Adenoviral Delivery of the EMX2 Gene Suppresses Growth in Human Gastric Cancer

Background EMX2 is a human orthologue of the Drosophila empty spiracles homeobox gene that has been implicated in embryogenesis. Recent studies suggest possible involvement of EMX2 in human cancers; however, the role of EMX2 in carcinogenesis needs further exploration. Results In this study, we reported that down-regulation of EMX2 expression was significantly correlated with EMX2 promoter hypermethylation in gastric cancer. Restoring EMX2 expression using an adenovirus delivery system in gastric cancer cell lines lacking endogenous EMX2 expression led to inhibition of cell proliferation and Wnt signaling pathway both in vitro and in a gastric cancer xenograft model in vivo. In addition, we observed that animals treated with the adenoviral EMX2 expression vector had significantly better survival than those treated with empty adenoviral vector. Conclusion Our study suggests that EMX2 is a putative tumor suppressor in human gastric cancer. The adenoviral-EMX2 may have potential as a novel gene therapy for the treatment of patients with gastric cancer.

[1]  M. Segal,et al.  Downregulation of EMX2 is associated with clinical outcomes in lung adenocarcinoma patients. , 2011, Clinical lung cancer.

[2]  C. Sheridan,et al.  Gene therapy finds its niche , 2011, Nature Biotechnology.

[3]  K Shimizu,et al.  EMX2 is epigenetically silenced and suppresses growth in human lung cancer , 2010, Oncogene.

[4]  Hai-Meng Zhou,et al.  Use of Serum Circulating Ccnb2 in Cancer Surveillance , 2010, The International journal of biological markers.

[5]  Saraswati Sukumar,et al.  The Hox genes and their roles in oncogenesis , 2010, Nature Reviews Cancer.

[6]  Hiromu Suzuki,et al.  A Single Recombinant Adenovirus Expressing p53 and p21-targeting Artificial microRNAs Efficiently Induces Apoptosis in Human Cancer Cells , 2009, Clinical Cancer Research.

[7]  S. Mittal,et al.  Adenoviral vector-based strategies for cancer therapy. , 2009, Current drug therapy.

[8]  S. Mittal,et al.  Adenovirus receptors and their implications in gene delivery , 2009, Virus Research.

[9]  D. Roukos.  Genome-Wide Association Studies and Aggressive Surgery Toward Individualized Prevention, and Improved Local Control and Overall Survival for Gastric Cancer , 2009, Annals of Surgical Oncology.

[10]  D. Fan,et al.  Molecular basis of therapeutic approaches to gastric cancer , 2009, Journal of gastroenterology and hepatology.

[11]  A. Jimeno,et al.  HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  W. Birchmeier,et al.  Wnt signalling and its impact on development and cancer , 2008, Nature Reviews Cancer.

[13]  Khean Lee Goh,et al.  Screening for gastric cancer in Asia: current evidence and practice. , 2008, The Lancet. Oncology.

[14]  C. Napoli,et al.  Adenovirus Serotype 5 Hexon Mediates Liver Gene Transfer , 2008, Cell.

[15]  R. Chandler,et al.  Adenovirus-Mediated Gene Delivery Rescues a Neonatal Lethal Murine Model of mut0 Methylmalonic Acidemia , 2008 .

[16]  David T. Curiel,et al.  Engineering targeted viral vectors for gene therapy , 2007, Nature Reviews Genetics.

[17]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[18]  C. V. D. van de Velde,et al.  Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. , 2006, The New England journal of medicine.

[19]  H. Taylor,et al.  Emx2 regulates mammalian reproduction by altering endometrial cell proliferation. , 2005, Molecular endocrinology.

[20]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[21]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[22]  I. Verma,et al.  Gene therapy with viral vectors. , 2003, Annual review of pharmacology and toxicology.

[23]  K. Ligon,et al.  Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia , 2003, Development.

[24]  S. Wadler,et al.  Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  C. Abate-Shen.  Deregulated homeobox gene expression in cancer: cause or consequence? , 2002, Nature Reviews Cancer.

[26]  Aller,et al.  Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. , 2002, The New England journal of medicine.

[27]  R. Galli,et al.  Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. , 2002, Development.

[28]  D. Nettelbeck,et al.  Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. , 2002, Cancer research.

[29]  K. Imai,et al.  Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells. , 2001, Cancer research.

[30]  P. Goodfellow,et al.  Characterization of the homeodomain gene EMX2: sequence conservation, expression analysis, and a search for mutations in endometrial cancers. , 2001, Genomics.

[31]  M. Cantile,et al.  Homeobox genes in normal and malignant cells , 2001, Journal of cellular physiology.

[32]  Serafino Pantano,et al.  Agenesis of the scapula in Emx2 homozygous mutants. , 2001, Developmental biology.

[33]  E. Boncinelli,et al.  Emx homeogenes and mouse brain development , 2000, Trends in Neurosciences.

[34]  P. Gruss,et al.  The Lack of Emx2 Causes Impairment ofReelin Signaling and Defects of Neuronal Migration in the Developing Cerebral Cortex , 2000, The Journal of Neuroscience.

[35]  M. Cantile,et al.  Homeobox genes and cancer. , 1999, Experimental cell research.

[36]  P Gruss,et al.  Dentate gyrus formation requires Emx2. , 1996, Development.

[37]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[38]  Florian Kreppel,et al.  Modification of adenovirus gene transfer vectors with synthetic polymers: a scientific review and technical guide. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  R. Chandler,et al.  Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. , 2008, Human gene therapy.

[40]  R. Chuck,et al.  Periocular triamcinolone enhances intraocular gene expression after delivery by adenovirus. , 2008, Investigative Ophthalmology and Visual Science.

[41]  A. Amalfitano,et al.  Adenovirus vectors for renal-targeted gene delivery. , 2008, Contributions to nephrology.

[42]  H. Clevers.  Wnt/beta-catenin signaling in development and disease. , 2006, Cell.

[43]  J. Herman,et al.  Methylation-specific polymerase chain reaction. , 2005, Methods in molecular medicine.

[44]  P. Goodfellow,et al.  Antisense transcripts at the EMX2 locus in human and mouse. , 2003, Genomics.

[45]  S. Aizawa,et al.  Emx1 and Emx2 functions in development of dorsal telencephalon. , 1997, Development.