Cell and Developmental Biology Commons^™

Hnrnpa2 Is A Novel Histone Acetyltransferase That Mediates Mitochondrial Stress-Induced Nuclear Gene Expression, Manti Guha, Satish Srinivasan, Kip Guja, Edison Mejia, Miguel Garcia-Diaz, F. Brad Johnson, Gordon Ruthel, Brett A. Kaufman, Eric F. Rappaport, M. Rebecca Glineburg, Ji-Kang Fang, Andres J. Klein-Szanto, Hiroshi Nakagawa, Jeelan Basha, Tapas Kundu, Narayan G. Avadhani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced …

Targeted And Controlled Anticancer Drug Delivery And Release With Magnetoelectric Nanoparticles, Alexandra Rodzinski

FIU Electronic Theses and Dissertations

A major challenge of cancer treatment is successful discrimination of cancer cells from healthy cells. Nanotechnology offers multiple venues for efficient cancer targeting. Magnetoelectric nanoparticles (MENs) are a novel, multifaceted, physics-based cancer treatment platform that enables high specificity cancer targeting and externally controlled loaded drug release. The unique magnetoelectric coupling of MENs allows them to convert externally applied magnetic fields into intrinsic electric signals, which allows MENs to both be drawn magnetically towards the cancer site and to electrically interface with cancer cells. Once internalized, the MEN payload release can be externally triggered with a magnetic field. MENs uniquely allow …

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

Talin2-Mediated Traction Force Drives Matrix Degradation And Cell Invasion, Lei Qi, Naser Jafari, Xiang Li, Zaozao Chen, Liqing Li, Vesa P. Hytönen, Benjamin T. Goult, Chang-Guo Zhan, Cai Huang

Markey Cancer Center Faculty Publications

Talin binds to β-integrin tails to activate integrins, regulating cell migration, invasion and metastasis. There are two talin genes, TLN1 and TLN2, encoding talin1 and talin2, respectively. Talin1 regulates focal adhesion dynamics, cell migration and invasion, whereas the biological function of talin2 is not clear and, indeed, talin2 has been presumed to function redundantly with talin1. Here, we show that talin2 has a much stronger binding to β-integrin tails than talin1. Replacement of talin2 Ser339 with Cys significantly decreased its binding to β1-integrin tails to a level comparable to that of talin1. Talin2 localizes at invadopodia and is indispensable …

Selective Anticancer Activity Of Hydroxyapatite/Chitosan-Poly(D,L)-Lactide-Co-Glycolide Particles Loaded With An Androstane-Based Cancer Inhibitor, Nenad Ignjatović, Katarina M. Penov-Gaši, Victoria M. Wu, Jovana J. Ajduković, Vesna V. Kojić, Dana Vasiljević-Radović, Maja Kuzmanović, Vuk Uskoković, Dragab Uskoković

Pharmacy Faculty Articles and Research

In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. ¹H NMR and ¹³C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the …

Regulation Of Nachrs And Stemness By Nicotine And E-Cigarettes In Nsclc, Courtney Schaal

USF Tampa Graduate Theses and Dissertations

Lung cancer is the leading cause of cancer-related death in both men and women, nationally and internationally and kills more people each year than breast, prostate, and colon cancers combined. Non-small cell lung carcinoma (NSCLC) is the most common histological subtype of lung cancer, and accounts for 85% of all cases. Cigarette smoking is the single greatest risk factor for lung cancer, and is correlated with 80-90% of all lung cancer deaths. Nicotine, the addictive component of tobacco smoke, is not a carcinogen and cannot initiate tumors itself; however, it is known to act as a tumor promoter, by enhancing …

Nanobubbles Provide Theranostic Relief To Cancer Hypoxia, Christopher M. Long, Pushpak N. Bhandari, Joseph Irudayaraj

The Summer Undergraduate Research Fellowship (SURF) Symposium

Hypoxia is a common motif among tumors, contributing to metastasis, angiogenesis, cellular epigenetic abnormality, and resistance to cancer therapy. Hypoxia also plays a pivotal role in oncological studies, where it can be used as a principal target for new anti-cancer therapeutic methods. Oxygen nanobubbles were designed in an effort to target the hypoxic tumor regions, thus interrupting the hypoxia-inducible factor-1α (HIF-1α) regulatory pathway and inhibiting tumor progression. At less than 100nm, oxygen nanobubbles act as a vehicle for site-specific oxygen delivery, while also serving as an ultrasound contrast agent for advanced imaging purposes. Through in vitro and in vivo studies, …

Inhibition Of Nuclear Factor-Kappa B Enhances The Tumor Growth Of Ovarian Cancer Cell Line Derived From A Low-Grade Papillary Serous Carcinoma In P53-Independent Pathway, Xue Xiao, Gong Yang, Peng Bai, Shunping Gui, Tri M. Bui Nguyen, +8 Additional Authors

Biochemistry and Molecular Medicine Faculty Publications

Background: NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-kB in the low-grade serous ovarian cancer.

Methods: The ovarian cancer cell line, HOC-7, derived from a low-grade papillary serous carcinoma. Introduction of a dominant negative mutant, IkBαM, which resulted in decrease of NF-kB function in ovarian cancer cell lines. The transcription ability, tumorigenesis, cell proliferation and apoptosis were observed in derivative cell lines in comparison with parental cells.

Results: Western blot analysis indicated increased …

Tricurin, A Novel Formulation Of Curcumin, Epicatechin Gallate, And Resveratrol, Inhibits The Tumorigenicity Of Human Papillomaviruspositive Head And Neck Squamous Cell Carcinoma, Longzhu Piao, Sumit Mukherjee, Qing Chang, Xiujie Xie, Hong Li, Mario R. Castellanos, Probal Banerjee, Hassan Iqbal, Ryan Ivancic, Xueqian Wang, Theodoros N. Teknos, Quintin Pan

Publications and Research

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) has rapidly increased over the past 30 years prompting the suggestion that an epidemic may be on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients. TriCurin is a composition of three food-derived polyphenols in unique stoichiometric proportions consisting of curcumin from the spice turmeric, resveratrol from red grapes, and …

Alternative Methods For The Treatment Of Chemo-Resistant Cancers, Kaitlyn Wong

Doctoral Dissertations

Great strides have been made in cancer therapy in the past century, yet it remains one of the leading causes of death in the United States today. This work aimed to shed light on novel methods to treat a variety of aggressive and often chemo-resistant cancers both in vitro and in vivo. The first aim of this work was to evaluate the therapeutic efficacy of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) prodrugs compared to standard chemotherapeutic agents. Conjugation of polyMPC to drugs such as doxorubicin (Dox) can result in its improved solubility, prolonged half-life and therapeutic efficacy. PolyMPC and polyMPC-Dox (at a …

Hexavalent Chromium Induces Malignant Transformation Of Human Lung Bronchial Epithelial Cells Via Ros-Dependent Activation Of Mir-21-Pdcd4 Signaling, Poyil Pratheeshkumar, Young-Ok Son, Sasidharan Padmaja Divya, Lilia Turcios, Ram Vinod Roy, John Andrew Hitron, Lei Wang, Donghern Kim, Jin Dai, Padmaja Asha, Zhuo Zhang, Xianglin Shi

Center for Research on Environmental Disease Faculty Publications

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of …

Klf4 Deletion Alters Gastric Cell Lineage And Induces Muc2 Expression, Tianxin Yu, Xi Chen, T. Lin, J. Liu, M. Li, W. Zhang, X. Xu, W. Zhao, M. Liu, Dana L. Napier, Chi Wang, B. Mark Evers, Chunming Liu

Markey Cancer Center Faculty Publications

Gastric cancer is one of the most common types of cancer in the world, particularly in underdeveloped countries. The mechanism of gastric cancer is less understood compared with other types of gastrointestinal (GI) cancers. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor and is a potential tumor suppressor in GI cancers. In this study, we have generated two mouse models, Rosa-Cre;Klf4^fl/fl and Lgr5-Cre;Klf4^fl/fl. KLF4 was deleted by Rosa-Cre in the gastric epithelia cells or by Lgr5-Cre in the antral stem cells in the adult mice. KLF4 deletion resulted in increased proliferating cells and decreased pit mucous …

Identification Of Genes That Are Essential To Restrict Genome Duplication To Once Per Cell Division., Alex Vassilev, Chrissie Y. Lee, Boris Vassilev, Wenge Zhu, Pinar Ormanoglu, Scott E. Martin, Melvin L. Depamphilis

Biochemistry and Molecular Medicine Faculty Publications

Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor …

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

Dissertations & Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation …

S100a4 Drives Non-Small Cell Lung Cancer Invasion, Associates With Poor Prognosis, And Is Effectively Targeted By The Fda-Approved Anti-Helminthic Agent Niclosamide, Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Lili Liu, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Eric B. Durbin, Susanne M. Arnold, Kathleen L. O'Connor, Min Chen

Markey Cancer Center Faculty Publications

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular …

Oncolytic Virus Therapy For The Treatment Of Metastatic Ovarian Cancer, Jessica Tong

Electronic Thesis and Dissertation Repository

The management of patients with epithelial ovarian cancer (EOC) faces two major challenges which standard treatments fail to effectively address: 1) Diffuse metastasis as a consequence of late stage diagnosis and 2) intra-tumoral heterogeneity, which fuels tumor evolution and drives the acquisition of chemotherapeutic resistance. In this thesis, we tested new therapeutic strategies using a 3-dimensional in vitro spheroid culture model that mimics key steps of epithelial ovarian cancer metastasis; and another model that mimics both temporal and cellular heterogeneity by establishing multiple cell lines from a single patient over the course of disease progression. Using these models, we investigated …

P-Rex1 Promotes Resistance To Vegf/Vegfr-Targeted Therapy In Prostate Cancer, Hira Lal Goel, Bryan Pursell, Leonard D. Shultz, Dale L. Greiner, Rolf A Brekken, Craig W. Vander Kooi, Arthur M. Mercurio

Molecular and Cellular Biochemistry Faculty Publications

Autocrine VEGF signaling is critical for sustaining prostate and other cancer stem cells (CSCs), and it is a potential therapeutic target, but we observed that CSCs isolated from prostate tumors are resistant to anti-VEGF (bevacizumab) and anti-VEGFR (sunitinib) therapy. Intriguingly, resistance is mediated by VEGF/neuropilin signaling, which is not inhibited by bevacizumab and sunitinib, and it involves the induction of P-Rex1, a Rac GEF, and consequent Rac1-mediated ERK activation. This induction of P-Rex1 is dependent on Myc. CSCs isolated from the PTEN^pc−/− transgenic model of prostate cancer exhibit Rac1-dependent resistance to bevacizumab. Rac1 inhibition or P-Rex1 downregulation increases the …

Autocrine Epiregulin Activates Egfr Pathway For Lung Metastasis Via Emt In Salivary Adenoid Cystic Carcinoma, Shuli Liu, Dongxia Ye, Dongliang Xu, Yueling Liao, Ling Zhang, Liu Liu, Wenwen Yu, Yanan Wang, Yue He, Jingzhou Hu, Wenzheng Guo, Tong Wang, Beibei Sun, Hongyong Song, Huijing Yin, Jingyi Liu, Yadi Wu, Hanguang Zhu, Binhua P. Zhou, Jiong Deng, Zhiyuan Zhang

Markey Cancer Center Faculty Publications

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, …

Pi(4)P Promotes Phosphorylation And Conformational Change Of Smoothened Through Interaction With Its C-Terminal Tail, Kai Jiang, Yajuan Liu, Junkai Fan, Jie Zhang, Xiang-An Li, B. Mark Evers, Haining Zhu, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an …

Targeting Wnt/Β-Catenin Pathway In Hepatocellular Carcinoma Treatment, Valery Vilchez, Lilia M. Turcios, Francesc Marti, Roberto Gedaly

Surgery Faculty Publications

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug …

Phlpp Negatively Regulates Cell Motility Through Inhibition Of Akt Activity And Integrin Expression In Pancreatic Cancer Cells, Alena J. Smith, Yang-An Wen, Payton D. Stevens, Jingpeng Liu, Chi Wang, Tianyan Gao

Markey Cancer Center Faculty Publications

Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of β1 and β4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells …

Mir-671-5p Inhibits Epithelial-To-Mesenchymal Transition By Downregulating Foxm1 Expression In Breast Cancer., Xiaohui Tan, Yebo Fu, Liang Chen, Woojin Lee, Yinglei Lai, M. Katayoon Rezaei, Sana Tabbara, Patricia Latham, Christine B Teal, Yan-Gao Man, Robert S. Siegel, Rachel F. Brem, Sidney W. Fu

Medicine Faculty Publications

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 …

Overcoming Treatment Resistance In Heterogeneous Tumors, Nikhil Hebbar

Theses and Dissertations--Toxicology and Cancer Biology

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains …

Uncovering New Roles For The Aryl Hydrocarbon Receptor (Ahr) In Breast Cancer, Justin Kirk Tomblin

Theses, Dissertations and Capstones

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is responsive to many exogenous and endogenous ligands. AHR is of particular interest in cancer, and has been shown to play roles in tumor progression. As such, it has received growing attention as a possible chemotherapeutic target. Obesity increases the risk of breast cancer, complicates treatment of breast cancer, and stimulates the growth of larger, more aggressive mammary tumors. Many breast tumors in obese women are estrogen receptor (ER)-positive and, while targeting hormone receptors like ER is beneficial, many obese women see a recurrence of their cancer after standard …

Radio-Frequency Plasma Polymerized Biodegradable Carrier For In Vivo Release Of Cis-Platinum, Sudhir Bhatt, Fatemeh Valamanesh, Jerome Pulpytel, Rea Lo Dico, Aliby Baiyukha, Iman Al-Dybiat, Marc Pocard, Farzaneh Arefi-Khonsari, Massoud Mirshahi

Bioelectrics Publications

A low pressure plasma process based on plasma deposition has been used to develop a drug delivery strategy. In this study, a drug delivery system based on different layers of plasma co-polymerized Poly ε-caprolactone-Polyethylene glycol (PCL-PEG) co-polymers was deposited on biocompatible substrates. Cis-platinum (118 μgm/cm²) was used as an anti-cancer drug and incorporated for local delivery of the chemotherapeutic agent. The co-polymer layers and their interaction with cancer cells were analyzed by scanning electron microscopy. Our study showed that the plasma-PCL-PEG coated cellophane membranes, in which the drug, was included did not modify the flexibility and appearance of …