wei-chao Chang - Academia.edu (original) (raw)

Papers by wei-chao Chang

Anticancer Research, 2022

Background/Aim: The poor prognosis and chemoresistance of patients with triple-negative breast ca... more Background/Aim: The poor prognosis and chemoresistance of patients with triple-negative breast cancer (TNBC) urge the development of new therapeutic strategies. Snail mucus has shown its ability against inflammation, a process closely related to tumorigenesis, suggesting a potential anti-cancer activity. Materials and Methods: The effect and mechanisms of snail mucus on cell viability were determined by IncuCyte Live-cell analysis and molecular biological methods. The anti-cancer fractions of snail mucus were isolated and identified by medium pressure liquid chromatography (MPLC) and nuclear magnetic resonance (NMR) spectrometry analysis. Results: Snail mucus significantly decreased the viability of TNBC cells with relatively lower cytotoxicity to normal breast epithelial cells and enhanced their response to chemotherapy through activation of Fas signaling by suppressing nucleolin. Two peptide fractions have been identified as the anti-cancer ingredients of the snail mucus. Conclusion: Snail mucus can induce programmed cell death via the extrinsic apoptotic pathway and has therapeutic potential by achieving a chemo-sensitizing effect in TNBCs.

Pharmaceuticals, 2021

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading ... more Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK ...

Redox Biology, 2020

EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-RO... more EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis, Redox Biology (2020), doi:

Theranostics, 2020

Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by ... more Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure. Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression. Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression. Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.

Environmental toxicology, Jan 19, 2017

Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a... more Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water-soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive....

Nature medicine, Jan 18, 2016

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many di... more Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 ...

Journal of Clinical Investigation, 2015

American journal of translational research, 2015

BikDD, a phosphorylation-mimic mutant of pro-apoptotic protein Bik, elicits strong apoptosis in c... more BikDD, a phosphorylation-mimic mutant of pro-apoptotic protein Bik, elicits strong apoptosis in cancer cells when introduced via an expression platform termed VP16-GAL4-WPRE integrated systemic amplifier (VISA) under the control of a cancer-specific promoter both in vitro and in vivo. C-VISA-BikDD expression plasmid encapsulated in liposomes is currently in the process to initiate a phase I clinical trial for pancreatic cancer. In this study, we report a potential combination approach of BikDD with proteasome inhibitors on the basis of our findings that exogenously expressed BikDD protein undergoes proteasome-mediated degradation via both ubiquitin-dependent and -independent pathways. Inhibition of proteasome increases the protein stability of BikDD, enhancing the apoptotic effect of BikDD. Hence, high proteasome activity may be a mechanism by which intrinsic and acquired resistance occurs in BikDD gene therapy, and a combination therapy with current clinically approved proteasome i...

American journal of translational research, 2014

Nuclear translocation of EGFR has been shown to be important for tumor cell growth, survival, and... more Nuclear translocation of EGFR has been shown to be important for tumor cell growth, survival, and therapeutic resistance. Previously, we detected the association of EGFR with Keap1 in the nucleus. Keap1 is a Kelch-like ECH-associated protein, which plays an important role in cellular response to chemical and oxidative stress by regulating Nrf2 protein stability and nuclear translocation. In this study, we investigate the role of EGFR in regulating Keap1/Nrf2 cascade in the nucleus and provide evidence to show that nuclear EGFR interacts with and phosphorylates nuclear Keap1 to reduce its nuclear protein level. The reduction of nuclear Keap1 consequently stabilizes nuclear Nrf2 and increases its transcriptional activity in cancer cells, which contributes to tumor cell resistance to chemotherapy.

Proteome Science, 2012

Background: CD133-positive liver cancer stem cells, which are characterized by their resistance t... more Background: CD133-positive liver cancer stem cells, which are characterized by their resistance to conventional chemotherapy and their tumor initiation ability at limited dilutions, have been recognized as a critical target in liver cancer therapeutics. In the current work, we developed a label-free quantitative method to investigate the proteome of CD133-positive liver cancer stem cells for the purpose of identifying unique biomarkers that can be utilized for targeting liver cancer stem cells. Label-free quantitation was performed in combination with ID-based Elution time Alignment by Linear regression Quantitation (IDEAL-Q) and MaxQuant. Results: Initially, IDEAL-Q analysis revealed that 151 proteins were differentially expressed in the CD133-positive hepatoma cells when compared with CD133-negative cells. We then analyzed these 151 differentially expressed proteins by MaxQuant software and identified 10 significantly up-regulated proteins. The results were further validated by RT-PCR, western blot, flow cytometry or immunofluorescent staining which revealed that prominin-1, annexin A1, annexin A3, transgelin, creatine kinase B, vimentin, and EpCAM were indeed highly expressed in the CD133-positive hepatoma cells. Conclusions: These findings confirmed that mass spectrometry-based label-free quantitative proteomics can be used to gain insights into liver cancer stem cells.

Science Signaling, 2014

Activating a deacetylase may overcome resistance to a receptor-targeted inhibitor in some breast ... more Activating a deacetylase may overcome resistance to a receptor-targeted inhibitor in some breast cancer patients.

REPRODUCTION, 2008

We report a secreted serine protease inhibitor Kazal-type-like (SPINKL) protein. The SPINKL prote... more We report a secreted serine protease inhibitor Kazal-type-like (SPINKL) protein. The SPINKL protein was purified from mouse seminal vesicle secretions through a series of steps, including ion-exchange chromatography on a diethylaminoethyl-Sephacel column, gel filtration on a Sephadex G-75 column, and ion-exchange HPLC on a Q strong anion exchange column. Further analysis identified several SPINKL proteins with various N-linked carbohydrates. The SPINKL protein has six conserved cysteine residues that are nearly identical to those of members of the SPINK protein family. It was noted that the SPINKL protein showed no inhibitory activities against common serine proteases such as trypsin, chymotrypsin, subtilisin, or elastase. Spinkl mRNA and SPINKL proteins were found to be primarily expressed in seminal vesicles. Immunohistochemistry revealed that the SPINKL protein occurred in the luminal fluid and mucosal epithelium of the seminal vesicles and was regulated by testosterone. The SPIN...

PROTEOMICS – CLINICAL APPLICATIONS, 2008

Biomarkers for various diseases have been extensively searched for the past 5 years. Nevertheless... more Biomarkers for various diseases have been extensively searched for the past 5 years. Nevertheless, most efforts were focused on the search for protein biomarkers from serum samples. In this work, we tried to look for peptide biomarkers from gastric juice samples with MALDI-TOF-MS. More than 200 gastric juice samples from healthy people, gastric ulcer patients, duodenal ulcer patients, and cancer patients were examined. There were clear pattern differences of mass spectra among samples from healthy people and patients with different gastric diseases. We found five peptides for gastric cancer diagnosis with high sensitivity and specificity. Sequences of these five peptides, including two pepsinogen fragments, leucine zipper protein fragment, albumin fragment, and a-1-antitrypsin fragment, have been identified by mass spectrometric analysis and immuno-deplete assay with antibodies.

Proceedings of the National Academy of Sciences, 2010

EGF induces the translocation of EGF receptor (EGFR) from the cell surface to the nucleus where E... more EGF induces the translocation of EGF receptor (EGFR) from the cell surface to the nucleus where EGFR activates gene transcription through its binding to an AT-rich sequence (ATRS) of the target gene promoter. However, how EGFR, without a DNA-binding domain, can bind to the gene promoter is unclear. In the present study, we show that RNA helicase A (RHA) is an important mediator for EGFR-induced gene transactivation. EGF stimulates the interaction of EGFR with RHA in the nucleus of cancer cells. The EGFR/RHA complex then associates with the target gene promoter through binding of RHA to the ATRS of the target gene promoter to activate its transcription. Knockdown of RHA expression in cancer cells abrogates the binding of EGFR to the target gene promoter, thereby reducing EGF/EGFR-induced gene expression. In addition, interruption of EGFR–RHA interaction decreases the EGFR-induced promoter activity. Consistently, we observed a positive correlation of the nuclear expression of EGFR, RH...

Molecular Cell, 2012

Proinflammatory cytokine TNFa plays critical roles in promoting malignant cell proliferation, ang... more Proinflammatory cytokine TNFa plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFa-mediated tumor development remains unclear. Here, we show that IKKa, an important downstream kinase of TNFa, interacts with and phosphorylates FOXA2 at S107/S111, thereby suppressing FOXA2 transactivation activity and leading to decreased NUMB expression, and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKa, pFOXA2 (S107/ 111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKa and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFa/IKKa-associated FOXA2 inhibition likely contributes to inflammationmediated cancer pathogenesis. Here, we report a TNFa/IKKa/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.

Microelectronics Reliability, 2014

Different structures of a-IGZO (amorphous indium gallium zinc oxide) transparent thin film transi... more Different structures of a-IGZO (amorphous indium gallium zinc oxide) transparent thin film transistor (TTFT) were developed on glass substrate for study of gate barrier and channel buffer layer effects. The used gate barrier and the channel buffer layer are high energy band gap dielectric Al 2 O 3 and the rapid thermally annealed ZnO film, respectively. With both gate barrier and channel buffer layers, the TTFT promoted 3ordersinon/offcurrentratioandreducedleakagescurrent3 orders in on/off current ratio and reduced leakages current 3ordersinon/offcurrentratioandreducedleakagescurrent800 times. Furthermore, the average transparence was also enhanced from 84% to 86.4% in the range of 500-800 nm wavelengths. The improvement mechanisms are interpreted with comprehensive models in details.

Journal of Experimental Medicine, 2012

Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes poly(ADP-ribosylation) (PARylation) and induces r... more Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes poly(ADP-ribosylation) (PARylation) and induces replication networks involved in multiple nuclear events. Using mass spectrometry and Western blotting, Parp1 and PARylation activity were intensively detected in induced pluripotent stem cells (iPSCs) and embryonic stem cells, but they were lower in mouse embryonic fibroblasts (MEFs) and differentiated cells. We show that knockdown of Parp1 and pharmacological inhibition of PARylation both reduced the efficiency of iPSC generation induced by Oct4/Sox2/Klf4/c-Myc. Furthermore, Parp1 is able to replace Klf4 or c-Myc to enhance the efficiency of iPSC generation. In addition, mouse iPSCs generated from Oct4/Sox2/Parp1-overexpressing MEFs formed chimeric offspring. Notably, the endogenous Parp1 and PARylation activity was enhanced by overexpression of c-Myc and repressed by c-Myc knockdown. A chromatin immunoprecipitation assay revealed a direct interaction of c-Myc with the Parp1 promoter. P...

Journal of Biological Chemistry, 2012

Background: Nuclear translocation and activity of EGFR are correlated with radioresistance of can... more Background: Nuclear translocation and activity of EGFR are correlated with radioresistance of cancer. Results: PNPase, identified as a novel EGFR interacting partner, is inactivated by DNAPK-mediated Ser-776 phosphorylation and contributes to radiosensitivity of cancer. Conclusion: An entirely new mechanism of nuclear EGFR in radioresistance is discovered. Significance: This study provides new insight into resistance of breast cancer to radiotherapy. Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than two decades. Resistance of cancer to radiotherapy is frequently correlated with elevated EGFR expression, activity, and nuclear translocation. However, the role of nuclear EGFR (nEGFR) in radioresistance of cancers remains elusive. In the current study, we identified a novel nEGFR-associated protein, polynucleotide phosphorylase (PNPase), which possesses 3 to 5 exoribonuclease activity toward c-MYC mRNA. Knockdown of PNPase increased radioresistance. Inactivation or knock-down of EGFR enhanced PNPase-mediated c-MYC mRNA degradation in breast cancer cells, and also increased its radiosensitivity. Interestingly, the association of nEGFR with PNPase and DNA-dependent protein kinase (DNAPK) increased significantly in breast cancer cells after exposure to ionizing radiation (IR). We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. The phosphomimetic S776D mutant of PNPase impaired its ribonuclease activity whereas the nonphosphorylatable S776A mutant effectively degraded c-MYC mRNA. Here, we uncovered a novel role of nEGFR in radioresistance, and that is, upon ionizing radiation, nEGFR inactivates the ribonuclease activity of PNPase toward c-MYC mRNA through DNAPK-mediated Ser-776 phosphorylation, leading to increase of c-MYC mRNA, which contributes to radioresistance of cancer cells.

Hormone and Metabolic Research, 2010

Cell-cell interactions play a crucial role during embryogenesis and are enhanced during cell aggr... more Cell-cell interactions play a crucial role during embryogenesis and are enhanced during cell aggregation. P19 mouse embryonic carcinoma cells can differentiate into neural cells by the addition of retinoic acid (RA) or by overexpression of the Wnt1 gene, with both processes dependent on cell aggregation. To identify molecules involved in the cell aggregation process, two-dimensional gel electrophoresis (2DE) was used to establish the cell aggregation-associated protein profiles. MALDI-TOF/TOF was used to identify 71 protein spots with differential expression patterns. Among these spots, 54 were differentially expressed in both P19 and Wnt1-overexpressing P19 (Wnt1/P19) cell aggregates, with 42 proteins up-regulated and 12 proteins down-regulated. The other 17 spots were differentially expressed only in Wnt1/P19 cells. The expression patterns of 5 cell aggregation-associated proteins, N-myc downstream-regulated gene 1 (NDRG1), 14-3-3 epsilon, 14-3-3 gamma, acid calponin and cell division control protein 2 homologue (Cdc2), were confirmed by immunoblot and RT-PCR. To further investigate the relationship between cell aggregation and neural differentiation, NDRG1 expression was inhibited by RNA interference during P19 cell aggregation. Silencing of NDRG1 reduced the size of cell aggregates and the expression of N-cadherin, and it also impaired the RA-induced P19 cell neural differentiation. In conclusion, this study provides new clues for the possible mechanism underlying cell aggregation during pluripotent stem cell neural differentiation.

Clinical Cancer Research, 2009

Integral membrane proteins contain a hydrophobic transmembrane domain and mainly locate in the pl... more Integral membrane proteins contain a hydrophobic transmembrane domain and mainly locate in the plasma membrane lipid bilayer. The receptor tyrosine kinases (RTK) of the epidermal growth factor receptor (EGFR) superfamily, including ErbB-1, ErbB-2, ErbB-3, and ErbB-4, constitute an important group of such membrane proteins, which have a profound impact on cancer initiation, progression, and patient outcome. Although studies of their functions have conventionally focused on their membrane-associated forms, documented observations of the presence of these membrane receptors and their functioning partners in the nucleus have reshaped the intracellular geography and highlight the need to modify the central dogma. The ErbB proteins in the membrane can translocate to the nucleus through different mechanisms. Nuclear RTKs regulate a variety of cellular functions, such as cell proliferation, DNA damage repair, and signal transduction, both in normal tissues and in human cancer cell. In addit...