Can supervise: YES
Zhong, H-J, Sun, H-H, Xue, L-F, McGowan, EM & Chen, Y 2019, 'Differential hepatic features presenting in Wilson disease-associated cirrhosis and hepatitis B-associated cirrhosis.', World journal of gastroenterology, vol. 25, no. 3, pp. 378-387.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM:To delineate the liver features between WD-associated cirrhosis and hepatitis B-associated cirrhosis in the Chinese population. METHODS:In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS:No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WD-associated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.3...
Ren, M, McGowan, E, Li, Y, Zhu, X, Lu, X, Lin, Y & He, S 2019, 'Saikosaponin-d Suppresses COX2 through p-STAT3/C/EBPβ Signaling Pathway in Liver Cancer: a Novel Mechanism of Action', Frontiers in Pharmacology, vol. 10, pp. 1-12.View/Download from: UTS OPUS or Publisher's site
Saikosaponin d (SSd) is an active extract from Radix Bupleuri, the dried root from the plant Bupleurum falcatum used in China for thousands of years to treat liver diseases. The SSd extract possesses valuable pharmacological activities including anti-cancer and anti-inflammatory effects, however, the mechanism underlying the anti-cancer activity of SSd is largely unknown. Here we explored the mechanism of action of SSd as an anti-cancer agent for liver cancer in two human hepatocellular carcinoma cell lines. Using MTT and annexin-V-FITC/PI assays, Western blots, immunohistochemistry, qRT-PCR, luciferase reporter assay, and a JAK2 specific-inhibitor (AG490), we demonstrated that the anti-tumorigenic effects of SSd acts through the intermediatory p-STAT3/C/EBPβ signaling pathway to suppress cyclooxygenase (COX)-2. SSd effectively inhibited cell proliferation in a dose-dependent manner. Apoptosis was significantly increased in cells treated with SSd (2.5 µg/ml-15 µg/ml) with concurrent increase and decrease in pro-and anti-apoptosis proteins, respectively. COX-2, C/EBPβ, and p-STAT3 were significantly decreased, at both the translational and transcriptional levels, by SSd treatment. AG490 produced similar inhibitory effects on STAT3, p-STAT3, C/EBPβ and COX-2. In conclusion, our data suggests that SSd controls liver cancer proliferation through suppression of the p-STAT3/C/EBPβ signaling pathway inhibiting COX2 expression. These findings further our understanding of the pharmacological action of SSd providing new information on SSd mechanism of action and shows potential for SSd as a novel therapy for liver cancer.
Hu, P, Chen, H, McGowan, E, Ren, N, Xu, M & Lin, Y 2018, 'Assessment of FGFR1 Overexpression and Over-Activity in Lung Cancer Cells: A Toolkit for Anti-FGFR1 Drug Screening', Human Gene Therapy, vol. 29, no. 1.View/Download from: UTS OPUS or Publisher's site
Lung cancer, mainly caused by smoking, is one of the most prevalent diseases in China resulting in high mortality rates. The increasing incidence of chronic disease due to lung cancer places a huge burden on the welfare and cost to the Chinese society. Amplification of the fibroblast growth factor receptor 1 (FGFR1) is associated with high incidence and mortality in lung cancer patients. FGFR1 signaling is implicated in oncogenic traits such as proliferation, cell survival, angiogenesis and migration. Targeting the FGFR1 and its ligand basic FGF (bFGF) is a key step forward in developing new therapies for this crippling disease. Lung adenocarcinoma is the most common subtype of non-small cell lung cancer. In this study A549, a lung adenocarcinoma cell line widely used in vitro as a model for drug metabolism and as a transfection host, was used to study FGFR1. Here we describe a stable lentiviral FGFR1 overexpression system in lung cancer cells for the study of anti-lung cancer drug candidates targeting FGFR1. Ligand binding to FGFR1 activates the PI3K/Akt/mTOR signaling pathway and increases adhesion, invasion and migration in this model. Using a unique FGF monoclonal antibody developed in our laboratory we effectively blocked the overactive PI3K pathway abrogating the negative metastatic signaling pathways in lung cancer cells. Importantly, this model provides an effective and simple screening kit for anti-FGF1 drug compounds for lung cancer treatment and a tool for understanding the molecular mechanisms of the FGFR1 signaling pathway in lung cancer. Furthermore, this toolkit based on a FGFR1 lentiviral construct model is transferrable to study FGFR1 signaling in any type of cancer cell.
Boonyaratanakornkit, V, Hamilton, N, Márquez-Garbán, DC, Pateetin, P, McGowan, EM & Pietras, RJ 2018, 'Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer', Molecular and Cellular Endocrinology, vol. 466, pp. 51-72.View/Download from: UTS OPUS or Publisher's site
© 2017 Elsevier B.V. Estrogen and progesterone play essential roles in the development and progression of breast cancer. Over 70% of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), emphasizing the need for better understanding of ER and PR signaling. ER and PR are traditionally viewed as transcription factors that directly bind DNA to regulate gene networks. In addition to nuclear signaling, ER and PR mediate hormone-induced, rapid extranuclear signaling at the cell membrane or in the cytoplasm which triggers downstream signaling to regulate rapid or extended cellular responses. Specialized membrane and cytoplasmic proteins may also initiate hormone-induced extranuclear signaling. Rapid extranuclear signaling converges with its nuclear counterpart to amplify ER/PR transcription and specify gene regulatory networks. This review summarizes current understanding and updates on ER and PR extranuclear signaling. Further investigation of ER/PR extranuclear signaling may lead to development of novel targeted therapeutics for breast cancer management.
Bhullar, KS, Lagarón, NO, McGowan, EM, Parmar, I, Jha, A, Hubbard, BP & Rupasinghe, HPV 2018, 'Kinase-targeted cancer therapies: Progress, challenges and future directions', Molecular Cancer, vol. 17, no. 1.View/Download from: UTS OPUS or Publisher's site
© 2018 The Author(s). The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
McGowan, E, Lin, Y & Hatoum, D 2018, 'Good Guy or Bad Guy? The Duality ofWild-Type p53in Hormone-Dependent Breast Cancer Origin,Treatment, and Recurrence', Cancers, vol. 10, pp. 1-23.View/Download from: UTS OPUS or Publisher's site
Abstract: 'Lactation is at one point perilously near becoming a cancerous process if it is at all arrested',
Beatson, 1896. Most breast cancers arise from the milk-producing cells that are characterized by
aberrant cellular, molecular, and epigenetic translation. By understanding the underlying molecular
disruptions leading to the origin of cancer, we might be able to design novel strategies for more
efficacious treatments or, ambitiously, divert the cancerous process. It is an established reality
that full-term pregnancy in a young woman provides a lifetime reduction in breast cancer risk,
whereas delay in full-term pregnancy increases short-term breast cancer risk and the probability of
latent breast cancer development. Hormonal activation of the p53 protein (encode by the TP53 gene)
in the mammary gland at a critical time in pregnancy has been identified as one of the most important
determinants of whether the mammary gland develops latent breast cancer. This review discusses
what is known about the protective influence of female hormones in young parous women, with a
specific focus on the opportune role of wild-type p53 reprogramming in mammary cell differentiation.
The importance of p53 as a protector or perpetrator in hormone-dependent breast cancer, resistance to
treatment, and recurrence is also explored.
Moulder, D, Hatoum, D, Tay, E, Lin, Y & McGowan, E 2018, 'The Roles of p53 in Mitochondrial Dynamics andCancer Metabolism: The Pendulum between Survivaland Death in Breast Cancer?', Cancers, vol. 10, no. 189, pp. 1-22.View/Download from: UTS OPUS or Publisher's site
Abstract: Cancer research has been heavily geared towards genomic events in the development
and progression of cancer. In contrast, metabolic regulation, such as aberrant metabolism in
cancer, is poorly understood. Alteration in cellular metabolism was once regarded simply as a
consequence of cancer rather than as playing a primary role in cancer promotion and maintenance.
Resurgence of cancer metabolism research has identified critical metabolic reprogramming events
within biosynthetic and bioenergetic pathways needed to fulfill the requirements of cancer cell growth
and maintenance. The tumor suppressor protein p53 is emerging as a key regulator of metabolic
processes and metabolic reprogramming in cancer cells—balancing the pendulum between cell death
and survival. This review provides an overview of the classical and emerging non-classical tumor
suppressor roles of p53 in regulating mitochondrial dynamics: mitochondrial engagement in cell
death processes in the prevention of cancer. On the other hand, we discuss p53 as a key metabolic
switch in cellular function and survival. The focus is then on the conceivable roles of p53 in breast
cancer metabolism. Understanding the metabolic functions of p53 within breast cancer metabolism
will, in due course, reveal critical metabolic hotspots that cancers advantageously re-engineer for
sustenance. Illustration of these events will pave the way for finding novel therapeutics that target
cancer metabolism and serve to overcome the breast cancer burden.
Haddadi, N, Lin, Y, Travis, G, Simpson, AM, Nassif, NT & McGowan, EM 2018, 'PTEN/PTENP1: 'Regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy.', Molecular cancer, vol. 17, no. 1.View/Download from: UTS OPUS or Publisher's site
Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.
Lan, C, Peng, H, McGowan, EM, Hutvagner, G & Li, J 2018, 'An isomiR expression panel based novel breast cancer classification approach using improved mutual information.', BMC medical genomics, vol. 11, no. Suppl 6, pp. 118-118.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Gene expression-based profiling has been used to identify biomarkers for different breast cancer subtypes. However, this technique has many limitations. IsomiRs are isoforms of miRNAs that have critical roles in many biological processes and have been successfully used to distinguish various cancer types. Biomarker isomiRs for identifying different breast cancer subtypes has not been investigated. For the first time, we aim to show that isomiRs are better performing biomarkers and use them to explain molecular differences between breast cancer subtypes. RESULTS:In this study, a novel method is proposed to identify specific isomiRs that faithfully classify breast cancer subtypes. First, as a null hypothesis method we removed the lowly expressed isomiRs from small sequencing data generated from diverse breast cancers types. Second, we developed an improved mutual information-based feature selection method to calculate the weight of each isomiR expression. The weight of isomiR measures the importance of a given isomiR in classifying breast cancer subtypes. The improved mutual information enables to apply the dataset in which the feature is continuous data and label is discrete data; whereby, the traditional mutual information cannot be applied in this dataset. Finally, the support vector machine (SVM) classifier is applied to find isomiR biomarkers for subtyping. CONCLUSIONS:Here we demonstrate that isomiRs can be used as biomarkers in the identification of different breast cancer subtypes, and in addition, they may provide new insights into the diverse molecular mechanisms of breast cancers. We have also shown that the classification of different subtypes of breast cancer based on isomiRs expression is more effective than using published gene expression profiling. The proposed method provides a better performance outcome than Fisher method and Hellinger method for discovering biomarkers to distinguish different breast cancer subtypes. This novel techniqu...
Chen, H, McGowan, E, Ren, N, Nassif, N, Lal, S, Qu, X & Lin, Y 2018, 'Nattokinase: A Promising Alternative in Prevention andTreatment of Cardiovascular Diseases', Biomarker Insights, vol. 13.View/Download from: UTS OPUS or Publisher's site
Cardiovascular disease (CVD) is the leading cause of death in the world, however our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, lipid lowering, anti-platelet and neuroprotective effects. This review covers the major pharmacological effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for CVD patients and is therefore an ideal drug candidate for the prevention and treatment of CVD. NK is therefore a promising alternative in the management of CVD.
Ren, N, Chen, H, Li, Y, McGowan, E & Lin, Y 2017, 'A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia', Zhonghua Yixue Zazhi, vol. 97, no. 26, pp. 2038-2043.View/Download from: UTS OPUS or Publisher's site
A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia Nina Ren*, Hongjie Chen#, Yue Li, Eileen Mcgowan, Yiguang Lin.* Guangdong Online Hospital Clinic, Guangdong 2nd Provincial People's Hospital, Guangzhou 510317，China；#Department of Traditional Chinese Medicine, the 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630，China
Corresponding author: Yiguang Lin, School of Life Sciences, University of Technology Sydney, Broadway NSW 2007, Australia，Email: firstname.lastname@example.org
[Abstract] Objectives To evaluate the efficacy of oral nattokinase (NK) in the reduction of common carotid artery intimal medial thickness (CCA-IMT) and carotid artery plaque size and in lowering blood lipids, and to explore the underlying mechanism of actions of NK and its potential clinical use. Methods All enrolled patients were from the Out-Patient Clinic of the Department of TCM at the 3rd Affiliated Hospital of Sun Yat-sen University. Using randomised picking method, all patients were randomly assigned to one of two groups, NK and Statin (ST). NK Group-patients were given NK at a daily dose of 6000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks. CCA-IMT, carotid plaque size and blood lipid profile of the patients were measured before and after treatment. Results A total of 82 patients were enrolled in the study and 76 patients (NK=39, ST=37) completed the study. Following the treatments for 26 weeks, there was a significant reduction in CCA-IMT and carotid plaque size in both groups compared with the baseline before treatment. The carotid plaque size and CCA-IMT reduced from 0.25±0.12cm2 to 0.16±0.10cm2 and from 1.13±0.12mm to 1.01±0.11mm,repectively. The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group). Both treatments reduced total cholesterol (TC), low-density lipoprotein c...
Haddadi, N, Lin, Y, Simpson, AM, Nassif, NT & McGowan, EM 2017, ''Dicing and Splicing' Sphingosine Kinase and Relevance to Cancer', International Journal of Molecular Sciences, vol. 18, no. 9, pp. 1-25.View/Download from: UTS OPUS or Publisher's site
Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or 'non-oncogenic addiction'. Here we discuss additional theories of SphK cellular mislocation and aberrant 'dicing and splicing' as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics.
Hatoum, D, Haddadi, N, Lin, Y, Nassif, NT & McGowan, EM 2017, 'Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget.', Oncotarget, vol. 8, no. 22, pp. 36898-36929.View/Download from: UTS OPUS or Publisher's site
The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.
Hatoum, D, Yagoub, D, Ahadi, A, Nassif, NT & McGowan, EM 2017, 'Annexin/S100A protein family regulation through p14ARF-p53 activation: A role in cell survival and predicting treatment outcomes in breast cancer', PLoS ONE, vol. 12, no. 1.View/Download from: UTS OPUS or Publisher's site
© 2017 Hatoum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The annexin family and S100A associated proteins are important regulators of diverse calcium- dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.
Winata, P, Williams, M, McGowan, E, Nassif, N, Van Zandwijk, N & Reid, G 2017, 'The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection', BMC Research Notes, vol. 10, no. 1, pp. 1-7.View/Download from: UTS OPUS or Publisher's site
© 2017 The Author(s). Objective: MicroRNAs are frequently downregulated in cancer, and restoring expression has tumour suppressive activity in tumour cells. Our recent phase I clinical trial investigated microRNA-based therapy in patients with malignant pleural mesothelioma. Treatment with TargomiRs, microRNA mimics with novel sequence packaged in EGFR antibody-targeted bacterial minicells, revealed clear signs of clinical activity. In order to detect delivery of microRNA mimics to tumour cells in future clinical trials, we tested hydrolysis probe-based assays specific for the sequence of the novel mimics in transfected mesothelioma cell lines using RT-qPCR. Results: The custom assays efficiently and specifically amplified the consensus mimics. However, we found that these assays gave a signal when total RNA from untransfected and control mimic-transfected cells were used as templates. Further investigation revealed that the reverse transcription step using stem-loop primers appeared to introduce substantial non-specific amplification with either total RNA or synthetic RNA templates. This suggests that reverse transcription using stem-loop primers suffers from an intrinsic lack of specificity for the detection of highly similar microRNAs in the same family, especially when analysing total RNA. These results suggest that RT-qPCR is unlikely to be an effective means to detect delivery of microRNA mimic-based drugs to tumour cells in patients.
Udommethaporn, S, Tencomnao, T, McGowan, EM & Boonyaratanakornkit, V 2016, 'Assessment of anti-TNF-α activities in keratinocytes expressing inducible TNF- α: A novel tool for anti-TNF-α drug screening', PLoS ONE, vol. 11, no. 7.View/Download from: UTS OPUS or Publisher's site
© 2016 Udommethaporn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine important in normal and pathological biological processes. Newly synthesized pro-TNF-α is expressed on the plasma membrane and cleaved to release soluble TNF-α protein: both are biologically active. Secreted TNF-α signals through TNF receptors and the membrane-bound TNF-α acts by cell contact-dependent signaling. Anti-TNF-α antibodies have been used effectively for treatment of chronic inflammation, however with adverse side effects. Thus, there is a need for new anti-TNF-α small molecule compounds. Anti-TNF-α activity assays involve treatment of keratinocytes with exogenous TNF-α before or after anti-TNF-α incubation. However, this model fails to address the dual signaling of TNF-α. Here we describe a Doxycycline (Dox)-inducible TNF-α (HaCaT-TNF-α) expression system in keratinocytes. Using this in-vitro model, we show cell inhibition and induced expression of pro-inflammatory cytokines and markers, including IL-1β, IL-6, IL-8, NF-êB1, and KRT-16, similar to cells treated with exogenous TNF-α. Sufficient secreted TNF-α produced also activated IL-1β and IL-8 expression in wt HaCaT cells. Importantly, stimulated expression of IL-1β and IL-8 in HaCaT-TNF-α were blocked by Quercetin, a flavanol shown to possess anti-TNF-α activities. This novel in vitro cell model provides an efficient tool to investigate the dual signaling of TNF-α. Importantly, this model provides an effective, fast, and simple screening for compounds with anti-TNF-α activities for chronic inflammatory disease therapies.
Hatoum, D & McGowan, EM 2015, 'Recent Advances in the Use of Metformin: Can Treating Diabetes Prevent Breast Cancer?', BioMed Research International, vol. 2015, pp. 1-13.View/Download from: UTS OPUS or Publisher's site
McGowan, EM, Simpson, A, McManaman, J, Boonyaratanakornkit, V & Hardikar, AA 2015, 'Hijacking of Endocrine and Metabolic Regulation in Cancer and Diabetes', BioMed Research International, vol. 2015.View/Download from: UTS OPUS or Publisher's site
Haass, NK, Nassif, N & McGowan, EM 2015, 'Switching the Sphingolipid Rheostat in the Treatment of Diabetes and Cancer Comorbidity from a Problem to an Advantage', BIOMED RESEARCH INTERNATIONAL.View/Download from: UTS OPUS or Publisher's site
Yagoub, D, Wilkins, MR, Lay, AJ, Kaczorowski, DC, Hatoum, D, Bajan, S, Hutvagner, G, Lai, JH, Wu, W, Martiniello-Wilks, R, Xia, P & McGowan, EM 2014, 'Sphingosine Kinase 1 Isoform-Specific Interactions in Breast Cancer', MOLECULAR ENDOCRINOLOGY, vol. 28, no. 11, pp. 1899-1915.View/Download from: UTS OPUS or Publisher's site
McGowan, EM, Tran, NT, Alling, N, Yagoub, D, Sedger, LM & Martiniello-Wilks, R 2012, 'P14ARF Post-transcriptional Regulation Of Nuclear Cyclin D1 In Mcf-7 Breast Cancer Cells: Discrimination Between A Good And Bad Prognosis?', Plos One, vol. 7, no. 7, pp. 1-16.View/Download from: UTS OPUS or Publisher's site
As part of a cell's inherent protection against carcinogenesis, p14ARF is upregulated in response to hyperproliferative signalling to induce cell cycle arrest. This property makes p14ARF a leading candidate for cancer therapy. This study explores the con
Suurbach, JH, McGowan, EM, Simpson, A, Tran, N & Martiniello-Wilks, R 2012, 'A unique bioluminescent prostate cancer mouse model for the evaluation of stem-cell based gene therapy', JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, vol. 6, pp. 288-288.
Jackson, E, Righi, L, McGowan, E & Sapino, A 2011, '1104 POSTER Sphingosine Kinase 1 Correlates With a Neuroendocrine Phenotype in Breast Cancer in Vivo and in Vitro', European Journal of Cancer, vol. 47, pp. S125-S125.View/Download from: Publisher's site
McGowan, EM, Alling, N, Jackson, E, Yagoub, D, Haass, NK, Allen, J & Martiniello-Wilks, R 2011, 'Evaluation Of Cell Cycle Arrest In Estrogen Responsive MCF-7 Breast Cancer Cells: Pitfalls Of The MTS Assay', PLoS ONE, vol. 6, no. 6, pp. 0-0.View/Download from: UTS OPUS or Publisher's site
Endocrine resistance is a major problem with anti-estrogen treatments and how to overcome resistance is a major concern in the clinic. Reliable measurement of cell viability, proliferation, growth inhibition and death is important in screening for drug t
McGowan, E, Alling, N, Shephard, R, Yagoub, D, Tran, N & Xia, P 2010, 'Abstract P1-04-03: A Role for Cyclin D1 in Neoplastic Transformation in MCF-7 Breast Cancer Cells Post p14ARF-p53 Induced Senescence', Poster Session Abstracts.View/Download from: Publisher's site
Zhang, N, Wu, Z-M, McGowan, E, Shi, J, Hong, Z-B, Ding, C-W, Xia, P & Di, W 2009, 'Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: Therapeutic potential for ovarian cancer', CANCER SCIENCE, vol. 100, no. 12, pp. 2459-2464.View/Download from: Publisher's site
Martin, JL, Lin, MZ, McGowan, EM & Baxter, RC 2009, 'Potentiation of Growth Factor Signaling by Insulin-like Growth Factor-binding Protein-3 in Breast Epithelial Cells Requires Sphingosine Kinase Activity', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, no. 38, pp. 25542-25552.View/Download from: Publisher's site
McGowan, EM, Russell, AJ, Boonyaratanakornkit, V, Saunders, DN, Lehrbach, GM, Sergio, CM, Musgrove, EA, Edwards, DP & Sutherland, RL 2007, 'Progestins reinitiate cell cycle progression in antiestrogen-arrested breast cancer cells through the B-Isoform of progesterone receptor', CANCER RESEARCH, vol. 67, no. 18, pp. 8942-8951.View/Download from: Publisher's site
Boonyaratanakornkit, V, McGowan, E, Sherman, L, Mancini, MA, Cheskis, BJ & Edwards, DP 2007, 'The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle', MOLECULAR ENDOCRINOLOGY, vol. 21, no. 2, pp. 359-375.View/Download from: Publisher's site
McGowan, EM, Saad, S, Bendall, LJ, Bradstock, KF & Clarke, CL 2004, 'Effect of progesterone receptor A predominance on breast cancer cell migration into bone marrow fibroblasts', BREAST CANCER RESEARCH AND TREATMENT, vol. 83, no. 3, pp. 211-220.View/Download from: Publisher's site
McGowan, EM, Weinberger, RP, Graham, JD, Hill, HD, Hughes, JAI, O'Neill, GM & Clarke, CL 2003, 'Cytoskeletal responsiveness to progestins is dependent on progesterione receptor A levels', JOURNAL OF MOLECULAR ENDOCRINOLOGY, vol. 31, no. 2, pp. 241-253.View/Download from: Publisher's site
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 2000, 'Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma', HUMAN REPRODUCTION, vol. 15, pp. 48-56.View/Download from: Publisher's site
Saad, SR, Bendall, LJ, McGowan, EM, Gottlieb, DJ, Clarke, CL & Bradstock, KF 2000, 'Effects of progesterone on the migration of breast cancer cells within bone marrow stroma.', MOLECULAR BIOLOGY OF THE CELL, vol. 11, pp. 82A-82A.
McGowan, EM & Clarke, CL 1999, 'Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells', Molecular Endocrinology, vol. 13, no. 10, pp. 1657-1671.View/Download from: Publisher's site
The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which differ in the N-terminal region and exhibit different activities in vitro, with PRA demonstrating dominant negative inhibitory effects on the activity of PRB and other nuclear receptors. PRA and PRB are expressed in target tissues at comparable levels although cells expressing a predominance of one isoform can be identified. In breast cancers, PRA is expressed at high levels in some tumors, and this may be associated with features of poorer prognosis. To investigate the role of PRA overexpression in PR-positive target cells, the effect of PRA induction on cell proliferation and expression of endogenous progestin-sensitive genes, SOX4 and fatty acid synthetase (FAS), was examined using PR-positive T-47D cell lines, which express a pre-dominance of PRB, in which PRA could be increased 2- to 20-fold over basal levels. No effect of PRA induction was noted on cell proliferation, but marked changes in morphology, consistent with loss of adherent properties, were observed. Increases up to 4-fold in the relative PRA levels augmented progestin induction of SOX4 mRNA expression, and RU486 treatment revealed a progestin agonist effect. There was no consistent effect of PRA induction on progestin-mediated increases in FAS mRNA levels under these conditions. Clones with PRA:PRB ratios greater than 15 were associated with diminished progestin responses on both SOX4 and FAS mRNA expression. These data show that PRA overexpression is associated with alteration in adhesive properties in breast cancer cells and effects on endogenous progestin targets that were dependent on the cellular ratio of PRA:PRB. The results of this study are consistent with the view that PRA expression can fluctuate within a broad range in target cells without influencing the nature of progestin action on downstream targets, but that overexpression of PRA, such as is seen in a proportion of breast cancers, may be associat...
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 1999, 'Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle', JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 84, no. 8, pp. 2963-2971.View/Download from: Publisher's site
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 1999, 'Colocalization of Progesterone Receptors A and B by Dual Immunofluorescent Histochemistry in Human Endometrium during the Menstrual Cycle1', The Journal of Clinical Endocrinology & Metabolism, vol. 84, no. 8, pp. 2963-2971.View/Download from: Publisher's site
McGowan, EM & Clarke, CL 1999, 'Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells', MOLECULAR ENDOCRINOLOGY, vol. 13, no. 10, pp. 1657-1671.View/Download from: Publisher's site
Graham, JD, Roman, SD, McGowan, E, Sutherland, RL & Clarke, CL 1995, 'Preferential stimulation of human progesterone receptor B expression by estrogen in T-47D human breast cancer cells', JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 51, pp. 30693-30700.View/Download from: Publisher's site
Haddadi, N, Nassif, N & McGowan, E 2017, 'Cancer-associated mutations alter PTEN cellular function', Australasian Genomic Technologies Conference 2017, Hobart.
Chen, S, Lin, Y, Zhong, S, An, H, Lu, Y, Yin, M, Liang, W & McGowan, E 2018, 'Anti-MUC1 CAR-T Cells combined with PD-1 Knockout Engineered T Cells for patients with non-small cell lung cancer (NSCLC): A pilot study, ESMO Immuno-oncology conference', Annals of Oncology, ESMO Immuno-oncology conference, Geneva, Oxford University Press (OUP), Geneva.
Pateetin, P, McGowan, E & Boonyaratanakornkit, V 2018, 'Quantitative proteomic analysis of breast cancer cells expressing progesterone receptor A and B', 4th Congress on Steroid Research, Seoul, Korea 2018, Seoul, Korea.
Lan, C, Peng, H, McGowan, EM, Hutvagner, G & Li, J 2018, 'An isomIR expression panel based novel breast cancer classification approach using improved mutual information', International Conference on Genome Informatics, Kunming, Yunnan, China.View/Download from: UTS OPUS
Lin, Y, McGowan, EM & Xu, M 2017, 'FGFR1 lentivirus lung cancer cell model for anti-cancer drug discovery and the study of FGFR1 signaling pathway', Journal of stem cell research & therapy, Cell Signaling, Cell Therapy and Cancer Therapeutics 2017, Chicago, pp. 62-62.View/Download from: UTS OPUS
McGowan, EM & hatoum, D 2015, 'P14ARF-p53-p21 alters the metabolic pathway in breast cancer – a novel proteomic global approach', Annals of Oncology 26, IMPAKT Breast cancer conference, Brussels May 6th-9th, Brussels.
Hatoum, D, Yagoub, D, Brennan, S & Nassif, N 2015, 'P14ARF-p53-p21: P14ARF-p53-p21: reprogramming metabolic regulation and function in breast cancer', New Horizons 2015, University of Technology Sydney (UTS).
Hatoum, D, Nassif, N & McGowan, E 2015, 'P14ARF-p53 plays a major role in mitochondria dynamics in breast cancer cells', New Horizons 2015, University of Technolgy Sydney (UTS).
Moulder, D, Mitchell, H, Hatoum, D & McGowan, E 2015, 'P14ARF-p53 plays a major role in mitochondria dynamics in breast cancer cells', New Horizons 2015, University of Technology Sydney.
Hatoum, D & McGowan, E 2015, 'p14ARF-p53-p21 reversing the Warburg effect – a novel proteomic global approach', 1st Australian Cancer and Metabolism Meeting, April 29th-1st May, 2015, Garvan Institute of Medical Research.
Haddadi, N, McGowan, E & Nassif, N 2015, 'Determining the Frequency and Involvment of PTEN Pseudogene (PTENP1) Expression in Cancer', New Horizons 2015, University of Technology Sydney.View/Download from: UTS OPUS
Hatoum, D, Bok, CF, Touw, A, Nassif, N & McGowan, E 2015, 'Sphingosine Kinase 1 (SK1-43kDa) isoform expression may contribute to cancer aggressiveness', New Horizons 2015, University of Technology Sydney.View/Download from: UTS OPUS
Johnson, T, Cheng, YY, Williams, M, Nassif, N, McGowan, E & Reid, G 2015, 'YB1: a potential therapeutic target in malignant pleural mesothelioma', New Horizons 2015, University of Technology Sydney (UTS).
Suurbach, JH, Habib, R, Brennan, S, Larsen, SR, Simpson, A & Martiniello-Wilks, R 2015, 'CELLULAR AND GENETIC MEDICINES ADVANCING THE TREATMENT OF METASTATIC PROSTATE CANCER', JOURNAL OF GENE MEDICINE, 9th Biennial Meeting of the Australasian-Gene-and-Cell-Therapy-Society (AGCTS), WILEY-BLACKWELL, Univ Melbourne, Univ Coll, Parkville, AUSTRALIA, pp. 198-199.View/Download from: UTS OPUS
McGowan, EM & Hatoum 2017, 'Activation of the p14ARF-p53 Pathway: A Role for p14ARF-p53 in the Differential Regulation of the Annexin Family and S100-Associated Proteins.', Endocrine Reviews, 94th Annual Meeting of the USA Endocrine Society, Houston, Texas. (EM, senior author), Oxford University Press (OUP), Chicago.
Brennan, SE, Nham, T, Clayton, A, McGowan, EM, Cozzi, PJ & Martiniello-Wilks, R 2013, 'PROSTATE CANCER EXOSOMES OFFERING NOVEL CIRCULATING BIOMARKERS FOR EARLY CANCER DIAGNOSIS AND PROGNOSIS', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 331-332.
Habib, R, McGowan, E, Larsen, SR & Martiniello-Wilks, R 2013, 'CHARACTERISATION OF A PRIMITIVE BONE MARROW DERIVED MESENCHYMAL STEM CELL SUBPOPULATION SHOWING IMPROVED PROSTATE CANCER TROPISM', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 333-333.
Hatoum, D, Martiniello-Wilks, R, Nassif, N, Yagoub, D & McGowan, EM 2013, 'THE MISNOMER OF ACTIVATING P14ARF-P53 FOR BREAST CANCER THERAPY', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 333-334.
Suurbach, JH, McGowan, EM, Simpson, AM & Martiniello-Wilks, R 2013, 'STEM CELL-BASED DELIVERY OF SUICIDE GENE YCDUPRT THERAPY TO PROSTATE CANCER', JOURNAL OF GENE MEDICINE, 8th Meeting of the Australasian-Gene-Therapy-Society, WILEY-BLACKWELL, Univ Technol, Sydney, AUSTRALIA, pp. 323-323.
McGowan, EM & yagoub, D 2012, 'Sphingosine kinase 1 isoform-specific interactions revealed through stable isotope labelling by amino acids in cell culture (SILAC)', Endocrine Reviews, June 2012. 94th Annual Meeting of the USA Endocrine Society, Houston, Texas., Oxford University Press (OUP), Houston.
McGowan, EM & Jackson, E 2011, 'Sphingosine Kinase 1 Correlates With a Neuroendocrine Phenotype in Breast Cancer in Vivo and in Vitro', European Journal of Cancer vol. 47.
McGowan, EM & Yagoub, D 2010, 'A Role for Cyclin D1 in Neoplastic Transformation in MCF-7 Breast Cancer Cells Post p14ARF-p53 Induced Senescence', Cancer Research, Supplement, P1-04-03., 33rd Annual San Antonio Breast Cancer Symposium, San Antonio.
Mote, PA, Balleine, RL, McGowan, EM & Clarke, CL 2000, 'Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma', Human Reproduction, pp. 48-56.View/Download from: Publisher's site
The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which function as ligand-activated transcription factors. In-vitro studies suggest that the isoforms differ functionally and that their relative expression in a target cell may determine the nature and magnitude of response to progesterone. We have shown recently that PRA and PRB are co-expressed in target cells of the human endometrium. The purpose of this study was to investigate the homogeneity of expression of PRA and PRB in target cells of the human uterus throughout the menstrual cycle. In the functionalis, PRA and PRB were expressed in comparable levels in glandular epithelium during the proliferative phase of the cycle, whereas there was persistence of PRB but not PRA in the glands during mid-secretory phase. In the stroma, there was predominance of the PRA isoform throughout the cycle. There was remarkable homogeneity in the relative expression of PRA and PRB in adjacent cells within the same tissue compartment, suggesting that the mechanisms regulating relative PR isoform expression are similarly active in these cells. By contrast, heterogeneity between glands was observed under some circumstances in the functionalis of the endometrium, suggesting PR isoform down-regulation by progesterone to be asynchronous. Heterogeneity was also seen between the glands of the basalis and functionalis of the endometrium implying region-specific responses to hormonal stimuli. This study demonstrates adjacent cell homogeneity in the relative expression of PRA and PRB in normal human endometrial tissue and a differential response to ovarian steroid hormones between cell types and between different regions within the same tissue.