DOCSLIB.ORG

Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies ANTICANCER RESEARCH 37 : 301-308 (2017) doi:10.21873/anticanres.11321 Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies KEN SUZAWA 1* , KAZUHIKO SHIEN 1,2* , HUANG PENG 3, MASAKIYO SAKAGUCHI 4, MASAMI WATANABE 5,6,7 , SHINSUKE HASHIDA 1,2 , YUHO MAKI 1, HIROMASA YAMAMOTO 1, SHUTA TOMIDA 8, JUNICHI SOH 1, HIROAKI ASANO 1, KAZUNORI TSUKUDA 1, YASUTOMO NASU 5,6,7 , HIROMI KUMON 3,5,7 , SHINICHIRO MIYOSHI 1 and SHINICHI TOYOOKA 1,2 Departments of 1Thoracic Surgery, 2Clinical Genomic Medicine and 4Cell Biology, 5Urology, 3Collaborative Research Center for Okayama Medical Innovation Center, and 8Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 6Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 7Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama, Japan Abstract. Background: Reduced expression in immortalized Both advanced-stage non-small cell lung cancer (NSCLC) cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and malignant mesothelioma (MM) are aggressive tumors and and its overexpression by adenovirus vector (Ad-REIC) present a dismal prognosis. Despite advances in treatment exhibits a remarkable therapeutic effect on various human regimens for both diseases, such as surgical resection, cancer types through a mechanism triggered by endoplasmic chemotherapy, molecular-targeted therapy and radiotherapy, reticulum stress. Materials and Methods: We examined the treatment outcome is still unsatisfactory. Gene therapy for direct anti-tumor effect of Ad-REIC gene therapy on lung thoracic malignancies represents a novel therapeutic approach cancer and malignant mesothelioma cell lines in vitro, and and has been evaluated in a number of clinical trials over the the distant bystander effect using immunocompetent mouse last two decades (1). Previously, we identified expression of allograft models with bilateral flank tumors. Results: Ad- the tumor-suppressor gene Reduced expression in REIC treatment showed antitumor effect in many lung cancer immortalized cell ( REIC )/Dickkoph-3 ( DKK3 ) as being and malignant mesothelioma cell lines in vitro. In an in vivo reduced in many human cancer types (2-6). However, the model, Ad-REIC treatment inhibited the growth not only of impact of REIC/DKK3 in thoracic malignancies, such as the directly treated tumors but also of distant untreated tumors. frequency of its decreased expression among the subtypes of By immunohistochemical analysis, infiltration of T-cells and lung cancer, and the relationship between its loss and other natural killer (NK) cells and expression of the major oncogenic driver mutations, is yet to be investigated. histocompatibility complex (MHC) class I molecules were We demonstrated that overexpression of REIC/DKK3 by observed in bilateral tumors. Conclusion: Ad-REIC treatment adenovirus (Ad-REIC) led to remarkable therapeutic effects not only had a direct antitumor effect but also an indirect on several human cancer types, but not on normal cells (3, bystander effect through stimulation of the immune system. 4, 7-9). As the REIC/DKK3 gene expression is absent from cancer cells, the REIC/DKK3 protein folding system in cancer cells does not function well when the protein is overexpressed by Ad-REIC, which leads to endoplasmic reticulum (ER) stress-induced apoptosis. The activation of c- *These Authors contributed equally to this study. JUN N-terminal kinase (JNK) pathway occurs downstream of ER stress signaling, which is a critical event in apoptosis Correspondence to: Shinich Toyooka, MD, Ph.D., Department of (3, 4, 7-11). In addition to this direct antitumor effect, we Clinical Genomic Medicine, Okayama University Graduate School also showed Ad-REIC to have a host-mediated bystander of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, effect on human prostate cancer and scirrhous gastric cancer Japan. Tel: +81 862357436, Fax: +81 862357437, e-mail: [email protected] via the induction of anticancer immunity (12-14). Secreted REIC/DKK3 protein differentiates monocyte into the Key Words: REIC/DKK3 , gene therapy, lung cancer, mesothelioma, dendritic cells-like phenotype and then activates cytotoxic T- bystander effect. lymphocytes (CTLs) (12). Furthermore, in normal 0250-7005/2017 $2.00+.40 301 ANTICANCER RESEARCH 37 : 301-308 (2017) fibroblasts, Ad-REIC treatment does not cause apoptosis, but a modified 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]- induces interleukin 7 (IL7) secretion. This enhanced IL7 2-[4-sulfophenyl]-2H-tetrazolium, inner salt (MTS) assay with secretion activates natural killer (NK) cells (13, 14). These CellTiter 96 Aqueous One Solution Reagent (Promega, Madison, WI, USA) according to the manufacturer’s instruction. mechanisms up-regulate systemic antitumor immunity. Given this evidence, a clinical trial of REIC gene therapy Western blotting. The total cell lysate was extracted from cell lines for prostatic cancer is ongoing (UMIN000004929; with lysis buffer, a mixture of RIPA buffer, phosphatase inhibitor NCT01931046). In a first study in Man (a phase I/IIa study cocktails 2 and 3 (Sigma-Aldrich, St. Louis, MO, USA), and of in situ Ad-REIC therapy for prostate cancer), direct and Complete Mini (Roche, Basel, Switzerland). Western blot analysis systemic antitumor effects were clearly detected in a patient was performed by conventional methods using the following with metastatic castration-resistant prostate cancer following primary antibodies: rabbit anti-human REIC/DKK3 antibody raised chemotherapy (15). in our laboratory, rabbit anti- stress-activated protein kinases (SAPK)/JNK, phospho-SAPK/JNK (Thr183/Tyr185), cleaved poly In this study, we examined potential direct and indirect (ADP-ribose) polymerase (PARP) (Cell Signaling Technology, bystander effects of Ad-REIC via activation of systemic Danvers, MA, USA), and mouse anti-actin (Merck Millipore, antitumor immunity in lung cancer and mesothelioma cells. Billerica, MA, USA). The following secondary antibodies were In order to examine the immune-mediated response in vivo , used: goat anti-rabbit or anti-mouse IgG-conjugated horseradish we used murine cancer cell lines and an immunocompetent peroxidase (Santa Cruz Biotechnology, Dallas, TX, USA). To detect mouse model. specific signals, membranes were examined using the ECL Prime Western Blotting Detection System (GE Healthcare, Amersham, Materials and Methods UK) and LAS-3000 (Fujifilm, Tokyo, Japan). Gene expression analysis of clinical lung cancer tissues. Messenger Animal models. This study was carried out in accordance with the RNA (mRNA) expression, histological subtype, and genetic mutation Guidelines of the Okayama University Animal Committee. profiling for 158 lung carcinomas and five normal lung tissues (16) Pathogen-free immunocompetent female BALB/c mice aged 6 to 8 were obtained from Gene Expression Omnibus public database weeks were purchased from CLEA Japan (Tokyo, Japan). AB12 cells (1×10 6) were suspended in 100 μl of serum-free DMEM, and (GEO; http://www.ncbi.nlm.nih.gov/geo/; accession number 6 GSE11969). We assessed the association between mRNA expression KLN205 cells (1×10 ) were suspended in 200 μl DMEM with of REIC/DKK3 and the histological subtype or mutation profile. Matrigel, and each cell line was injected subcutaneously into the bilateral flanks of mice (n=3 per group and n=4 per group, 3 Cell lines. Four human lung cancer cell lines (A549, HCC827, respectively). When the tumors reached a volume of 200-250 mm , H1975, and PC9), three murine lung cancer cell lines (CMT64, the mice received intratumoral injection of Ad-SGE-REIC at a dose KLN205, and LL/2), four human MM cell lines (H28, H290, of 109 plaque-forming units (pfu) into the right-flank tumor on days 1 and 8. Control mice were treated in an analogous manner with H2052, and MSTO-211H), and three murine MM cell lines (AB1, 9 AB12, and AC29) were used in this study. A549 and LL/2 were injection of either 10 pfu Ad-LacZ or 100 μl of PBS. During the purchased from American Type Culture Collection (Manassas, VA, course of the study, mice were monitored for signs of pain or USA). HCC827, H1975, and four human MM cell lines were kindly distress, and loss of body weight twice a week. Tumor growth was provided by Dr. Adi F. Gazdar (University of Texas Southwestern monitored twice a week, and individual tumor volumes were measured using a digital caliper and approximated according to the Medical Center, Dallas, TX, USA). PC9 was purchased from 2 Immuno-Biological Laboratories (Takasaki, Japan). CMT64 was formula V=1/2 ab (a being the long diameter and b being the short obtained from the European Collection of Cell Cultures (Porton diameter of the tumor). No mouse encountered difficulty moving or Down, UK). KLN205 was obtained from RIKEN BioResource accessing feed and water due to tumor size, had to be euthanized Center (Tsukuba, Japan). AB1, AB12, and AC29 were were kindly prior to the experimental endpoint for the health reasons, nor provided by Steven M. Albelda (University of Pennsylvania, became severely ill or died. All mice were sacrificed on day 22 by Philadelphia, PA, USA). All human cells were cultured in RPMI- cervical dislocation under ketamine and xylazine anesthesia. After 1640 medium supplemented with 10% fetal bovine serum (FBS) sacrifice, tumors were subsequently harvested, measured, and and all murine cells were cultured in Dulbecco’s
Load more

Recommended publications
  • Single Nucleotide Polymorphisms in DKK3 Gene Are Associated with Prostate Cancer Risk and Progression ______
    ORIGINAL ARTICLE Vol. 41 (5): 869-897, September - October, 2015 doi: 10.1590/S1677-5538.IBJU.2014.0041 Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression _______________________________________________ Min Su Kim 1, Ha Na Lee 2, Hae Jong Kim 3,4, Soon Chul Myung 5 1Department of Urology, Seoul Medical Center, Seoul, Korea; 2Department of Urology, Seoul Seonam Hospital, EwhaWomans University, Seoul, Korea; 3Research Institue for Biomedical and Pharmaceutical Sciences, Chung-Ang University, Seoul, Korea; 4Advanced Urogenital Diseas Research Center, Chung-Ang University, College of Medicine, Seoul, Korea; 5Department of Urology, Chung-Ang University, College of Medicine, Seoul, Korea ABSTRACT ARTICLE INFO ______________________________________________________________ ______________________ We had investigated whether sequence variants within DKK3 gene are associated with Key words: the development of prostate cancer in a Korean study cohort. We evaluated the asso- Biological Markers; Genetic ciation between 53 single nucleotide polymorphisms (SNPs) in the DKK3 gene and Variation; Prostatic Neoplasms; prostate cancer risk as well as clinical characteristics (PSA, clinical stage, pathological Polymorphism, Single Nucleotide stage and Gleason score) in Korean men (272 prostate cancer subjects and 173 benign prostate hyperplasia subjects) using unconditional logistic regression analysis. Of the Int Braz J Urol. 2015; 41: 869-97 53 SNPs and 25 common haplotypes, 5 SNPs and 4 haplotypes were
    [Show full text]
  • Short Bowel Syndrome Results in Increased Gene Expression
    Schall et al. BMC Genomics (2017) 18:23 DOI 10.1186/s12864-016-3433-4 RESEARCH ARTICLE Open Access Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model Kathy A. Schall1, Matthew E. Thornton2, Mubina Isani1, Kathleen A. Holoyda1, Xiaogang Hou1, Ching-Ling Lien3, Brendan H. Grubbs2 and Tracy C. Grikscheit1,4* Abstract Background: Much of the morbidity associated with short bowel syndrome (SBS) is attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant effects on gene expression beyond epithelial proliferation, and tested this in a zebrafish SBS model. Methods: In a model of SBS in zebrafish (laparotomy, proximal stoma, distal ligation, n = 29) or sham (laparotomy alone, n = 28) surgery, RNA-Seq was performed after 2 weeks. The proximal intestine was harvested and RNA isolated. The three samples from each group with the highest amount of RNA were spiked with external RNA controls consortium (ERCC) controls, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. Gene expression of ctnnb1, ccnb1, ccnd1, cyp7a1a, dkk3, ifng1-2, igf2a, il1b, lef1, nos2b, saa1, stat3, tnfa and wnt5a were confirmed to be elevated in SBS by RT-qPCR. Results: RNA-seq analysis identified 1346 significantly upregulated genes and 678 significantly downregulated genes in SBS zebrafish intestine compared to sham with Ingenuity analysis. The upregulated genes were involved in cell proliferation, acute phase response signaling, innate and adaptive immunity, bile acid regulation, production of nitric oxide and reactive oxygen species, cellular barrier and coagulation.
    [Show full text]
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.
    [Show full text]
  • Transcriptome Profiling and Differential Gene Expression In
    G C A T T A C G G C A T genes Article Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis Dominique J. Wiener 1,* ,Kátia R. Groch 1 , Magdalena A.T. Brunner 2,3, Tosso Leeb 2,3 , Vidhya Jagannathan 2 and Monika M. Welle 3,4 1 Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Science, Texas A&M University, College Station, TX 77843, USA; [email protected] 2 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; [email protected] (M.A.T.B.); [email protected] (T.L.); [email protected] (V.J.) 3 Dermfocus, Vetsuisse Faculty, University Hospital of Bern, 3010 Bern, Switzerland; [email protected] 4 Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland * Correspondence: [email protected]; Tel.: +1-979-862-1568 Received: 30 June 2020; Accepted: 3 August 2020; Published: 4 August 2020 Abstract: The transcriptome profile and differential gene expression in telogen and late anagen microdissected hair follicles and the interfollicular epidermis of healthy dogs was investigated by using RNAseq. The genes with the highest expression levels in each group were identified and genes known from studies in other species to be associated with structure and function of hair follicles and epidermis were evaluated. Transcriptome profiling revealed that late anagen follicles expressed mainly keratins and telogen follicles expressed GSN and KRT15. The interfollicular epidermis expressed predominately genes encoding for proteins associated with differentiation. All sample groups express genes encoding for proteins involved in cellular growth and signal transduction.
    [Show full text]
  • Dickkopf-3 Links HSF1 and YAP/TAZ Signalling to Control Aggressive Behaviours in Cancer-Associated fibroblasts
    ARTICLE https://doi.org/10.1038/s41467-018-07987-0 OPEN Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts Nicola Ferrari 1,8, Romana Ranftl1, Ievgeniia Chicherova1, Neil D. Slaven2, Emad Moeendarbary3,4, Aaron J. Farrugia1, Maxine Lam1, Maria Semiannikova1, Marie C. W. Westergaard5, Julia Tchou6, Luca Magnani 2 & Fernando Calvo1,7 1234567890():,; Aggressive behaviours of solid tumours are highly influenced by the tumour microenviron- ment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer- associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour- promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs. 1 Tumour Microenvironment Team, Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK. 2 Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK. 3 Department of Mechanical Engineering, University College London, London WC1E 7JE, UK.
    [Show full text]
  • DKK3 Sirna (Human)
    For research purposes only, not for human use Product Data Sheet DKK3 siRNA (Human) Catalog # Source Reactivity Applications CRH8976 Synthetic H RNAi Description siRNA to inhibit DKK3 expression using RNA interference Specificity DKK3 siRNA (Human) is a target-specific 19-23 nt siRNA oligo duplexes designed to knock down gene expression. Form Lyophilized powder Gene Symbol DKK3 Alternative Names REIC; Dickkopf-related protein 3; Dickkopf-3; Dkk-3; hDkk-3 Entrez Gene 27122 (Human) SwissProt Q9UBP4 (Human) Purity > 97% Quality Control Oligonucleotide synthesis is monitored base by base through trityl analysis to ensure appropriate coupling efficiency. The oligo is subsequently purified by affinity-solid phase extraction. The annealed RNA duplex is further analyzed by mass spectrometry to verify the exact composition of the duplex. Each lot is compared to the previous lot by mass spectrometry to ensure maximum lot-to-lot consistency. Components We offers pre-designed sets of 3 different target-specific siRNA oligo duplexes of human DKK3 gene. Each vial contains 5 nmol of lyophilized siRNA. The duplexes can be transfected individually or pooled together to achieve knockdown of the target gene, which is most commonly assessed by qPCR or western blot. Our siRNA oligos are also chemically modified (2’-OMe) at no extra charge for increased stability and enhanced knockdown in vitro and in vivo. Directions for Use We recommends transfection with 100 nM siRNA 48 to 72 hours prior to cell lysis. Application key: E- ELISA, WB- Western blot, IH- Immunohistochemistry,
    [Show full text]
  • Transcriptome Analysis of Differentially Expressed Mrna Related to Pigeon Muscle Development
    animals Article Transcriptome Analysis of Differentially Expressed mRNA Related to Pigeon Muscle Development Hao Ding 1,2,† , Yueyue Lin 1,2,†, Tao Zhang 1,2,* , Lan Chen 1,2, Genxi Zhang 1,2, Jinyu Wang 1,2, Kaizhou Xie 1,2 and Guojun Dai 1,2 1 College of Animal Science and Technology, Yangzhou University, Yangzhou 225000, China; [email protected] (H.D.); [email protected] (Y.L.); [email protected] (L.C.); [email protected] (G.Z.); [email protected] (J.W.); [email protected] (K.X.); [email protected] (G.D.) 2 Joint International Research Laboratory of Agriculture and Agri−Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225000, China * Correspondence: [email protected] † These authors are contributed equally to this study. Simple Summary: The growth and development of skeletal muscle determine the meat production performance of pigeons and are regulated by complex gene networks. To explore the genes involved in regulating the growth and development of pigeon skeletal muscle, RNA sequencing (RNA−seq) was used to characterise gene expression profiles during the development and growth of pigeon breast muscle and identify differentially expressed genes (DEGs) among different stages. This study expanded the diversity of pigeon mRNA, and it was helpful to understand the role of mRNA in pigeon muscle development and growth. Abstract: The mechanisms behind the gene expression and regulation that modulate the development and growth of pigeon skeletal muscle remain largely unknown. In this study, we performed gene Citation: Ding, H.; Lin, Y.; Zhang, T.; expression analysis on skeletal muscle samples at different developmental and growth stages using Chen, L.; Zhang, G.; Wang, J.; Xie, K.; RNA sequencing (RNA−Seq).
    [Show full text]
  • DKK3 Is a Potential Tumor Suppressor Gene in Papillary Thyroid Carcinoma
    D Yin et al. Tumor suppressor genes in 20:4 507–514 Research thyroid carcinomas DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma De-tao Yin1,2, Wenxun Wu3, Mingchuang Li1,2, Qi-en Wang4, Hongqiang Li1,2, Yongfei Wang1,2, Yifeng Tang1,2 and Mingzhao Xing5 1Department of Thyroid Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, People’s Republic of China 2Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou 450052, People’s Republic of China Correspondence 3Department of Endocrinology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, should be addressed to People’s Republic of China D Yin or M Xing 4Division of Radiobiology, Department of Radiology, The Ohio State University, Columbus, Ohio 43210, USA Email 5Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, [email protected] or Maryland 21287, USA [email protected] Abstract The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human Key Words cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation of " thyroid carcinoma DKK3 in thyroid cancer have not been examined. In this study, we explored the relationship " DKK3 of promoter methylation with the inactivation of DKK3 and tumor behaviors in papillary " DNA methylation thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the " tumor suppressor gene promoter methylation and expression of DKK3 and tumor characteristics. We found mRNA " thyroid tumorigenesis expression of DKK3 in 44.9% of the PTC tissue samples vs 100% of the matched normal ! Endocrine-Related Cancer thyroid tissue samples (P 0.01).
    [Show full text]
  • Dickkopf-3 Maintains the PANC-1 Human Pancreatic Tumor Cells in a Dedifferentiated State
    40 INTERNATIONAL JOURNAL OF ONCOLOGY 40: 40-46, 2012 Dickkopf-3 maintains the PANC-1 human pancreatic tumor cells in a dedifferentiated state CHRIStopH ZENZMAIER1, Martin HERMANN2, PAUL HENGSTER2 and PETER BERGER1 1Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10; 2KMT Laboratory, Department of Visceral-, Transplant- and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Innrain 66, A-6020 Innsbruck, Austria Received June 22, 2011; Accepted July 15, 2011 DOI: 10.3892/ijo.2011.1180 Abstract. Pancreatic cancer (PaCa) is the fourth leading cause showed analogous induction of cell cycle inhibitors and differ- of cancer deaths in Western societies, with pancreatic ductal entiation markers. Thus, we conclude that Dkk-3 is required to adenocarcinomas (PDACs) accounting for >90% of such maintain a highly dedifferentiated and consequently prolifera- cases. PDAC is a heterogeneous disease that includes a subset tive state in PANC-1, indicating a similar function in the Dkk-3 showing overexpression of the secreted glycoprotein Dickkopf- overexpressing subset of PDACs. Therefore, Dkk-3 represents related protein 3 (Dkk-3), a protein shown to be downregulated a potential target for the treatment of Dkk-3-positive subtypes in various cancers of different tissues. The biological function of PaCa to drive cells into cell cycle arrest and differentiation. of Dkk-3 in this subset was studied using the Dkk-3 expressing PANC-1 cell line as a model for PDACs. The influence of Introduction Dkk-3 overexpression and knockdown on cellular differentia- tion and proliferation of PANC-1 was investigated. Confocal Pancreatic cancer (PaCa) is the fourth leading cause of cancer microscopy showed that Dkk-3 was expressed in a fraction deaths in Western societies.
    [Show full text]
  • P63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell
    Author Manuscript Published OnlineFirst on September 4, 2018; DOI: 10.1158/0008-5472.CAN-18-1749 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. p63-dependent Dickkopf3 expression promotes esophageal cancer cell proliferation via CKAP4 Chihiro Kajiwara1#, Katsumi Fumoto1#, Hirokazu Kimura1, Satoshi Nojima2, Keita Asano1, Kazuki Odagiri3, Makoto Yamasaki3, Hayato Hikita4, Tetsuo Takehara4, Yuichiro Doki3, Eiichi Morii2, and Akira Kikuchi1* 1Departments of Molecular Biology and Biochemistry, 2Pathology, 3Gastroenterological Surgery, 4Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan. # These authors contributed equally to this work. Running title: DKK3-CKAP4 axis promotes esophageal cancer proliferation All authors have declared no conflict of interest. *Correspondence author. Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan. Phone, 81-6-6879-3410. Fax, 81-6-6879-3419. E-mail:[email protected] Word count, 5268/5000. Total number of figures, 7. 1 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 4, 2018; DOI: 10.1158/0008-5472.CAN-18-1749 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family but exhibits structural divergence from other family members; and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promotes tumorigenesis remains to be clarified.
    [Show full text]
  • Network Pharmacology Approach Reveals the Potential Immune Function Activation and Tumor Cell Apoptosis Promotion of Xia Qi Decoction in Lung Cancer
    medical sciences Article Network Pharmacology Approach Reveals the Potential Immune Function Activation and Tumor Cell Apoptosis Promotion of Xia Qi Decoction in Lung Cancer Song Zhang and Yun Wang * School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 10029, China; [email protected] * Correspondence: [email protected]; Tel./Fax: +86-010-8473-8620 Received: 25 November 2019; Accepted: 24 December 2019; Published: 29 December 2019 Abstract: As the leading cause of cancer death worldwide, lung cancer (LC) has seriously affected human health and longevity. Chinese medicine is a complex system guided by traditional Chinese medicine theories (TCM). Nowadays, the clinical application of TCM for LC patients has become the focus for its effectiveness and security. In this paper, we will analyze and study the mechanism of Xia Qi Decoction (XQD) in the treatment of LC. The results collectively show that XQD could act on 41 therapeutic targets of LC. At the same time, 8 of 41 targets were significantly expressed in immune tissues and cells by activating CD8+T cells to promote apoptosis of cancer cells. It reveals the molecular mechanism of XQD in the treatment of LC from the perspective of network pharmacology. In addition, in the treatment of LC, XQD can activate (up-regulate) the function of immune cells, promote the apoptosis of tumor cells, and have an active anti-tumor immune effect. In conclusion, this study reveals the unique advantages of traditional Chinese medicine in the treatment of cancer, in reinforcing the healthy qi and eliminating the pathogenic factors. More research, however, is needed to verify the potential mechanisms.
    [Show full text]
  • Anti-DKK3 (Full Length) Polyclonal Antibody (DPABH-06257) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-DKK3 (full length) polyclonal antibody (DPABH-06257) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Antigen Description Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease. Immunogen Recombinant full length mature protein, corresponding to amino acids 23-350 of Human Dkk3, Human cell expressed. Isotype IgG Source/Host Rabbit Species Reactivity Human Purification Protein A purified Conjugate Unconjugated Applications WB, ELISA Format Liquid Size 250 μg Buffer pH: 7.00; Constituents: 5% Trehalose, 0.75% Glycine, 0.61% Tris. Note: 5-10% trehalose is commonly used for freeze drying, and after reconstitution, the trehalose is mostly about 3-5%. Preservative 0.05% Sodium Azide Storage Shipped at 4°C. Upon delivery aliquot and store at -20°C or -80°C. Avoid repeated freeze / thaw cycles. GENE INFORMATION 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Gene Name DKK3 dickkopf 3 homolog (Xenopus laevis) [ Homo sapiens ] Official Symbol Dkk3 Synonyms DKK3; dickkopf 3 homolog (Xenopus laevis); dickkopf (Xenopus laevis) homolog 3; dickkopf- related protein 3; regulated in glioma; REIC; RIG; dkk-3; hDkk-3; dickkopf-3; RIG-like 5-6; RIG- like 7-1; dickkopf homolog 3; Entrez Gene ID 27122 Protein Refseq NP_001018067 UniProt ID Q9UBP4 Chromosome Location 11p15.3 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 2 © Creative Diagnostics All Rights Reserved.
    [Show full text]