Medicine and Health Sciences Commons^™

Targeting Tgf-Β During Epithelial-To-Mesenchymal Progression As An Effective Therapy Against Colorectal Cancer, Joyce Fan

Undergraduate Research

Colorectal cancer is one of the most common cancers worldwide. Understanding the mechanisms of colorectal cancer progression is crucial for the development of effective therapeutics. Epithelial-to-mesenchymal transition is a hallmark feature of cancer and is defined as the loss of epithelial cell features, such as apical-basal polarity and high expression of cell adhesion molecules, and the development of mesenchymal features, such as lack of polarity and increased cell mobility. Epithelial-to-mesenchymal is essential for cell migration, proliferation, and tumor growth. Both the TGF-β and SMAD pathway are associated with colorectal cancer progression. TGF-β is crucial to the cellular mechanism of cell …

Uncovering Molecular Targets To Overcome Immunosuppression In Non-Small Cell Lung Cancer With Acquired Tki Resistance, Sonia A. Patel

Dissertations & Theses (Open Access)

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Targeted therapeutic agents, such as epidermal-like growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting vascular endothelial growth factor (VEGF/R), can effectively inhibit upregulated signaling pathways driving tumorigenesis in NSCLC and many other cancers. Unfortunately, however, resistance to such targeted therapies inevitably arise in most patients and can occur through a variety of resistance mechanisms including genomic alterations and upregulation of bypass pathways. Additionally, patients who have acquired resistance to these targeted agents typically have tumors characterized by an immunosuppressive tumor microenvironment and thus …

Loss Of Connective Tissue Growth Factor Expression Promotes Remodeling Of The Extracellular Matrix And Epithelial-To-Mesenchymal Transition In Ovarian Cancer, Mc Harry Ramos, Sandra Galoforo, Colton Morris, Gil Mor, Ayesha Alvero, Radhika Gogoi

Medical Student Research Symposium

Background: Ovarian Cancer (OC) is the leading cause of death from gynecologic malignancies in the United States largely due to the advanced stage at the time of diagnosis. Epithelial-to-mesenchymal transition (EMT) is a key biological process implicated in the pathophysiology of the metastatic spread of OC. Discovering the “trigger/s,” its downstream targets, and therapeutic targeting are essential to substantively improve the survival of women with OC. The objective of our study is to evaluate the role of Connective Tissue Growth Factor (CTGF) in EMT in OC.

Methods: R182 and R2615 are well-described epithelial OC cell and MR182 and MR2615 are …

Inhibition Of Ribosome Assembly Factor Pno1 By Crispr/Cas9 Technique Suppresses Lung Adenocarcinoma And Notch Pathway: Clinical Application, Sanjit K. Roy, Shivam Srivastava, Andrew Hancock, Anju Shrivastava, Jason Morvant, Sharmila Shankar, Rakesh K. Srivastava

School of Medicine Faculty Publications

Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial–mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with …

Role Of Histone Deacetylase (Hdac) In Epithelial To Mesenchymal Transition (Emt) In A Human Cholangiocyte Model Of Ischemic Cholangiopathy, Priyanshi Pragnesh Parikh

Theses and Dissertations

Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential …

The Role Of Connective Tissue Growth Factor In Maintaining The Epithelial Phenotype Of Ovarian Cancer Cells During Epithelial-To-Mesenchymal Transition, Harry Ramos, Sandra Galoforo, Gil Mor, Radhika Gogoi

Medical Student Research Symposium

Objective: The transition from epithelial to mesenchymal is essential for the process of ovarian cancer (OC) metastasis. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in epithelial to mesenchymal transition (EMT).

Methods: R182 is an epithelial OC cell line. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot and ELISA. R182 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector. Anoikis resistance and invasion assays were performed to characterized phenotypes of R182 wild type (WT) and KO cells. For anoikis resistance, cells …

Targeting Vulnerabilities In Cell State And Calcium Signaling For The Treatment Of Lung Cancer, Clark Jones

Graduate Theses, Dissertations, and Problem Reports

Lung cancer remains the deadliest of all cancers due to the high mutational burden associated with the disease. Combating mutational drivers and drug resistance proves to be essential in the development of novel therapies to improve patient outcomes. A first-in-class cyclic peptide known as MTI-101 has been shown to induce necrotic cell death in a caspase independent manner. MTI-101 was derived from the linear peptide known as HYD1 that was found in a high throughput screen to block cell adhesion with the extracellular matrix. The compound was further optimized and cyclized to the currently used MTI-101 that was found to …

Epigenetic Regulation And Post-Translational Modifications Of Snai1 In Cancer Metastasis, Bo Dong, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelialmesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and posttranslational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help …

Dissecting Tumor Heterogeneity In Lung Cancer, Aparna Padhye

Dissertations & Theses (Open Access)

Lung cancer is a heterogeneous disease composed of genetically and phenotypically distinct tumor cells as well as a heterogeneous microenvironment consisting of non-cancer cells and extracellular matrix. Constant interactions among these components ultimately leads to a complex tumor tissue that is ever evolving and poses a therapeutic challenge for sustained benefit. Strategies for targeting lung cancers are largely guided by the genetic alterations identified in the tumor specimens. However, in order to gain a better understanding of lung cancer progression and develop effective treatment modalities, studying tumor in context of its microenvironment is crucial. The first aim of this project …

Role Of Methyltransferase Like-3 (Mettl3) In Pancreatic Ductal Adenocarcinoma (Pdac) Progression, Bhargavi Brahmendra Barathi

Dissertations & Theses (Open Access)

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer with about a 10% five-year survival rate. The grim prognostic situation of pancreatic cancer patients underlines the need to identify novel molecular targets. Recent studies have brought to attention, the need to therapeutically exploit epigenetic pathways, apart from only targeting genetic mutations to effectively combat PDAC. To that effect, METTL3-mediated post-transcriptional methylation of RNA transcripts have been shown to contribute to cancer progression in multiple cancer types.

METTL3 deposits methyl groups onto adenosine bases within specific consensus sequences in RNA, resulting in the formation of N-6 methyl adenosine (m6A). m6A is the …

Molecular Drivers Of Bladder Cancer Motility, Bryan Wehrenberg

Dissertations & Theses (Open Access)

Bladder cancer (BC) progression is measured by the degree of tumor cell invasion into the bladder wall and dissemination to distant sites. The study of BC cell motility will both enable development of anti-invasion therapeutics to limit progression of early-stage disease and improve our understanding of the metastatic process which drives patient mortality in BC. BCs display a great deal of intertumoral heterogeneity, and can be divided into basal and luminal subtypes, which are biologically and clinically distinct entities. Here, I examine the invasion phenotypes of BC as a function of both subtype and epithelial to mesenchymal transition (EMT) status. …

The Context-Dependent Impact Of Integrin-Associated Cd151 And Other Tetraspanins On Cancer Development And Progression: A Class Of Versatile Mediators Of Cellular Function And Signaling, Tumorigenesis And Metastasis, Sonia F. Erfani, Hui Hua, Yueyin Pan, Binhua P. Zhou, Xiuwei H. Yang

Molecular and Cellular Biochemistry Faculty Publications

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition …

Molecular Mechanisms Of Epithelial To Mesenchymal Transition Regulated By Erk5 Signaling, Akshita B. Bhatt, Saloni Patel, Margarite D. Matossian, Deniz A. Ucar, Lucio Miele, Matthew E. Burow, Patrick T. Flaherty, Jane E. Cavanaugh

School of Medicine Faculty Publications

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription …

Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs In Cancer, Bo Dong, Zhaoping Qiu, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding …

Lsd1 Promotes Bladder Cancer Progression By Upregulating Lef1 And Enhancing Emt., Qiubo Xie, Tang Tang, Jian Pang, Jing Xu, Xingxia Yang, Linang Wang, Yiqiang Huang, Zhuowei Huang, Gaolei Liu, Dali Tong, Yao Zhang, Luofu Wang, Dianzheng Zhang, Weihua Lan, Qiuli Liu, Jun Jiang

PCOM Scholarly Papers

Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with …

Investigating The Role Of Oncogene C-Terminal Binding Protein (Ctbp) In Pancreatic Ductal Adenocarcinoma, Kranthi Kumar Chougoni

Theses and Dissertations

The transcriptional coregulator CtBP2 has been implicated as an oncogene in colon, prostate, breast and ovarian cancers. Previously, we reported overexpression of CtBP2 in human PDAC specimens. However, its exact role in PDAC is still unclear. In the current study, we attempt to delineate the oncogenic role CtBP2 in PDAC growth and metastasis. Using an orthotopic syngeneic pancreatic tumor mouse model (CKP), we found that deletion of Ctbp2 decreases PDAC tumor growth, proliferation, metastasis, EMT and significantly prolongs survival. Further, we identified significant downregulation of Erbb3 mRNA levels upon deletion of Ctbp2 in CKP PDAC cells As ErbB3 signaling was …

Employee Burnout And Job Retention Scores Among Ems Workers In Vermont, Caitlin Eckert, Andrew Gross, Chris Haines, Deanna Kish, Jacob Porter, Thomas Delaney

Master of Public Health Culminating Projects

Objective: To assess whether shift length and employment status were positively associated with increased burnout and retention among emergency medical service (EMS) workers in the state of Vermont.

Methods: We conducted a secondary analysis of cross-sectional data using the Vermont EMS Retention Survey from the Vermont Department of Health. 545 participants provided data from August to November 2019. Measures included burnout and retention using the Maslach Burnout Inventory.

Results: In an adjusted model, the 24-hour shift length was associated with higher burnout compared to the eight-hour shift. Volunteer workers displayed lower instances of burnout and had higher retention rates than …

The Identification Of Long Non-Coding Rna Zfas1 Through An Exploratory Rna-Sequencing Analysis And Its Association With Epithelial-To-Mesenchymal Transition In Colon Cancer Adenocarcinoma., Stephen J. O'Brien

Electronic Theses and Dissertations

Colorectal adenocarcinoma is the fourth most common cancer diagnosed worldwide and is a significant cause of morbidity and mortality. This dissertation performed an exploratory RNA-sequencing analysis comparing gene expression between colon adenocarcinoma tissue and paired normal colon epithelium. After identification of a number of lncRNAs that were increased in expression in colon adenocarcinoma compared to normal colon epithelium, we aimed to validate the expression and investigate their function in vitro. Specifically, we focused on the lncRNA ZFAS1 and its association with epithelial-to-mesenchymal transition. These studies found the following: 1. Seven candidate lncRNAs were identified from the exploratory RNA-sequencing analysis to …

Peritoneal Dialysis Vintage And Glucose Exposure But Not Peritonitis Episodes Drive Peritoneal Membrane Transformation During The First Years Of Pd., Maria Bartosova, Betti Schaefer, Karel Vondrak, Peter Sallay, Christina Taylan, Rimante Cerkauskiene, Maria Dzierzega, Gordana Milosevski-Lomic, Rainer Büscher, Ariane Zaloszyc, Philipp Romero, Felix Lasitschka, Bradley A. Warady, Franz Schaefer, Akos Ujszaszi, Claus Peter Schmitt

Manuscripts, Articles, Book Chapters and Other Papers

The impact of peritoneal dialysis (PD) associated peritonitis on peritoneal membrane integrity is incompletely understood. Children are particularly suited to address this question, since they are largely devoid of preexisting tissue damage and life-style related alterations. Within the International Peritoneal Biobank, 85 standardized parietal peritoneal tissue samples were obtained from 82 children on neutral pH PD fluids with low glucose degradation product (GDP) content. 37 patients had a history of peritonitis and 16 of the 37 had two or more episodes. Time interval between tissue sampling and the last peritonitis episode was 9 (4, 36) weeks. Tissue specimen underwent digital …

Investigating The Involvement Of Runx1 And Hif-1Α In Hypoxia-Induced Epithelial-To-Mesenchymal Transition And Generation Of Breast Cancer Stem Cells, Lizzi Hahn

Larner College of Medicine Fourth Year Advanced Integration Teaching/Scholarly Projects

No abstract provided.

The Role Of P62/Imp2 In Hepatocellular Carcinoma Progression, Mengtao Xing

Open Access Theses & Dissertations

The family of insulin- like growth factor 2 mRNA binding proteins (IMPs) contains three members: IMP1, p62/IMP2 and IMP3. All these proteins are oncofetal proteins, expressed during embryogenesis and lost in most tissues in adults. However, p62/IMP2 were found overexpressed in various cancers but its function in carcinogenesis remains to be investigated. Our previous studies found that p62/IMP2 was not only overexpressed in hepatocellular carcinoma (HCC) tissues, but also overexpressed in HCC cell lines. To explore the biological roles of p62/IMP2 in HCC progression, p62/IMP2 was knockout in two p62/IMP2 positive HCC cell lines (SNU449, HepG2). Due to the low …

Becoming A Washington Firefighter, Connor Ridgeway

Undergraduate Honors Theses

For this project, under direction of Judy Beard and Matthew Martinson, I have created a manual to further assist individuals in the process of fulfilling dreams to become a firefighter. I have researched the vast number steps it takes to become a firefighter and provided helpful suggestions that will aid individuals throughout the process. Becoming a firefighter is a demanding process with physical abilities that need to be taken into consideration when going through the elaborate process. This project includes background information on structure firefighting, volunteer firefighting, wildland firefighting, emergency medical technicians, paramedics, and what the role of each of …

Receptor Sialylation By St6gal-I Promotes Tumor Progression By Enhancing Tumor Cell Survival And Epithelial To Mesenchymal Transition, Colleen Maeve Britain

All ETDs from UAB

The upregulation of a certain subset of glycosyltransferases was an early marker for cancer development. Specifically, ST6Gal-I, which adds an α2-6 linked sialic acid to N-glycans on proteins bound for the plasma membrane or secretion, is selectively upregulated upon malignant transformation. Our laboratory has shown that ST6Gal-I is implicated in many facets of tumor biology and is an important mediator of tumorigenesis. For example, ST6Gal-I activity promotes the survival of cells when challenged with hypoxia, FasL, or TNFα, confers resistance to chemotherapeutics, enhances tumor cell migration and invasion, and fosters a cancer stem cell phenotype. The work presented in this …

The Role Of Tumor Suppressor Dear1 In The Acquisition Of Mammary Stem/Progenitor Cell Properties, Uyen Le

Dissertations & Theses (Open Access)

Breast cancer is the most commonly diagnosed cancer in women in America. Ductal carcinoma in situ (DCIS), one of the earliest pre-invasive forms of invasive ductal carcinoma (IDC), has a 30-50% risk of progressing to IDC. Understanding the mechanisms regulating progression from DCIS to IDC would help identify biomarkers to stratify patients at higher risk of progression or metastasis. Cumulative literature suggests the earliest phase of dissemination from the primary tumor is driven by the epithelial-mesenchymal transition (EMT) program. DEAR1 is a tumor suppressor gene which is mutated, undergoes loss of heterozygosity in breast cancer, and is downregulated in DCIS …

Trim24 As An Oncogene In The Mammary Gland, Aundrietta Duncan

Dissertations & Theses (Open Access)

Despite the many advances made in breast cancer research and treatments, breast cancer remains one of the deadliest diseases plaguing women worldwide. While many findings on genetic mutations and their role in predisposing people to breast cancer have been uncovered, we are just beginning to understand the extent to which epigenetic regulators promote tumorigenic phenotypes, metastasis, and chemotherapeutic resistance. Moreover, new experimental tools offer the ability to address questions we were previously unable to assess. My project takes advantage of a new mouse model to understand the role of a proto-oncogenic, transcriptional co-regulator, TRIM24, in mammary gland development and disease. …

Epithelial To Mesenchymal Transition As A Predictor Of Response To Polo-Like Kinase 1 Inhibition-Induced Apoptosis In Non-Small Cell Lung Carcinoma, Pavitra Viswanath

Dissertations & Theses (Open Access)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Outcomes are poor for patients with recurrent, advanced or metastatic NSCLC. Polo-like kinase 1 (PLK1), involved in the regulation of mitotic processes and the response to DNA damage, is overexpressed in NSCLC. Inhibiting PLK1 may be an effective treatment for NSCLC patients as it is involved in the mechanisms of resistance to several chemotherapy drugs. PLK1 inhibition or knock-down has various effects in cancer cells, including mitotic arrest, apoptosis, and senescence. Predictive biomarkers have not been identified to select those patients who are likely to respond to …

Twist Promotes Tumor Metastasis In Basal-Like Breast Cancer By Transcriptionally Upregulating Ror1, Jingying Cao, Xin Wang, Tao Dai, Yuanzhong Wu, Meifang Zhang, Renxian Cao, Ruhua Zhang, Gang Wang, Rou Jiang, Binhua P. Zhou, Jian Shi, Tiebang Kang

Markey Cancer Center Faculty Publications

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive.

Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung …

Exogenous Fniii 12-14 Regulates Tgf-Β1-Induced Markers, Hilmi M. Humeid

Theses and Dissertations

The extracellular matrix protein Fibronectin (FN) plays an important role in cell contractility, differentiation, growth, adhesion, and migration. The 12th -14th Type III repeats of FN (FNIII 12-14), also referred to as the Heparin-II domain, comprise a highly promiscuous growth factor (GF) binding region. This binding domain aids in cellular signaling initiated from the ECM. Additionally, FN has the ability to assemble into fibrils under certain conditions, mostly observed during cell contractile processes such as those that initiate due to upregulation of Transforming Growth Factor Beta 1 (TGF-β1) [1], [2]. Previous work from our lab has shown that self-assembly of …

Are Audience Response Systems Worth The Cost? Comparing Question-Driven Teaching Strategies For Emergency Medical Technician Education, Lauren M. Maloney, James P. Dilger, Paul A. Werfel, Linda M. Cimino

Internet Journal of Allied Health Sciences and Practice

Purpose: As Emergency Medical Technician educators develop curricula to meet new national educational standards, effective teaching strategies validated for course content and unique student demographics are warranted. Three methods for answering multiple choice questions presented during lectures were compared: a) Audience Response System (ARS, clickers), b) hand-raising-with-eyes-closed (no-cost option), and c) passive response (no-cost option). The purpose was to determine if using the ARS resulted in improved exam scores. Method: 113 Emergency Medical Technician (EMT) students participated in this cross-over, block randomized, controlled trial, which was incorporated into their Cardiac Emergencies and Pulmonary Emergencies course lectures. Students took …

The Function Of Erbin, A Scaffold Protein, As A Tumor Suppressor In Colon Cancer, Payton D. Stevens

Theses and Dissertations--Molecular and Cellular Biochemistry

Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides with …