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Yasunao Kogashiwa, Hitoshi Inoue, Kiyomi Kuba, Ryuichiro Araki, Masanori Yasuda, Mitsuhiko Nakahira, Masashi Sugasawa
BACKGROUND: Cetuximab combined with chemoradiotherapy is the standard therapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, survival benefit is limited. The purpose of this study was to investigate the expression of epiregulin (EREG) and amphiregulin (AREG), as predictive prognostic markers for the efficacy of cetuximab combined with chemotherapy in R/M HNSCC. METHODS: We conducted a retrospective analysis of 37 patients diagnosed with R/M HNSCC...
October 10, 2018: Head & Neck
Georgia E Fouli, Luigi Gnudi
Diabetic nephropathy is the commonest cause of end-stage renal disease and affects between 30 and 45% of patients with diabetes mellitus. There is no cure for diabetic nephropathy and the current management of this condition includes glycaemic control, blockade of the renin-angiotensin aldosterone system and lifestyle changes. However, many patients eventually progress to end-stage renal disease. The exact pathogenesis of diabetic nephropathy is still being researched, and recent advances have led to the development of several novel potential therapeutic targets...
September 26, 2018: Nephron
Felix Bormann, Sebastian Stinzing, Sascha Tierling, Markus Morkel, Maria Rivera Markelova, Jörn Walter, Wilko Weichert, Florian Roßner, Natalia Kuhn, Juliane Perner, Johanna Dietz, Sylvia Ispasanie, Manfred Dietel, Reinhold Schäfer, Volker Heinemann, Christine Sers
Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2´-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression...
September 25, 2018: International Journal of Cancer. Journal International du Cancer
Yangyang Cao, Liping Wang, Haoqing Yang, Xiao Lin, Guoqing Li, Nannan Han, Juan Du, Zhipeng Fan
To investigate the function of epiregulin (EREG) in the migration and chemotaxis ability of mesenchymal stem cells. Adipose-derived stem cells (ADSCs) were used in this investigation. Lentiviral EREG short hairpin RNA was applied to silence EREG expression in ADSCs. Human recombinant EREG protein (rhEREG) was used to perform a gain-of-function study. Scratch-simulated wound migration and transwell chemotaxis assays were used to examine the migration and chemotaxis capacity of ADSCs in vitro. Using a Western blot assay, the expressions of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), and protein kinase B were detected...
July 16, 2018: Journal of Cellular Biochemistry
Joabel T Dos Santos, Matheus P De Cesaro, Juliana G Ferst, Andressa M Pereira Dau, Paulo R A da Rosa, Bruno M Pasqual, Alfredo Q Antoniazzi, Bernardo G Gasperin, Vilceu Bordignon, Paulo B D Gonçalves
During folliculogenesis, the luteinizing hormone (LH) surge triggers dynamic events in granulosa cells that culminate with ovulation. The aim of this study was to evaluate if the epidermal growth factor receptor (EGFR) is required for ovulation in cattle, and if it regulates the expression of the natriuretic peptide (NP) system in granulosa cells after gonadotropin-releasing hormone (GnRH)/LH stimulation. It was observed that GnRH induces amphiregulin (AREG) and epiregulin (EREG) mRNA at 3 and 6 h after in vivo treatment, but the expression of these genes was not regulated by atrial (ANP) and C-type (CNP) NPs in granulosa cells cultured in vitro...
June 22, 2018: Theriogenology
Wenjing Zhao, Liping Yang, Xudong Chen, Hongyan Qian, Suqing Zhang, Yali Chen, Runhua Luo, Jingjing Shao, Huanliang Liu, Jianguo Chen
AIMS: Tumor endothelial cells (TECs) have been investigated using human tumor xenografts in mice models. In order to provide pure human TECs for the updating of clinical anti-angiogenic cancer therapy, in the present study we established a protocol of purification of TECs derived from clinical hepatocellular carcinoma (HCC) and revealed the TEC features by in vitro and in vivo assays. METHODS: We isolated TECs from fresh surgical resections of HCC by magnetic-activated cell sorting and purified by flow cytometry sorting upon CD31 expression, referred to as ECDHCCs...
June 28, 2018: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Thiagarajan Venkatesan, Ali Alaseem, Aiyavu Chinnaiyan, Sivanesan Dhandayuthapani, Thanigaivelan Kanagasabai, Khalid Alhazzani, Priya Dondapati, Saad Alobid, Umamaheswari Natarajan, Ruben Schwartz, Appu Rathinavelu
The Murine Double Minute 2 (MDM2) amplification or overexpression has been found in many tumors with high metastatic and angiogenic ability. Our experiments were designed to explore the impact of MDM2 overexpression, specifically on the levels of angiogenesis-related genes, which can also play a major role in tumor propagation and increase its metastatic potential. In the present study, we have used the human angiogenesis RT² profiler PCR array to compare the gene expression profile between LNCaP and LNCaP-MST (MDM2 transfected) prostate cancer cells, along with LNCaP-MST cells treated with Nutlin-3, an MDM2 specific inhibitor...
May 10, 2018: Cells
Yoji Kyotani, Asako Itaya-Hironaka, Akiyo Yamauchi, Sumiyo Sakuramoto-Tsuchida, Mai Makino, Shin Takasawa, Masanori Yoshizumi
Patients with obstructive sleep apnea (OSA) experience repetitive episodes of desaturation and resaturation of blood oxygen (known as intermittent hypoxia or IH), during sleep. We showed previously that IH induced excessive proliferation of rat vascular smooth muscle cells through upregulation of members of the epidermal growth factor family, especially epiregulin (EREG), and the erbB2 receptor. In this study, we exposed human coronary artery smooth muscle cells to IH and found that IH significantly increased the expression of EREG...
May 2018: FEBS Open Bio
Marian Acevedo-Alvarez, Judy Yeh, Lery Alvarez-Lugo, Ming Lu, Nitin Sukumar, Warren G Hill, Toby C Chai
AIMS: Symptoms from overactive bladder (OAB) and cystitis secondary to urinary tract infection (UTI) can be similar in post-menopausal women. Effects of ovariectomy (OVX) on voiding behavior after lipopolysaccharide (LPS) intravesical exposure (surrogate for cystitis) in mice were measured. Urothelial genes associated with micturition changes were identified. METHODS: Female C57BL6/J mice underwent OVX or sham surgeries (n = 10 for each). Voiding spot assays (VSA) were performed prior to surgery, 4 weeks post-surgery, and each time after 3 consecutive days of transurethral instillation of LPS...
April 23, 2018: Neurourology and Urodynamics
Joanne Sloan-Lancaster, Eyas Raddad, Mark A Deeg, Michelle Eli, Amy Flynt, James Tumlin
Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo...
September 2018: Clinical Pharmacology in Drug Development
Keiko Shinoda, Hideaki Fujitani
Proline cis-trans isomerisation is a regulatory mechanism used in a range of biological processes, and is related to various diseases such as Alzheimers disease and cancer. However, the details of the exact molecular mechanism by which it occurs are not known. Using X-ray crystallography, proline isomerisation has been shown to occur following formation of an antigen-antibody complex between the target epiregulin (EPR) and the antibody 9E5, at proline (Pro103), located in the third complementarity-determining region (CDR) of the heavy chain of 9E5...
December 5, 2017: Scientific Reports
L A Owens, A Abbara, A Lerner, S O'floinn, G Christopoulos, S Khanjani, R Islam, K Hardy, A C Hanyaloglu, S A Lavery, W S Dhillo, S Franks
STUDY QUESTION: What are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation? SUMMARY ANSWER: The use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS...
February 1, 2018: Human Reproduction
Petra Vychytilova-Faltejskova, Jana Merhautova, Tana Machackova, Irene Gutierrez-Garcia, José Garcia-Solano, Lenka Radova, Dominika Brchnelova, Katerina Slaba, Marek Svoboda, Jana Halamkova, Regina Demlova, Igor Kiss, Rostislav Vyzula, Pablo Conesa-Zamora, Ondrej Slaby
Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p...
December 4, 2017: Oncogenesis
Ming Liu, Zheng Zhang, Leesa Sampson, Xuan Zhou, Kodandaramireddy Nalapareddy, Yuxin Feng, Shailaja Akunuru, Jaime Melendez, Ashley Kuenzi Davis, Feng Bi, Hartmut Geiger, Mei Xin, Yi Zheng
RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage...
December 12, 2017: Stem Cell Reports
Wen-Wen Yang, Lin-Qian Yang, Fei Zhao, Chu-Wen Chen, Li-Hua Xu, Jia Fu, Sheng-Lin Li, Xi-Yuan Ge
Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8...
2017: Theranostics
Macarena Massip-Copiz, Mariángeles Clauzure, Ángel G Valdivieso, Tomás A Santa-Coloma
CFTR is a cAMP-regulated chloride channel, whose mutations produce cystic fibrosis. The impairment of CFTR activity increases the intracellular Cl- concentration, which in turn produces an increased interleukin-1β (IL-1β) secretion. The secreted IL-1β then induces an autocrine positive feedback loop, further stimulating IL-1β priming and secretion. Since IL-1β can transactivate the epidermal growth factor receptor (EGFR), we study here the levels of expression for different EGFR ligands in Caco-2/pRS26 cells (expressing shRNA against CFTR resulting in a reduced CFTR expression and activity)...
March 2018: Journal of Cellular Biochemistry
S E Tahaei, G Couasnay, Y Ma, N Paria, J Gu, B F Lemoine, X Wang, J J Rios, F Elefteriou
Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 gene. Recalcitrant bone healing following fracture (i.e. pseudarthrosis) is one of the most problematic skeletal complications associated with NF1. The etiology of this condition is still unclear; thus, pharmacological options for clinical management are limited. Multiple studies have shown the reduced osteogenic potential of Nf1-deficient osteoprogenitors. A recent transcriptome profiling investigation revealed that EREG and EGFR, encoding epiregulin and its receptor Epidermal Growth Factor Receptor 1, respectively, were among the top over-expressed genes in cells of the NF1 pseudarthrosis site...
January 2018: Bone
Daniel M Freed, Nicholas J Bessman, Anatoly Kiyatkin, Emanuel Salazar-Cavazos, Patrick O Byrne, Jason O Moore, Christopher C Valley, Kathryn M Ferguson, Daniel J Leahy, Diane S Lidke, Mark A Lemmon
Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF-making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation...
October 19, 2017: Cell
Cédric Boudot, Lucie Hénaut, Ursula Thiem, Sandra Geraci, Mariangela Galante, Paulo Saldanha, Zuzana Saidak, Isabelle Six, Philippe Clézardin, Said Kamel, Romuald Mentaverri
INTRODUCTION AND AIMS: Osteolytic bone metastases are observed in advanced cases of breast cancer. In vitro data suggest that the activity of the calcium-sensing receptor (CaSR) expressed by metastatic cells could potentiate their osteolytic potential. This study aimed to demonstrate in vivo the involvement of the CaSR in breast cancer cells osteolytic potential and to identify potential targets linked to CaSR activity. METHODS AND RESULTS: MDA-MB-231 stably transfected with plasmids containing either a full-length wild-type CaSR (CaSR-WT), or a functionally inactive dominant negative mutant (CaSR-DN) or an empty vector (EV) were intratibially injected into Balb/c-Nude mice...
August 22, 2017: Oncotarget
Kristina Pogrmic-Majkic, Dragana Samardzija, Natasa Stojkov-Mimic, Jelena Vukosavljevic, Aleksandra Trninic-Pjevic, Vesna Kopitovic, Nebojsa Andric
Atrazine (ATR) alters female reproductive functions in different animal species. Here, we analyzed whether ATR disturbs steroidogenic and ovulatory processes in hormone-stimulated human cumulus granulosa cells and mechanism of its action. Results showed that treatment of human cumulus granulosa cells with 20 μM ATR for 48 h resulted in lower FSH-stimulated estradiol and progesterone production. ATR reduced mRNA levels of aromatase (CYP19A1), steroidogenic acute regulatory protein (STAR) and luteinizing hormone/choriogonadotropin receptor (LHCGR)...
February 5, 2018: Molecular and Cellular Endocrinology
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