Medical Specialties Commons^™

Frameless Image-Guided Radiosurgery For Trigeminal Neuralgia, Lisa B. E. Shields, Todd S. Shanks, Andrew J. Shearer, Lauren A. Shelton, Brent J. Shelton, Jonathan Howe, James M. Coons, Brian Plato, Aaron C. Spalding

Markey Cancer Center Faculty Publications

Background: Frameless image-guided radiosurgery (IGRS) is a safe and effective noninvasive treatment for trigeminal neuralgia (TN). This study evaluates the use of frameless IGRS to treat patients with refractory TN.

Methods: We reviewed the records of 20 patients diagnosed with TN who underwent frameless IGRS treatments between March 2012 and December 2013. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. The initial setup uncertainty from simulation to treatment and the patient intrafraction uncertainty were measured. The median follow-up was 32 months.

Results: All patients' pain was BNI Grade IV or V before the frameless IGRS treatment. …

Phase Iii Prospective Randomized Comparison Trial Of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab In Patients With Advanced Carcinoid Tumors: Swog S0518, James C. Yao, Katherine A. Guthrie, Cesar Moran, Jonathan R. Strosberg, Matthew H. Kulke, Jennifer A. Chan, Noelle Loconte, Robert R. Mcwilliams, Edward M. Wolin, Bassam Mattar, Shannon Mcdonough, Helen Chen, Charles D. Blanke, Howard S. Hochster

Markey Cancer Center Faculty Publications

Purpose

Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs.

Patients and Methods

Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary …

Temperature Induces Significant Changes In Both Glycolytic Reserve And Mitochondrial Spare Respiratory Capacity In Colorectal Cancer Cell Lines, Mihail I. Mitov, Jennifer W. Harris, Michael Alstott, Yekaterina Y. Zaytseva, B. Mark Evers, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, in a microplate, label-free detection approach.

This study investigate how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32°C, 37°C and 42°C using assay …

Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells, Dasha E. Kenlan, Piotr G. Rychahou, Vitaliy M. Sviripa, Heidi L. Weiss, Chunming Liu, David S. Watt, B. Mark Evers

Markey Cancer Center Faculty Publications

Colorectal cancer is the second-leading cause of cancer-related mortality in the United States. More than 50% of patients with colorectal cancer will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on colorectal cancer metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell-cycle progression and subsequent cellular proliferation. In addition, we demonstrated …

Incidence Of Cns Tumors In Appalachian Children, Bin Huang, Alice Luo, Eric B. Durbin, Ellen Lycan, Thomas Tucker, Quan Chen, Craig Horbinski, John L. Villano

Markey Cancer Center Faculty Publications

Determine whether the risk of astrocytomas in Appalachian children is higher than the national average. We compared the incidence of pediatric brain tumors in Appalachia versus non-Appalachia regions, covering years 2000–2011. The North American Association of Central Cancer Registries (NAACCR) collects population-based data from 55 cancer registries throughout U.S. and Canada. All invasive primary (i.e. non-metastatic tumors), with age at diagnosis 0–19 years old, were included. Nearly 27,000 and 2200 central nervous system (CNS) tumors from non-Appalachia and Appalachia, respectively comprise the cohorts. Age-adjusted incidence rates of each main brain tumor subtype were compared. The incidence rate of pediatric CNS …

Paracrine Regulation Of Melanocyte Genomic Stability: A Focus On Nucleotide Excision Repair, Stuart Gordon Jarrett, Katharine Marie Carter, John August D'Orazio

Markey Cancer Center Faculty Publications

UV radiation is a major environmental risk factor for the development of melanoma by causing DNA damage and mutations. Resistance to UV damage is largely determined by the capacity of melanocytes to respond to UV injury by repairing mutagenic photolesions. The nucleotide excision repair (NER) pathway is the major mechanism by which cells correct UV photodamage. This multistep process involves the basic steps of damage recognition, isolation, localized strand unwinding, assembly of a repair complex, excision of the damage‐containing strand 3′ and 5′ to the photolesion, synthesis of a sequence‐appropriate replacement strand, and finally ligation to restore continuity of genomic …

Role Of Modern Immunotherapy In Gastrointestinal Malignancies: A Review Of Current Clinical Progress, Zin W. Myint, Gaurav Goel

Markey Cancer Center Faculty Publications

Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of …

Sumo Regulates The Activity Of Smoothened And Costal-2 In Drosophila Hedgehog Signaling, Jie Zhang, Yajuan Liu, Kai Jiang, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 …

Adipocytes Activate Mitochondrial Fatty Acid Oxidation And Autophagy To Promote Tumor Growth In Colon Cancer, Yang-An Wen, Xiaopeng Xing, Jennifer W. Harris, Yekaterina Y. Zaytseva, Mihail I. Mitov, Dana L. Napier, Heidi L. Weiss, B. Mark Evers, Tianyan Gao

Markey Cancer Center Faculty Publications

Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to …

Phlpp Regulates Hexokinase 2-Dependent Glucose Metabolism In Colon Cancer Cells, Xiaopeng Xiong, Yang-An Wen, Mihail I. Mitov, Mary C. Oaks, Shigeki Miyamoto, Tianyan Gao

Markey Cancer Center Faculty Publications

Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer cells. Knockdown of PHLPP increased the rate of glucose consumption and lactate production, whereas overexpression of PHLPP had the opposite effect. Bioenergetic analysis using Seahorse …

Crispr-Cas9 Mediated Nox4 Knockout Inhibits Cell Proliferation And Invasion In Hela Cells, Naser Jafari, Hyunju Kim, Rackhyun Park, Liqing Li, Minsu Jang, Andrew J. Morris, Junsoo Park, Cai Huang

Markey Cancer Center Faculty Publications

Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M …

Phase 3 Trial Of 177Lu-Dotatate For Midgut Neuroendocrine Tumors, Jonathan Strosberg, Ghassan El-Haddad, Edward M. Wolin, Andrew Hendifar, James Yao, Beth Chasen, Erik Mittra, Pamela L. Kunz, Matthew H. Kulke, Heather Jacene, David Bushnell, Thomas M. O’Dorisio, Richard P. Baum, Harshad R. Kulkarni, Martyn Caplin, Rachida Lebtahi, Timothy Hobday, Ebrahim Delpassand, Eric Van Cutsem, Al Benson, Rajaventhan Srirajaskanthan, Marianne Pavel, Jaime Mora, Jordan Berlin, Enrique Grande, Nicholas Reed, Ettore Seregni, Kjell Öberg, Maribel Lopera Sierra, Paola Santoro

Markey Cancer Center Faculty Publications

BACKGROUND

Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (¹⁷⁷Lu)–Dotatate in patients with advanced, progressive, somatostatin-receptor–positive midgut neuroendocrine tumors.

METHODS

We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either ¹⁷⁷Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (¹⁷⁷Lu-Dotatate group) or octreotide LAR …

Increased Ros Production In Non-Polarized Mammary Epithelial Cells Induces Monocyte Infiltration In 3d Culture, Linzhang Li, Jie Chen, Gaofeng Xiong, Daret K. St. Clair, Wei Xu, Ren Xu

Markey Cancer Center Faculty Publications

Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is …

Prevalence Of Triple-Negative Breast Cancer In India: Systematic Review And Meta-Analysis, Gurprataap S. Sandhu, Sebhat Erqou, Heidi Patterson, Aju Mathew

Markey Cancer Center Faculty Publications

Purpose There is considerable variation in prevalence rates of triple-negative breast cancer (TNBC) reported by various studies from India. We performed a systematic review and literature-based meta-analysis of these studies.

Methods We searched databases of Medline, Scopus, EMBASE, and Web of Science for studies that reported on the prevalence of TNBC in India that were published between January 1, 1999, and December 31, 2015. We extracted relevant information from each study by using a standardized form. We pooled study-specific estimates by using random-effects meta-analysis to provide summary estimates. We explored sources of heterogeneity by using subgroup analyses and metaregression.

Results …

P70s6k1 (S6k1)-Mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I Γ Degradation And Cell Invasion, Naser Jafari, Qiaodan Zheng, Liqing Li, Wei Li, Lei Qi, Jianyong Xiao, Tianyan Gao, Cai Huang

Markey Cancer Center Faculty Publications

Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKIγ90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKIγ90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 …

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 …

5-Fluorouracil Upregulates Cell Surface B7-H1 (Pd-L1) Expression In Gastrointestinal Cancers, Lauren Van Der Kraak, Gaurav Goel, Krishnaveni Ramanan, Christof Kaltenmeier, Lin Zhang, Daniel P. Normolle, Gordon J. Freeman, Daolin Tang, Katie S. Nason, Jon M. Davison, James D. Luketich, Rajeev Dhupar, Michael T. Lotze

Markey Cancer Center Faculty Publications

Background: Resistance to chemotherapy is a major obstacle in the effective treatment of cancer patients. B7-homolog 1, also known as programmed death ligand-1 (PD-L1), is an immunoregulatory protein that is overexpressed in several human cancers. Interaction of B7-H1 with programmed death 1 (PD-1) prevents T-cell activation and proliferation, sequestering the T-cell receptor from the cell membrane, inducing T-cell apoptosis, thereby leading to cancer immunoresistance. B7-H1 upregulation contributes to chemoresistance in several types of cancer, but little is known with respect to changes associated with 5-fluorouracil (5-FU) or gastrointestinal cancers.

Methods: HCT 116 p53^+/+, HCT 116 p53^−/− colorectal …

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 …

Capecitabine-Induced Coronary Vasospasm, Danish Henry, Francine Rudzik, Allison Butts, Aju Mathew

Markey Cancer Center Faculty Publications

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is approved for early-stage and advanced colorectal cancer and metastatic breast cancer. Cardiotoxicity of 5-FU is well described in the literature. However, cardiac adverse effects of capecitabine are poorly described. We report a case of coronary vasospasm induced by capecitabine. A 41-year-old female with metastatic breast cancer presented with chest pain 3 days after starting capecitabine. The chest pain was relieved by rest and exacerbated by exertion. Her physical examination was unremarkable except for a rapid heart rate of 100 bpm. Electrocardiogram test showed no acute ischemic changes. Troponin tests were negative. CT …

Integrated Molecular Pathway Analysis Informs A Synergistic Combination Therapy Targeting Pten/Pi3k And Egfr Pathways For Basal-Like Breast Cancer, Qing-Bai She, Sofia K. Gruvberger-Saal, Matthew Maurer, Yilun Chen, Mervi Jumppanen, Tao Su, Meaghan Dendy, Ying-Ka Ingar Lau, Lorenzo Memeo, Hugo M. Horlings, Marc J. Van De Vijver, Jorma Isola, Hanina Hibshoosh, Neal Rosen, Ramon Parsons, Lao H. Saal

Markey Cancer Center Faculty Publications

Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.

Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor …

Cellular And Molecular Features Of Developmentally Programmed Genome Rearrangement In A Vertebrate (Sea Lamprey: Petromyzon Marinus), Vladimir A. Timoshevskiy, Joseph R. Herdy, Melissa C. Keinath, Jeramiah J. Smith

Markey Cancer Center Faculty Publications

The sea lamprey (Petromyzon marinus) represents one of the few vertebrate species known to undergo large-scale programmatic elimination of genomic DNA over the course of its normal development. Programmed genome rearrangements (PGRs) result in the reproducible loss of ~20% of the genome from somatic cell lineages during early embryogenesis. Studies of PGR hold the potential to provide novel insights related to the maintenance of genome stability during the cell cycle and coordination between mechanisms responsible for the accurate distribution of chromosomes into daughter cells, yet little is known regarding the mechanistic basis or cellular context of PGR in this or …

Duplication And Remolding Of Trna Genes In The Mitochondrial Genome Of Reduvius Tenebrosus (Hemiptera: Reduviidae), Pei Jiang, Hu Li, Fan Song, Yao Cai, Jianyun Wang, Jinpeng Liu, Wanzhi Cai

Markey Cancer Center Faculty Publications

Most assassin bugs are predators that act as important natural enemies of insect pests. Mitochondrial (mt) genomes of these insects are double-strand circular DNAs that encode 37 genes. In the present study, we explore the duplication and rearrangement of tRNA genes in the mt genome of Reduvius tenebrosus, the first mt genome from the subfamily Reduviinae. The gene order rearranges from CR (control region)-trnI-trnQ-trnM-ND2 to CR-trnQ-trnI2-trnI1-trnM-ND2. We identified 23 tRNA genes, including 22 tRNAs commonly found in insects and an additional trnI (trnI2), which has high sequence similarity to trnM. We found several …

Fh535, A Β-Catenin Pathway Inhibitor, Represses Pancreatic Cancer Xenograft Growth And Angiogenesis, Lu Liu, Qiaoming Zhi, Meng Shen, Fei-Ran Gong, Binhua P. Zhou, Lian Lian, Bairong Shen, Kai Chen, Weiming Duan, Meng-Yao Wu, Min Tao, Wei Li

Markey Cancer Center Faculty Publications

The WNT/β-catenin pathway plays an important role in pancreatic cancer carcinogenesis. We evaluated the correlation between aberrant β-catenin pathway activation and the prognosis pancreatic cancer, and the potential of applying the β-catenin pathway inhibitor FH535 to pancreatic cancer treatment. Meta-analysis and immunohistochemistry showed that abnormal β-catenin pathway activation was associated with unfavorable outcome. FH535 repressed pancreatic cancer xenograft growth in vivo. Gene Ontology (GO) analysis of microarray data indicated that target genes responding to FH535 participated in stemness maintenance. Real-time PCR and flow cytometry confirmed that FH535 downregulated CD24 and CD44, pancreatic cancer stem cell (CSC) markers, suggesting FH535 …

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 …

Breast-Cancer-Specific Mortality In Patients Treated Based On The 21-Gene Assay: A Seer Population-Based Study, Valentina I. Petkov, Dave P. Miller, Nadia Howlader, Nathan Gliner, Will Howe, Nicola Schussler, Kathleen Cronin, Frederick L. Baehner, Rosemary Cress, Dennis Deapen, Sally L. Glaser, Brenda Y. Hernandez, Charles F. Lynch, Lloyd Mueller, Ann G. Schwartz, Stephen M. Schwartz, Antoinette Stroup, Carol Sweeney, Thomas C. Tucker, Kevin C. Ward, Charles Wiggins, Xiao-Cheng Wu, Lynne Penberthy, Steven Shak

Markey Cancer Center Faculty Publications

The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40–84 years of age, and had node-negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results …

Ubr3, A Novel Modulator Of Hh Signaling Affects The Degradation Of Costal-2 And Kif7 Through Poly-Ubiquitination, Tongchao Li, Junkai Fan, Bernardo Blanco-Sánchez, Nikolaos Giagtzoglou, Guang Lin, Shinya Yamamoto, Manish Jaiswal, Kuchuan Chen, Jie Zhang, Wei Wei, Michael T. Lewis, Andrew K. Groves, Monte Westerfield, Jianhang Jia, Hugo J. Bellen

Markey Cancer Center Faculty Publications

Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require …

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 …

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 …

Differences And Similarities In The Clinicopathological Features Of Pancreatic Neuroendocrine Tumors In China And The United States: A Multicenter Study, Li-Ming Zhu, Laura Tang, Xin-Wei Qiao, Edward M. Wolin, Nicholas N. Nissen, Deepti Dhall, Jie Chen, Lin Shen, Yihebali Chi, Yao-Zong Yuan, Qi-Wen Ben, Bin Lv, Ya-Ru Zhou, Chun-Mei Bai, Jie Chen, Yu-Li Song, Tian-Tian Song, Chong-Mei Lu, Run Yu, Yuan-Jia Chen

Markey Cancer Center Faculty Publications

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria.

This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based …