Publications by authors named "Yu-Ting Chou"

68 Publications

Evaluation of the diagnostic accuracy of bronchial brushing cytology in lung cancer: A meta-analysis.

Cancer Cytopathol 2021 Apr 22. Epub 2021 Apr 22.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: Flexible bronchoscopy is commonly used to examine patients suspected to have lung cancer. Bronchial brushing is one of the cytological technologies for lung specimens obtained through a bronchoscope. However, the accuracy of bronchial brushing cytology (BBC) for lung cancer diagnosis is still inconclusive. The aim of this study was to evaluate the diagnostic accuracy of BBC.

Methods: A literature search was conducted with PubMed, Embase, the Cochrane Library, Web of Science, Biomed Central, Clinical Key, and ClinicalTrials.gov. Studies that assessed the efficacy of BBC in detecting lung cancer were included. Articles that estimated the accuracy on a per-patient basis were included. Review articles, case reports, and research that provided insufficient data to construct a 2 × 2 table were excluded. Both prospective trials and retrospective studies were included. English language studies were reviewed. Data synthesis was performed with a random-effects model.

Results: Seventeen studies with 2538 patients were included in the study. The meta-analysis for BBC generated a pooled sensitivity of 0.67 (95% confidence interval [CI], 0.65-0.70) and a pooled specificity of 0.91 (95% CI, 0.89-0.93). The pooled diagnostic odds ratio for BBC was 24.55 (95% CI, 12.39-48.66). The subgroup analysis for studies using liquid-based cytology (LBC) generated a pooled sensitivity of 0.68 and a pooled specificity of 0.92. The pooled diagnostic odds ratio of studies using LBC was 114.18.

Conclusions: These findings indicate that BBC is a discriminative diagnostic approach with moderate sensitivity and high specificity for diagnosing peripheral pulmonary lesions. BBC using LBC has higher diagnostic performance.
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http://dx.doi.org/10.1002/cncy.22436DOI Listing
April 2021

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.

Cell 2021 May 12;184(10):2649-2664.e18. Epub 2021 Apr 12.

Department of Medicine, Division of Hematology and Oncology, UCSF, San Francisco, CA 94143, USA. Electronic address:

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.
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http://dx.doi.org/10.1016/j.cell.2021.03.031DOI Listing
May 2021

Cyproterone acetate acts as a disruptor of the aryl hydrocarbon receptor.

Sci Rep 2021 Mar 9;11(1):5457. Epub 2021 Mar 9.

Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, ROC.

Prostate cancer is a major cause of death in males. Cyproterone acetate (CPA), the steroidal anti-androgen for part of androgen deprivation therapy, may block the androgen-receptor interaction and then reduce serum testosterone through its weak anti-gonadotropic action. In addition to CPA inducing hepatitis, CPA is known to cause liver tumors in rats also. Aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and regulates multiple physiological functions. CYP1A1 is an AhR-targeted gene. We found that CPA induced CYP1A1 expression, transcriptional activity of the aryl hydrocarbon response element (AHRE), and the nuclear localization of AhR in mouse Hepa-1c1c7 cells. However, CPA suppressed CYP1A1 mRNA expression and the transcriptional activity of AHRE in human HepG2 and MCF7 cells, and also decreased AhR ligand-induced CYP1A1 protein expression and transcriptional activity of AHRE in HepG2 cells. In summary, CPA is an AhR agonist in mouse cells, but an AhR antagonist in human cells. Accordingly, CPA potentially plays a role as an endocrine disruptor of the AhR. This study helps us to understand why CPA induces acute hepatitis, gene mutation, and many other side effects. In addition, it may trigger further studies investigating the relationships between CPA, glucocorticoid receptor and castration-resistant prostate cancer in the future.
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http://dx.doi.org/10.1038/s41598-021-84769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943802PMC
March 2021

Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report.

J Ovarian Res 2020 Dec 8;13(1):143. Epub 2020 Dec 8.

Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.

Background: Patients with ovarian clear cell carcinoma (OCCC) have a poor prognosis because they show low sensitivity to platinum-based chemotherapy. New treatments for refractory OCCC are urgently needed.

Case Presentation: We present a patient with refractory OCCC in whom conventional chemotherapy failed. Cachexia was induced by the disseminating recurrent tumors. Tumor tissue staining and genomic analysis revealed PD-L1 negativity, a low tumor burden, stable microsatellite instability, and two mutations in ARID1A. The patient was administered pembrolizumab combined with bevacizumab triweekly. Her serum CA-125 level decreased dramatically after the first cycle. A computerized tomography scan showed marked regression of the recurrent masses after 3 cycles, and the patient reached complete remission after 9 cycles. She showed good recovery from cachexia. We observed no marked side effects except for mild polyarthritis of the small joints.

Conclusions: The therapeutic effect of checkpoint inhibitors combined with angiogenesis inhibitors is very promising in our patient with OCCC. Further clinical trials of tumors including ARID1A mutations are warranted.
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http://dx.doi.org/10.1186/s13048-020-00751-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725117PMC
December 2020

Antimicrobial Peptides with Enhanced Salt Resistance and Antiendotoxin Properties.

Int J Mol Sci 2020 Sep 16;21(18). Epub 2020 Sep 16.

Institute of Biotechnology and Department of Medical Science, National Tsing Hua University, Hsinchu 300, Taiwan.

A strategy was described to design antimicrobial peptides (AMPs) with enhanced salt resistance and antiendotoxin activities by linking two helical AMPs with the Ala-Gly-Pro (AGP) hinge. Among the designed peptides, KR12AGPWR6 demonstrated the best antimicrobial activities even in high salt conditions (NaCl ~300 mM) and possessed the strongest antiendotoxin activities. These activities may be related to hydrophobicity, membrane-permeability, and α-helical content of the peptide. Amino acids of the C-terminal helices were found to affect the peptide-induced permeabilization of LUVs, the α-helicity of the designed peptides under various LUVs, and the LPS aggregation and size alternation. A possible model was proposed to explain the mechanism of LPS neutralization by the designed peptides. These findings could provide a new approach for designing AMPs with enhanced salt resistance and antiendotoxin activities for potential therapeutic applications.
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http://dx.doi.org/10.3390/ijms21186810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554977PMC
September 2020

Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR-TKI Tolerance and Lung Cancer Dissemination.

Cancer Res 2020 10 19;80(20):4426-4438. Epub 2020 Aug 19.

Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination. SIGNIFICANCE: These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3228DOI Listing
October 2020

Critical role of SOX2-IGF2 signaling in aggressiveness of bladder cancer.

Sci Rep 2020 05 19;10(1):8261. Epub 2020 May 19.

Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low-serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells' spheroid-forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated spheroid formation of bladder cancer cells. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished bladder cancer cell growth. Lastly, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Our findings indicate the SOX2-IGF2 signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.
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http://dx.doi.org/10.1038/s41598-020-65006-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237425PMC
May 2020

A mammalian axis controls the cytoskeleton and confers cellular properties required for alveologenesis.

Elife 2020 05 12;9. Epub 2020 May 12.

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.

Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in alveolar epithelial cells and myofibroblasts for alveologenesis in mammals. Our studies uncovered a cascade that endows cellular properties and novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior.
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http://dx.doi.org/10.7554/eLife.53688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217702PMC
May 2020

Heparan sulfate targeting strategy for enhancing liposomal drug accumulation and facilitating deep distribution in tumors.

Drug Deliv 2020 Dec;27(1):542-555

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.

Nanoparticles (NPs), such as liposomes, effectively evade the severe toxicity of unexpected accumulation and passively shuttle drugs into tumor tissues by enhanced permeability and retention. In the case of non-small cell lung cancer and pancreatic ductal adenocarcinoma, cancer-associated fibroblasts promote the aggregation of a gel-like extracellular matrix that forms a physical barrier in the desmoplastic stroma of the tumor. These stroma are composed of protein networks and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of NPs. Moreover, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor extracellular matrix may serve as molecular targets for NP-mediated drug delivery. Here, a GAG-binding peptide (GBP) with high affinity for HS and high cell-penetrating activity was used to develop an HS-targeting delivery system. Specifically, liposomal doxorubicin (L-DOX) was modified by post-insertion with the GBP. We show that the uptake of L-DOX in A549 lung adenocarcinoma cells increased by GBP modification. Cellular uptake of GBP-modified L-DOX (L-DOX-GBP) was diminished in the presence of extracellular HS but not in the presence of other GAGs, indicating that the interaction with HS is critical for the cell surface binding of L-DOX-GBP. The cytotoxicity of doxorubicin positively correlated with the molecular composition of GBP. Moreover, GBP modification improved the distribution and anticancer efficiency of L-DOX, with enhanced desmoplastic targeting and extensive distribution. Taken together, GBP modification may greatly improve the tissue distribution and delivery efficiency of NPs against HS-abundant desmoplastic stroma-associated neoplasm.
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http://dx.doi.org/10.1080/10717544.2020.1745326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170378PMC
December 2020

PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells.

J Cell Sci 2020 04 28;133(8). Epub 2020 Apr 28.

Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan

Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. Although transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.
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http://dx.doi.org/10.1242/jcs.240325DOI Listing
April 2020

Association of Divergent Carcinoembryonic Antigen Patterns and Lung Cancer Progression.

Sci Rep 2020 02 7;10(1):2066. Epub 2020 Feb 7.

Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan, ROC.

Changes in expression patterns of serum carcinoembryonic antigen at initial diagnosis (CEA) and disease progression (CEA) in lung cancer patients under EGFR-tyrosine kinase inhibitors (TKI) treatment may reflect different tumor progression profiles. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on EGFR mutation status and CEA, among whom were 288 patients with data on CEA, eligible for inclusion in the correlation analysis of clinical characteristics and survival. Multivariable analysis revealed that CEA expression was associated with poor progression-free survival in patients harboring mutant EGFR. Moreover, CEA and CEA were associated with the good and poor post-progression survival, respectively, in the EGFR-mutant group. Cell line experiments revealed that CEA expression and cancer dissemination can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high CEA (≥5 ng/mL) and low CEA (<5 ng/mL), showed a potential toward displaying new metastasis. Taken together, these findings support the conclusion that EGFR mutation status is a critical factor in determining prognostic potential of CEA and CEA in patients under EGFR-TKI treatment, and CEA and CEA are associated with distinct cancer progression profiles.
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http://dx.doi.org/10.1038/s41598-020-59031-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005848PMC
February 2020

A novel CXCL8 analog is effective in inhibiting the growth via cell cycle arrest and attenuating invasion of Lewis lung carcinoma.

Onco Targets Ther 2019 16;12:7611-7621. Epub 2019 Sep 16.

Department of Medical Science, Institute of Biotechnology, National Tsing Hua University, Hsinchu 300, Taiwan.

Purpose: Lung cancer and other solid tumors contain not only tumor cells but various types of stromal cells, such as fibroblasts and endothelial cells. In addition, tumors are infiltrated by inflammatory cells (neutrophils, macrophages, and lymphocytes). Tumor cells, stromal cells, and the tumor-associated leukocytes are responsible for the production of chemokines inside the tumor and the maintenance of systemic circulating chemokine levels. CXCL8 and its receptors, CXCR1 and CXCR2, were found to play important roles in tumor proliferation, migration, survival, and growth. We have developed a novel ELR-CXC chemokine antagonist CXCL8-IP10 based on the structure of CXCL8 and IP10.

Patients And Methods: We assessed the anticancer efficacies of the blockade of CXCL8-CXCR1/2 axis in the Lewis lung carcinoma (LL/2) model using CXCL8-IP10.

Results: We found that CXCL8-IP10 markedly reduced LL/2 cell anchorage-independent growth and invasion. Moreover, we demonstrated that CXCL8-IP10 could significantly suppress tumor growth and improve survival rate as well as lifespan of C57BL/6 mice inoculated with LL/2 cells.

Conclusion: Our results suggest that ELR-CXC chemokine antagonism would potentially be a useful therapeutic approach in patients with lung cancer.
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http://dx.doi.org/10.2147/OTT.S215824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754332PMC
September 2019

Dietary Compliance Among Renal Transplant Recipients: A Single-Center Study in Taiwan.

Transplant Proc 2019 Jun 2;51(5):1325-1330. Epub 2019 May 2.

School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan; Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address:

Background: Extensive food and lifestyle changes are the major issues in renal transplant recipients (RTRs). Poor adherence to diet can contribute to increased health problems such as obesity, cardiovascular disease, and graft failure; however, comparative data regarding dietary compliance with the national recommendations has rarely been investigated, especially among RTRs in Taiwan.

Methods: In this descriptive analytical study, we compared patients' reported dietary intake of macronutrients and micronutrients with evidence-based guidelines developed for the nutritional management of adult kidney transplant recipients (NMAKTR) by the Dietitians Association of Australia. A total of 90 maintenance-phase RTRs were recruited from September 2016 to June 2018. All patients completed a 3-day dietary record (2 weekdays and 1 day on the weekend). In addition, routine anthropometric and laboratory data were obtained.

Results: The mean age, post-transplant years, and estimated glomerular filtration rate of participants were 49.7 ± 12.5 years, 9.1 ± 6.1 years, and 55.5 ± 20.8 mL/min/1.73 m, respectively. Daily energy and protein intakes were 1869.1 ± 383.5 kcal (30.4 ± 7.2 kcal/kg/d) and 66.9 ± 14.4 g (1.1 ± .2 g/kg/d), respectively. The percentage of energy intake from fat and saturated fat exceeded recommendations, whereas dietary fibers and calcium remained less than the recommended levels. At our center, a large percentage of RTRs did not meet NMAKTR dietary recommendations.

Conclusion: The low degree of dietary compliance calls for a continued effort to deliver effective nutritional advice in this population.
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http://dx.doi.org/10.1016/j.transproceed.2019.02.026DOI Listing
June 2019

Crosstalk between SOX2 and cytokine signaling in endometrial carcinoma.

Sci Rep 2018 12 3;8(1):17550. Epub 2018 Dec 3.

Department of Life Science and Institute of Biotechnology, National Tsing-Hua University, HsinChu, 300, Taiwan (R.O.C.).

Endometrial carcinoma is a cancer derived from oncogenesis of the regenerating uterine cavity, in which cytokine stimulation shapes cell differentiation and tissue remodeling. Expression of the stem cell factors SOX2, OCT4, NANOG, and MYC has been linked to tumor malignancy in several cancers. However, how these stem cell factors crosstalk with cytokine signaling to promote malignancy in endometrial carcinoma is still elusive. Here we report that the expression of SOX2 and MYC, but not that of OCT4 and NANOG, correlate with poor histological differentiation and prognosis, while SOX2 expression is negatively associated with MYC level. We found that SOX2-high endometrial carcinoma cells possessed a higher colony-forming ability than their SOX2-low counterparts, and knockdown of SOX2 attenuated the colony-forming ability. We observed that SOX2 regulated EGFR expression in a SOX2-EGFR positive feedback loop. EGF stimulation induced SOX2 expression and promoted migration of endometrial carcinoma cells, whereas TGF-β stimulation inhibited SOX2 expression and attenuated the colony-forming ability. Immunohistochemistry analysis revealed that SOX2 expression correlated with lymph node infiltration of endometrial carcinoma. Our findings support that cytokine-induced stem cell factor SOX2 possesses oncogenic properties, with the potential to serve as a prognostic biomarker in endometrial carcinoma.
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http://dx.doi.org/10.1038/s41598-018-35592-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277382PMC
December 2018

Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways.

Carcinogenesis 2019 05;40(3):461-473

Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.

Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5-phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA-mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and β-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and β-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIA-mediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC.
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http://dx.doi.org/10.1093/carcin/bgy155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514454PMC
May 2019

Protease-activated receptor 2 induces migration and promotes Slug-mediated epithelial-mesenchymal transition in lung adenocarcinoma cells.

Biochim Biophys Acta Mol Cell Res 2019 03 13;1866(3):486-503. Epub 2018 Oct 13.

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC; Department of Life Science, National Tsing Hua University, Hsinchu, 30013, Taiwan, ROC. Electronic address:

Protease-activated receptor 2 (PAR2), a G protein-coupled receptor for trypsin, contributes to growth, anti-apoptosis, and migration in lung cancer. Given that PAR2 activation in airway epithelial cells compromises the airway epithelium barrier by disruption of E-cadherin adhesion, PAR2 may be involved in epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells. Although PAR2 is known to promote the migration of lung cancer cells, the detailed mechanism of this event is still not clear. Here, we found that PAR2 is highly expressed in several lung adenocarcinoma cell lines. In two lung adenocarcinoma cell lines, CL1-5 and H1299 cells, activation of PAR2 induces migration and Slug-mediated EMT. The underlying mechanisms involved in PAR2-induced migration and EMT in CL1-5 cells were further investigated. We showed that PAR2-induced migration of CL1-5 cells is mediated by the Src/p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. β-arrestin 1, not G protein, is involved in this PAR2-mediated Src/p38 MAPK signaling pathway. PAR2-induced EMT in CL1-5 cells is dependent on the activation of extracellular-signal-regulated kinase 2 (ERK2). The activation of ERK2 further mediates Slug stabilization through suppressing the activity of glycogen synthase kinase 3β. In addition, a poor prognosis was observed in lung adenocarcinoma patients with a high expression of PAR2. Thus, PAR2 regulates migration through β-arrestin 1-dependent activation of p38 MAPK and EMT through ERK2-mediated stabilization of Slug in lung adenocarcinoma cells. Our finding also suggests that PAR2 might serve as a therapeutic target for metastatic lung adenocarcinoma and a potential biomarker for predicting the prognosis of lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.bbamcr.2018.10.011DOI Listing
March 2019

OCT4B mediates hypoxia-induced cancer dissemination.

Oncogene 2019 02 12;38(7):1093-1105. Epub 2018 Sep 12.

Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.

Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. OCT4, a homeobox transcription factor, is essential for self-renewal of embryonic stem cells, but little is known about the role of OCT4 in non-germ-cell tumorigenesis. Here, we report that hypoxia stimulates a short isoform of OCT4, called OCT4B, via a HIF2α-dependent pathway to induce the epithelial-mesenchymal transition (EMT) and facilitate cancer dissemination. OCT4B overexpression decreased epithelial barrier properties, which led to an increase in cell migration and invasion in lung cancer cells. OCT4B knockdown attenuated HIF2α-induced EMT and inhibited cancer dissemination in cell-line and animal models. We observed that OCT4B bound the SLUG promoter and enhanced its expression, and SLUG silencing inhibited OCT4B-mediated EMT, accompanied with decreased cell migration and invasion. Correlation analysis revealed that OCT4B expression was significantly associated with the SLUG level in lung tumors. These results provide novel insights into OCT4B-mediated oncogenesis in cancer dissemination.
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http://dx.doi.org/10.1038/s41388-018-0487-6DOI Listing
February 2019

Three-dimensional photography for the evaluation of facial profiles in obstructive sleep apnoea.

Respirology 2018 06 20;23(6):618-625. Epub 2018 Feb 20.

Sleep Center, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background And Objective: Craniofacial structure is an important determinant of obstructive sleep apnoea (OSA) syndrome risk. Three-dimensional stereo-photogrammetry (3dMD) is a novel technique which allows quantification of the craniofacial profile. This study compares the facial images of OSA patients captured by 3dMD to three-dimensional computed tomography (3-D CT) and two-dimensional (2-D) digital photogrammetry. Measurements were correlated with indices of OSA severity.

Methods: Thirty-eight patients diagnosed with OSA were included, and digital photogrammetry, 3dMD and 3-D CT were performed. Distances, areas, angles and volumes from the images captured by three methods were analysed.

Results: Almost all measurements captured by 3dMD showed strong agreement with 3-D CT measurements. Results from 2-D digital photogrammetry showed poor agreement with 3-D CT. Mandibular width, neck perimeter size and maxillary volume measurements correlated well with the severity of OSA using all three imaging methods. Mandibular length, facial width, binocular width, neck width, cranial base triangle area, cranial base area 1 and middle cranial fossa volume correlated well with OSA severity using 3dMD and 3-D CT, but not with 2-D digital photogrammetry.

Conclusion: 3dMD provided accurate craniofacial measurements of OSA patients, which were highly concordant with those obtained by CT, while avoiding the radiation associated with CT.
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http://dx.doi.org/10.1111/resp.13261DOI Listing
June 2018

Up-regulation of golgi α-mannosidase IA and down-regulation of golgi α-mannosidase IC activates unfolded protein response during hepatocarcinogenesis.

Hepatol Commun 2017 05 19;1(3):230-247. Epub 2017 Apr 19.

Institute of Molecular and Genomic Medicine National Health Research Institutes Zhunan Miaoli Taiwan.

α-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α-1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α-1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α-fetoprotein level, and invasion status were positively correlated with the expression levels of , and . In contrast, the expression of was decreased as early as stage I of HCC. Survival analyses showed that high , , and expression levels combined with low expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of promoted proliferation, migration, and transformation as well as migration in zebrafish. Conversely, overexpression of reduced the migration ability both and , decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in -overexpressing cells but decreased in -overexpressing cells. activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of -activated genes. Using the liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up-regulation of activates the UPR and might initiate metastasis. : MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. ( 2017;1:230-247).
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http://dx.doi.org/10.1002/hep4.1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721452PMC
May 2017

Identification of a noncanonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain.

PLoS Biol 2018 01 16;16(1):e2003714. Epub 2018 Jan 16.

Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.

Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA) in the pentose phosphate pathway (PPP) is known to promote tumorigenesis in liver, lung, and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC) is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of β-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC) and β-catenin. This association protects β-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acids 290 to 311), a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of β-catenin and its target genes, and induces tumorigenesis in gut-specific promotor-carrying RPIA transgenic zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes β-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.
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http://dx.doi.org/10.1371/journal.pbio.2003714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786329PMC
January 2018

The role of EpCAM in tumor progression and the clinical prognosis of endometrial carcinoma.

Gynecol Oncol 2018 02 6;148(2):383-392. Epub 2017 Dec 6.

Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan; Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan. Electronic address:

Objective: EpCAM is a transmembrane glycoprotein that functions as an epithelial marker in endometrial tissues. However, the correlation between EpCAM and endometrial carcinoma (EC) is not clear.

Methods: This study investigated the association between EpCAM and EC. Immunohistochemistry staining and bioinformatics analysis disclosed the clinical importance of low EpCAM expression. The migratory ability of cells expressing low EpCAM levels was studied in transwell invasion assays in vitro and an orthotopic intra-uterine tumor injection model in vivo. The Connectivity MAP was used to identify drugs that effectively inhibit cells with low EpCAM expression.

Results: According to immunohistochemistry analysis results, low EpCAM expression was associated with an advanced stage and lymph node metastasis in patients with endometrioid EC, and high EpCAM expression favored survival. EpCAM silencing promoted cell invasion, and EpCAM re-expression in EpCAM-silenced EC cells attenuated their invasiveness. EpCAM suppression in an orthotopic uterine implantation model promoted the lymph node metastasis of EC cells. According to quantitative PCR and promoter reporter analyses, estrogen receptor alpha signaling regulated EpCAM expression by enhancing its promoter activity. As shown in the Connectivity MAP analysis, transamin inhibited the invasiveness of EpCAM-silenced EC cells.

Conclusions: The loss of EpCAM may increase the malignancy of EC, and these findings provide new insights into the prognostic role of EpCAM in patients with EC.
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http://dx.doi.org/10.1016/j.ygyno.2017.11.033DOI Listing
February 2018

Modified Z-palatoplasty with one-layer closure in one-stage multilevel surgery for severe obstructive sleep apnea.

Auris Nasus Larynx 2018 Aug 6;45(4):791-795. Epub 2017 Nov 6.

Sleep Center of Chang Gung Memorial Hospital, Chiayi, Taiwan; Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; Department of Nursing, Chang-Gung University of Science and technology, Chiayi, Taiwan.

Objective: The meticulous two-layer closure is a step to complete the modified Z-palatoplasty, which has been reported to serve as an effective element in multilevel sleep surgery for patients with severe obstructive sleep apnea, especially with Friedman anatomical stages II and III diseases. A single layer closure-the suture closure as originally described in uvulopalatopharyngoplasty by Fujita et al., is an alternative of the two-layer closure, featured by simplicity while its efficacy has not been completely proved in patients with severe obstructive sleep apnea.

Methods: By apnea-hypopnea index (AHI), we investigated 7 patients with severe obstructive sleep apnea undergoing the modified Z-palatoplasty with one-layer closure in a multilevel surgery.

Results: The mean apnea-hypopnea index is reduced from 52.9±17.1 (preoperative) to 18.4±9.7 events/h (postoperative) without any wound dehiscence or bleeding that results in an unplanned return to the operating room. In comparison, the percentage of reduction in mean apnea-hypopnea index is 65%. The improvement of apnea-hypopnea index is statistically significant with the p-value 0.004.

Conclusion: Our results support that one-layer closure remains the efficacy of modified Z-palatoplasty (with two-layer closure) in one-stage multilevel surgery for severe obstructive sleep apnea with an unfavorable anatomical stage.
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http://dx.doi.org/10.1016/j.anl.2017.10.002DOI Listing
August 2018

Brain metastases in patients with non-small cell lung cancer: the role of mutated- with an exon 19 deletion or L858R point mutation in cancer cell dissemination.

Oncotarget 2017 Aug 16;8(32):53405-53418. Epub 2017 Jun 16.

Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan.

Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors () in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated- was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type (WT-). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-s predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% . 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated- subgroup was at a higher risk for SBM compared to the older WT- one (58.1% .10.9%, HR=6.57, P<0.001). Additionally, exon 19 deletion, despite having a slightly longer overall survival (20.6 . 14.2 months, P=0.368), was comparable to mutation in predicting SBM (39.5% . 34.5%, HR=0.91, P=0.770). , the overexpression of mutated-s induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated- NSCLC displayed a higher proportion of vimentin-positive expression (75.3% . 51.2%; P=0.007) and a shorter median time to SBM (23.5 months . not reached, P=0.017) than WT- NSCLC. These results suggest that NSCLC patients carrying mutated- may require a higher frequency of brain imaging assessments than those with WT- to facilitate earlier SBM detection during follow-up.
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http://dx.doi.org/10.18632/oncotarget.18509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581119PMC
August 2017

Levobuipivacaine-Induced Dissemination of A549 Lung Cancer Cells.

Sci Rep 2017 08 17;7(1):8646. Epub 2017 Aug 17.

Department of Anaesthesiology, Tri-Service General Hospital, National Defence Medical Centre, Taipei, 114, Taiwan.

While anaesthetics are frequently used on cancer patients during surgical procedures, their consequence on cancer progression remains to be elucidated. In this study, we sought to investigate the influence of local anesthetics on lung cancer cell dissemination in vitro and in vivo. A549 human non-small lung cancer cells were treated with various local anaesthetics including ropivacaine, lidocaine, levobupivacaine and bupivacaine. Cell barrier property was assessed using an electric cell-substrate impedance sensing (ECIS) system. The epithelial-to-mesenchymal transition (EMT) of treated cells was studied by immunofluorescence staining. In vitro and in vivo cancer cell dissemination were investigated.Gene expression microarray and quantitative real-time PCR (qrt-PCR) assays were used to identify the genes responsible for levobupivacaine-mediated cancer cell dissemination.The results illustrated that only levobupivacaine induced EMT in the treated cells and also caused the dissemination of cancer cells in vitro. In addition, after intravenous injection, levobupivacaine encouraged cancer cell dissemination in vivo. Gene expression microarray, qrt-PCR and immunoblotting revealed that after levobupivacaine treatment, the hypoxia-inducible factor (HIF)- 2α gene was upregulated in cancer cells. Our findings suggest that levobupivacaine may induce A549 lung cancer cell dissemination both in vitro and in vivo. More specifically, HIF-2α signaling possibly contributes to levobupivacaine-mediated A549 lung cancer cell dissemination.
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http://dx.doi.org/10.1038/s41598-017-08885-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561232PMC
August 2017

Identification of anti-HBV activities in Andr. using GRP78 as a drug target on Herbochip.

Chin Med 2017 24;12:11. Epub 2017 Apr 24.

Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.

Background: Herbochip technology is a high throughput drug screening platform in a reverse screening manner, in which potential chemical leads in herbal extracts are immobilized and drug target proteins can be used as probes for screening process [BMC Complementary and Alternative Medicine (2015) 15:146]. While herbal medicines represent an ideal reservoir for drug screenings, here a molecular chaperone GRP78 is demonstrated to serve as a potential target for antiviral drug discovery.

Methods: We cloned and expressed a truncated but fully functional form of human GRP78 (hGRP78) and used it as a probe for anti-HBV drug screening on herbochips. In vitro cytotoxicity and in vitro anti-HBV activity of the herbal extracts were evaluated by MTT and ELISA assays, respectively. Finally, anti-HBV activity was confirmed by in vivo assay using DHBV DNA levels in DHBV-infected ducklings as a model.

Results: Primary screenings using GRP78 on 40 herbochips revealed 11 positives. Four of the positives, namely , , and were subjected to subsequent assays. None of the above extracts was cytotoxic to AML12 cells, but extract (PCE) was found to be cytotoxic to HepG2 2.2.15 cells. Both PCE and extract (PSE) suppressed secretion of HBsAg and HBeAg in HepG2 2.2.15 cells. The anti-HBV activity of PSE was further confirmed in vivo.

Conclusion: We have demonstrated that GRP78 is a valid probe for anti-HBV drug screening on herbochips. We have also shown that PSE, while being non-cytotoxic, possesses in vitro and in vivo anti-HBV activities. Taken together, our data suggest that PSE may be a potential anti-HBV agent for therapeutic use.
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http://dx.doi.org/10.1186/s13020-017-0132-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402670PMC
April 2017

α2,3-sialyltransferase type I regulates migration and peritoneal dissemination of ovarian cancer cells.

Oncotarget 2017 Apr;8(17):29013-29027

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.

Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecologic cancers due to advanced stage presentation, peritoneal dissemination, and refractory ascites at diagnosis. We investigated the role of α2,3-sialyltransferase type I (ST3GalI) by analyzing human ovarian cancer datasets and human EOC tissue arrays. We found that high expression of ST3GalI was associated with advanced stage EOC. Transwell migration and cell invasion assays showed that high ST3GalI expression enhanced migration of EOC cells. We also observed that there was a linear relation between ST3GalI expression and epidermal growth factor receptor (EGFR) signaling in EOC patients, and that high ST3GalI expression blocked the effect of EGFR inhibitors. Co-Immunoprecipitation experiments demonstrated that ST3GalI and EGFR were present in the same protein complex. Inhibition of ST3GalI using a competitive inhibitor, Soyasaponin I (SsaI), inhibited tumor cell migration and dissemination in the in vivo mouse model with transplanted MOSEC cells. Further, SsaI synergistically enhanced the anti-tumor effects of EGFR inhibitor on EOC cells. Our study demonstrates that ST3GalI regulates ovarian cancer cell migration and peritoneal dissemination via EGFR signaling. This suggests α2,3-linked sialylation inhibitors in combination with EGFR inhibitors could be effective agents for the treatment of EOC.
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http://dx.doi.org/10.18632/oncotarget.15994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438708PMC
April 2017

Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition.

Cancer Res 2017 06 5;77(11):3013-3026. Epub 2017 Apr 5.

Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3168DOI Listing
June 2017

Antagonistic effect of N-ethylmaleimide on arsenic-mediated oxidative stress-induced poly(ADP-ribosyl)ation and cytotoxicity.

J Appl Toxicol 2017 05 4;37(5):573-582. Epub 2016 Nov 4.

Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, People's Republic of China.

Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As O ) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H O )-induced PARylation was suppressed by As O exposure in different human cancer cells. Moreover, As O treatment promoted H O -induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As O -mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l-buthionine-sulfoximine blocked the antagonistic effect of NEM on As O , thereby continuing As O -mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As O -mediated DNA damage in a glutathione-dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jat.3394DOI Listing
May 2017

Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity.

Cancer Res 2016 12 7;76(23):7036-7048. Epub 2016 Oct 7.

Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.

Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM-p21-cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036-48. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3178DOI Listing
December 2016