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.
References
[1]
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108.
[2]
Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12: 354–362.
[3]
Roukos DH (2009) Genome-wide association studies and aggressive surgery toward individualized prevention, and improved local control and overall survival for gastric cancer. Ann Surg Oncol 16: 795–798.
[4]
Wu K, Nie Y, Guo C, Chen Y, Ding J, et al. (2009) Molecular basis of therapeutic approaches to gastric cancer. J Gastroenterol Hepatol 24: 37–41.
[5]
Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, et al. (2008) Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol 9: 279–287.
[6]
Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19: 1523–1529.
[7]
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, et al. (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355: 11–20.
[8]
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, et al. (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345: 725–730.
[9]
Kreppel F, Kochanek S (2008) Modification of adenovirus gene transfer vectors with synthetic polymers: a scientific review and technical guide. Mol Ther 16: 16–29.
[10]
Kootstra NA, Verma IM (2003) Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol 43: 413–439.
[11]
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, et al. (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445: 661–665.
[12]
Idogawa M, Sasaki Y, Suzuki H, Mita H, Imai K, et al. (2009) A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells. Clin Cancer Res 15: 3725–3732.
[13]
Nishimura S, Adachi M, Ishida T, Matsunaga T, Uchida H, et al. (2001) Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells. Cancer Res 61: 7009–7014.
[14]
Abate-Shen C (2002) Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer 2: 777–785.
[15]
Cecchi C, Boncinelli E (2000) Emx homeogenes and mouse brain development. Trends Neurosci 23: 347–352.
[16]
Pellegrini M, Pantano S, Fumi MP, Lucchini F, Forabosco A (2001) Agenesis of the scapula in Emx2 homozygous mutants. Dev Biol 232: 149–156.
[17]
Pellegrini M, Mansouri A, Simeone A, Boncinelli E, Gruss P (1996) Dentate gyrus formation requires Emx2. Development 122: 3893–3898.
[18]
Yoshida M, Suda Y, Matsuo I, Miyamoto N, Takeda N, et al. (1997) Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124: 101–111.
[19]
Mallamaci A, Mercurio S, Muzio L, Cecchi C, Pardini CL, et al. (2000) The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex. J Neurosci 20: 1109–1118.
[20]
Galli R, Fiocco R, De Filippis L, Muzio L, Gritti A, et al. (2002) Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. Development 129: 1633–1644.
[21]
Taylor HS, Fei X (2005) Emx2 regulates mammalian reproduction by altering endometrial cell proliferation. Mol Endocrinol 19: 2839–2846.
[22]
Okamoto J, Hirata T, Chen Z, Zhou HM, Mikami I, et al. (2010) EMX2 is epigenetically silenced and suppresses growth in human lung cancer. Oncogene 29: 5969–5975.
[23]
Okamoto J, Kratz JR, Hirata T, Mikami I, Raz D, et al. (2011) Downregulation of EMX2 is Associated with Clinical Outcomes in Lung Adenocarcinoma Patients. Clin Lung Cancer 12: 237–244.
[24]
Noonan FC, Mutch DG, Ann Mallon M, Goodfellow PJ (2001) Characterization of the homeodomain gene EMX2: sequence conservation, expression analysis, and a search for mutations in endometrial cancers. Genomics 76: 37–44.
[25]
Noonan FC, Goodfellow PJ, Staloch LJ, Mutch DG, Simon TC (2003) Antisense transcripts at the EMX2 locus in human and mouse. Genomics 81: 58–66.
[26]
Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8: 387–398.
[27]
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.
[28]
Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781–810.
[29]
Ligon KL, Echelard Y, Assimacopoulos S, Danielian PS, Kaing S, et al. (2003) Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia. Development 130: 2275–2287.
[30]
Galm O, Herman JG (2005) Methylation-specific polymerase chain reaction. Methods Mol Med 113: 279–291.
[31]
Mo ML, Chen Z, Li J, Li HL, Sheng Q, et al. (2010) Use of serum circulating CCNB2 in cancer surveillance. Int J Biol Markers 25: 236–242.
[32]
Shah N, Sukumar S (2010) The Hox genes and their roles in oncogenesis. Nature Reviews Cancer 10: 361–371.
[33]
Cillo C, Faiella A, Cantile M, Boncinelli E (1999) Homeobox genes and cancer. Exp Cell Res 248: 1–9.
[34]
Appledorn DM, Seregin S, Amalfitano A (2008) Adenovirus vectors for renal-targeted gene delivery. Contrib Nephrol 159: 47–62.
[35]
Chandler RJ, Venditti CP (2008) Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. Hum Gene Ther 19: 53–60.
[36]
Park CY, Chuck RS, Cano M, Yew M, Nguyen V, et al. (2008) Periocular triamcinolone enhances intraocular gene expression after delivery by adenovirus. Invest Ophthalmol Vis Sci 49: 399–406.
Sharma A, Li X, Bangari DS, Mittal SK (2009) Adenovirus receptors and their implications in gene delivery. Virus Res 143: 184–194.
[39]
Makower D, Rozenblit A, Kaufman H, Edelman M, Lane ME, et al. (2003) Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res 9: 693–702.
[40]
Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, et al. (2002) Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 62: 1266–1270.
[41]
Waehler R, Russell SJ, Curiel DT (2007) Engineering targeted viral vectors for gene therapy. Nat Rev Genet 8: 573–587.
[42]
Sharma A, Tandon M, Bangari DS, Mittal SK (2009) Adenoviral vector-based strategies for cancer therapy. Curr Drug ther. 4: 117–138.
[43]
Sheridan C (2011) Gene therapy finds its niche. Nat Biotech 29: 121–128.