mRNA Using Antisense Morpholino Oligonucleotides Induces Apoptosis in Basal Cell Carcinoma Cells

Jeng-Jer Shieh; Kuang-Ting Liu; Shi-Wei Huang; Yi-Ju Chen; Tsu-Yi Hsieh

Myeloid cell leukemia-1 (Mcl-1, Mcl-1L) is an anti-apoptotic protein of the Bcl-2 family that acts as a critical molecule in apoptosis control. Mcl-1 pre-mRNA can undergo alternative splicing to yield the short isoform, Mcl-1S, which resembles BH3-only pro-apoptotic proteins and induces apoptosis. Overexpression of Mcl-1 may play a role in various human tumors, and Mcl-1 may serve as a target in cancer therapy. In this study, we found an imbalance between the expression levels of Mcl-1L and Mcl-1S in the skin basal cell carcinoma (BCC) cell line when compared with primary keratinocytes. We showed that overexpression of Mcl-1S induces apoptosis in BCC cells. Finally, we showed that Mcl-1 antisense morpholino oligonucleotides (AMOs) can specifically target Mcl-1 pre-mRNA and shift the splicing pattern from Mcl-1L to Mcl-1S mRNA and protein. This shift increases the level of pro-apoptotic Mcl-1S and reduces the level of anti-apoptotic Mcl-1L, which induces apoptosis in BCC cells and AGS cells, a human gastric adenocarcinoma epithelial cell line. Thus, this report provides a strategy for cancer therapy in which AMOs change the alternative splicing pattern of Mcl-1 pre-mRNA and thereby induce apoptosis.


British Journal of Dermatology | 2010

Imiquimod simultaneously induces autophagy and apoptosis in human basal cell carcinoma cells

Shi-Wei Huang; Liu Kt; Chia-Che Chang; Yu-Ju Chen; Wu Cy; Tsai Jj; Lu Wc; Wang Yt; Liu Cm; Jeng-Jer Shieh

Background  Imiquimod shows antitumour activity through the stimulation of cell‐mediated immunity in vivo. Recent studies have shown that imiquimod promotes apoptosis in melanoma cells and induces autophagy in macrophage cell lines.


British Journal of Pharmacology | 2012

Prodigiosin down-regulates SKP2 to induce p27KIP1 stabilization and antiproliferation in human lung adenocarcinoma cells

Hsin-Ying Hsieh; Jeng-Jer Shieh; Chun-Jung Chen; Mu-Yun Pan; Shu-Yi Yang; Shin-Chang Lin; Jo Shu Chang; Alan Yueh-Luen Lee; Chia-Che Chang

BACKGROUND AND PURPOSE High levels of SKP2 are a poor prognostic factor in multiple human cancers and mostly correlate with low p27KIP1 levels. Prodigiosin is a bacterial tripyrrole pigment with strong pro‐apoptotic activity. Induction of cell cycle blockade underlies one of its anticancer actions but the mechanisms involved are unclear. The aim of this study was to explore the role of the SKP2–p27KIP1 axis in prodigiosins cytostatic effect on human lung adenocarcinoma cells.


Journal of The American Academy of Dermatology | 2015

Association between antidiabetic drugs and psoriasis risk in diabetic patients: results from a nationwide nested case-control study in Taiwan.

Chun-Ying Wu; Jeng-Jer Shieh; Jui-Lung Shen; Yi-Ya Liu; Yun-Ting Chang; Yi-Ju Chen

BACKGROUND The risk of psoriasis in diabetic patients has rarely been explored. OBJECTIVES We sought to investigate the association between antidiabetic therapies and psoriasis. METHODS The incidence of psoriasis was compared between a representative diabetic cohort and a matched nondiabetic cohort. We next conducted a nationwide cohort study with 1,659,727 diabetic patients using the National Health Insurance Research Database of Taiwan 1997 through 2011. Multivariate conditional logistic regression was used for nested case-control analyses. RESULTS Incidence rates of psoriasis among diabetic patients and nondiabetic matched control subjects were 70.2 (95% confidence interval [CI] 59.5-80.9) and 42.3 (95% CI 39.5-45.5) per 100,000 person-years, respectively (P < .0001). Frequent insulin use was associated with higher risk of incident psoriasis (adjusted odds ratio 1.29, 95% CI 1.18-1.42) after adjusting for comorbidities, disease duration, and number of hospital visits. Among diabetic patients without history of insulin use, frequent use of thiazolidinedione was associated with lower risk of psoriasis (adjusted odds ratio 0.87, 95% CI 0.77-0.99). LIMITATIONS The National Health Insurance Research Database did not contain information regarding disease severity, diet, body mass index, lifestyle, or family history. CONCLUSION Among diabetic patients, regular insulin use is associated with psoriasis development. Frequent use of thiazolidinedione may be associated with modest reduction in psoriasis risk.


Toxicology and Applied Pharmacology | 2013

p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells.

Shi-Wei Huang; Chun-Ying Wu; Yen-Ting Wang; Jun-Kai Kao; Chi-Chen Lin; Chia-Che Chang; Szu-Wei Mu; Yu-Yu Chen; Husan-Wen Chiu; Chuan-Hsun Chang; Shu-Mei Liang; Yi-Ju Chen; Jau-Ling Huang; Jeng-Jer Shieh

Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cells p53 status.


Journal of Dermatological Science | 2016

Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line

Shi-Wei Huang; Shu-Hao Chang; Szu-Wei Mu; Hsin-Yi Jiang; Sin-Ting Wang; Jun-Kai Kao; Jau-Ling Huang; Chun-Ying Wu; Yi-Ju Chen; Jeng-Jer Shieh

BACKGROUND The tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells. OBJECTIVE To evaluate the role of p53 in IMQ-induced cell death in skin cancer cells. METHODS The expression, phosphorylation and subcellular localization of p53 were detected by real-time PCR, luciferase reporter assay, cycloheximide chase analysis, immunoblotting and immunocytochemistry. Using BCC/KMC1 cell line as a model, the upstream signaling of p53 activation was dissected by over-expression of TLR7/8, the addition of ROS scavenger, ATM/ATR inhibitors and pan-caspase inhibitor. The role of p53 in IMQ-induced apoptosis and autophagy was assessed by genetically silencing p53 and evaluated by a DNA content assay, immunoblotting, LC3 puncta detection and acridine orange staining. RESULTS IMQ induced p53 mRNA expression and protein accumulation, increased Ser15 phosphorylation, promoted nuclear translocation and up-regulated its target genes in skin cancer cells in a TLR7/8-independent manner. In BCC/KMC1 cells, the induction of p53 by IMQ was achieved through increased ROS production to stimulate the ATM/ATR-Chk1/Chk2 axis but was not mediated by inducing DNA damage. The pharmacological inhibition of ATM/ATR significantly suppressed IMQ-induced p53 activation and apoptosis. Silencing of p53 significantly decreased the IMQ-induced caspase cascade activation and apoptosis but enhanced autophagy. Mutant p53 skin cancer cell lines were more resistant to IMQ-induced apoptosis than wildtype p53 skin cancer cell lines. CONCLUSION IMQ induced ROS production to stimulate ATM/ATR pathways and contributed to p53-dependent apoptosis in a skin basal cell carcinoma cell line BCC/KMC1.


Journal of Dermatological Science | 2012

Mcl-1 determines the imiquimod-induced apoptosis but not imiquimod-induced autophagy in skin cancer cells.

Shi-Wei Huang; Chia-Che Chang; Chi-Chen Lin; Jaw-Ji Tsai; Yi-Ju Chen; Chun-Ying Wu; Kuang-Ting Liu; Jeng-Jer Shieh

BACKGROUND Imiquimod had been shown to induce apoptosis and autophagy in several skin cancer cells, especially basal cell carcinoma (BCC) cells. OBJECTIVE We evaluate the molecular mechanisms of imiquimod-induced apoptosis and autophagy in skin cancer cell lines. METHODS The Mcl-1, Bcl-2 and Bcl-xL proteins were determined by immunoblotting. The Mcl-1 mRNA level was examined by RT-PCR and real-time PCR. The mechanisms of imiquimod-induced decrease in Mcl-1 protein were evaluated by addition of cycloheximide, MG132 proteasome inhibitor or pan-caspase inhibitor. The phosphorylation of eIF4E, 4E-BP1 and eEF2 in imiquimod treated cells were examined by immunoblotting. The imiquimod-induced apoptosis and autophagy were evaluated in Mcl-1-overexpressing cells by XTT test, mitochondrial membrane potential measurement, DNA content assay, LC3 immunoblotting, EGFP-LC3 puncta formation and quantification of acidic vesicular organelle with acridine orange staining. RESULTS The decrease in the Mcl-1 protein level was faster and stronger than the decrease in Bcl-2 and Bcl-xL in imiquimod-treated skin cancer cells. The imiquimod-induced decrease in Mcl-1 protein was not caused by blocked transcription or the promotion of degradation but was associated with inactivation of translation factors in BCC cells. The Mcl-1-overexpressing BCC cells were more resistant to intrinsic cellular apoptosis than control BCC cells during imiquimod treatment. Mcl-1 overexpression in BCC cells resulted in the basal activation of autophagy but did not modulate imiquimod-induced autophagy or rescue imiquimod-induced autophagic cell death in BCC cells. CONCLUSIONS Imiquimod may rapidly downregulate Mcl-1 protein levels by inhibiting translation in skin cancer cells. Mcl-1 may act to protect against apoptosis but not autophagy and autophagic cell death during imiquimod treatment in skin cancer cells.


Medicine | 2016

Depression and Insomnia in Patients With Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor Antagonists

Chun-Ying Wu; Yun-Ting Chang; Chao-Kuei Juan; Jui-Lung Shen; Yu-Pu Lin; Jeng-Jer Shieh; Han-Nan Liu; Yi-Ju Chen

AbstractPsoriasis patients with moderate to severe disease often present with depression and insomnia. Treatment targeting both psoriasis and psychological comorbidities is needed to improve the quality of life of these patients.In this nationwide cohort study, a total of 980 patients with psoriatic arthritis or psoriasis who had received nonbiological disease-modifying antirheumatic drugs and biologics therapy between 2009 and 2012 were identified. The prevalence rates of patients taking medications for depression and insomnia were compared before and after biologics therapy. Logistic regression method was used to investigate the risk factors for depression and insomnia. Further stratified analyses were performed to examine the prevalence of use of medications for depression and insomnia among different patient subgroups.The prevalence of patients taking regular antidepressants before starting biologics therapy was about 20%. There was a more than 40% reduction in this prevalence after biologics therapy for 2 years. Age higher than 45 years, female sex, presence of comorbidities, and psoriatic arthritis were independently associated with depression and insomnia. Further stratified analyses revealed a more rapid and significant reduction in depression/insomnia in those undergoing continuous biologics therapy, younger than 45 years, without psoriatic arthritis and not taking concomitant methotrexate, when compared with their counterparts.The results suggest that biologics therapy may be associated with reduced rates of depression and insomnia, and a reduced rate of regular antidepressants use in psoriasis patients.


Cell Death and Disease | 2017

Simvastatin-induced cell cycle arrest through inhibition of STAT3/SKP2 axis and activation of AMPK to promote p27 and p21 accumulation in hepatocellular carcinoma cells

Sin-Ting Wang; Hsiu J. Ho; Jaw-Town Lin; Jeng-Jer Shieh; Chun-Ying Wu

Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and is one of the leading causes of cancer-related death worldwide. Simvastatin, an HMG-CoA reductase inhibitor, which decreases cholesterol synthesis by inhibiting mevalonate pathways and is widely used to treat cardiovascular diseases. Simvastatin exhibits anticancer effects against several malignancies. However, the molecular mechanisms underlying the anticancer effects of simvastatin on HCC are still not well understood. In this study, we demonstrated simvastatin-induced G0/G1 arrest by inducing p21 and p27 accumulation in HepG2 and Hep3B cells. Simvastatin also promoted AMP-activated protein kinase (AMPK) activation, which induced p21 upregulation by increasing its transcription. Consistent with this finding, we found genetic silencing of AMPK reduced p21 expression; however, AMPK silencing had no effect on p27 expression in HCC cells. Simvastatin decreased Skp2 expression at the transcriptional level, which resulted in p27 accumulation by preventing proteasomal degradation, an effect mediated by signal transducer and activator of transcription 3 (STAT3) inhibition. Constitutive STAT3 activation maintained high-level Skp2 expression and lower level p27 expression and significantly prevented G0/G1 arrest in simvastatin-treated HCC cells. Mevalonate decreased simvastatin-induced AMPK activation and rescued phospho-STAT3 and Skp2 expression in HCC cells, which resulted in the prevention of G0/G1 arrest through inhibition of p21 and p27 accumulation. Moreover, simvastatin significantly decreased tumor growth in HepG2 xenograft mice. Consistently, we found that simvastatin also increased p21 and p27 expression in tumor sections by reducing Skp2 expression and inducing AMPK activation and STAT3 suppression in the same tumor tissues. Taken together, these findings are demonstrative of the existence of a novel pathway in which simvastatin induces G0/G1 arrest by upregulating p21 and p27 by activating AMPK and inhibiting the STAT3–Skp2 axis, respectively. The results identify novel targets that explain the beneficial anticancer effects of simvastatin treatment on HCC in vitro and in vivo.

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Chun-Ying Wu

National Yang-Ming University

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Shi-Wei Huang

National Chung Hsing University

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Yi-Ju Chen

National Yang-Ming University

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Sin-Ting Wang

National Chung Hsing University

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Jun-Kai Kao

Boston Children's Hospital

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Chia-Che Chang

National Chung Hsing University

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Hsiu J. Ho

Taipei Veterans General Hospital

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Jaw-Town Lin

Fu Jen Catholic University

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Yun-Ting Chang

Taipei Veterans General Hospital

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