Abnormal expression of FOSB correlates with tumor progression and poor survival in patients with gastric cancer.

FOSB protein is encoded by the FOSB gene in humans, which shares structural similarities with the prototype of the Fos family. FOSB plays a role by AP-1 complex which is composed of heterodimers of Jun and Fos members. Our experiment aimed to evaluate the effect of FOSB in gastric cancer (GC) patients and then probe its significance in prognosis. We detected the expression of FOSB in GC and adjacent non-cancerous tissues by western blot analysis and real-time quantitative PCR (qRT-PCR). Moreover, we analyzed FOSB expression in patients who underwent resection procedures using immunohistochemistry. The relationship between the expression of FOSB, the clinicopathological characteristics and the patients survival were also investigated. Furthermore, in vitro, we evaluated the effects of FOSB gene on gastric cancer cell viability, proliferation and migration by MTT, clone formation and transwell assays. Finally, the Kaplan-Meier method and log-rank test were used to compare the overall survival between high FOSB expression group and low FOSB expression group. Immunohistochemical staining data showed that FOSB expression was significantly decreased in gastric cancer cases. In addition, we confirmed FOSB downregulation in both mRNA and protein levels in GC tissues compared with matched adjacent non-cancerous tissues. Downregulated expression of FOSB was correlated with poor differentiation, lymph node metastasis and advanced TNM stage. Moreover, we found that low FOSB expression exhibited a significant correlation with poor prognosis for GC patients by Kaplan-Meier survival analysis. Overexpression of FOSB significantly suppressed cell proliferation, clone formation and migration in GC cell lines. In contrast, silencing of FOSB expression in GC cells promoted proliferation, clone formation and migration. Our results showed that FOSB plays a crucial role in the suppression of GC, and that it may be a useful biomarker in diagnosis and prognosis for GC patients.

[1]  W. Kang,et al.  Treatment strategy for early gastric cancer. , 2012, Surgical oncology.

[2]  S. Kanner,et al.  Focal adhesion kinase regulates β1 integrin‐dependent T cell migration through an HEF1 effector pathway , 2001, European journal of immunology.

[3]  M. Zerial,et al.  The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. , 1989, The EMBO journal.

[4]  Stuart Schwartz,et al.  Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. , 2008, Cancer research.

[5]  A. Giraud,et al.  Cytokine signalling via gp130 in gastric cancer. , 2009, Biochimica et biophysica acta.

[6]  J. Melamed,et al.  Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. , 2012, The Journal of clinical investigation.

[7]  Z. Dong,et al.  Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. , 1999, Cancer research.

[8]  S. Choi,et al.  RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression , 2010, Tumor Biology.

[9]  Y. Yamaoka,et al.  Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains. , 2008, Internal medicine.

[10]  T. S. Panetti,et al.  Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects on cell spreading and migration. , 2002, Frontiers in bioscience : a journal and virtual library.

[11]  N. Heisterkamp,et al.  CRKL Links p210BCR/ABL with Paxillin in Chronic Myelogenous Leukemia Cells (*) , 1995, The Journal of Biological Chemistry.

[12]  C. Turner Paxillin and focal adhesion signalling , 2000, Nature Cell Biology.

[13]  A. van der Eb,et al.  E1A + cHa-ras transformed rat embryo fibroblast cells are characterized by high and constitutive DNA binding activities of AP-1 dimers with significantly altered composition. , 1999, Gene expression.

[14]  Hui Wang,et al.  MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. , 2011, Carcinogenesis.

[15]  F. C. Lucibello,et al.  Mutual transrepression of Fos and the glucocorticoid receptor: involvement of a functional domain in Fos which is absent in FosB. , 1990, The EMBO journal.

[16]  Yu-hong Li,et al.  DNA polymeraseη protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy , 2010, Journal of Translational Medicine.

[17]  Michael D Schaller,et al.  Paxillin: a focal adhesion-associated adaptor protein , 2001, Oncogene.

[18]  M. Yaniv,et al.  Transformation by ras modifies AP1 composition and activity , 1997, Oncogene.

[19]  Sabine Riethdorf,et al.  FosB is Highly Expressed in Normal Mammary Epithelia, but Down-Regulated in Poorly Differentiated Breast Carcinomas , 2003, Breast Cancer Research and Treatment.

[20]  Y. Zou,et al.  Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer. , 2013, Current oncology.

[21]  J. Glenney,et al.  Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton , 1989, The Journal of cell biology.

[22]  D. Jun,et al.  The clinical significance of HbA1c as a predictive factor for abnormal postprandial glucose metabolism in NAFLD patients with an elevated liver chemistry. , 2011, Hepato-gastroenterology.

[23]  B. Werness,et al.  Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18 , 1997, Oncogene.

[24]  L. Helyer,et al.  A systematic review of surgery for non-curative gastric cancer , 2012, Gastric Cancer.

[25]  Fenghua Wang,et al.  Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer , 2012, Carcinogenesis.

[26]  Dan Li,et al.  Fibronectin Promotes Tyrosine Phosphorylation of Paxillin and Cell Invasiveness in the Gastric Cancer Cell Line AGS , 2009, Tumori.

[27]  B. Rollins,et al.  Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility , 1999, Oncogene.

[28]  R. Salgia,et al.  Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  R. Xu,et al.  Prognostic relevance of melanoma antigen D1 expression in colorectal carcinoma , 2012, Journal of Translational Medicine.

[30]  D. Siderovski,et al.  A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes. , 1990, DNA and cell biology.

[31]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[32]  W. R. McCombie,et al.  Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3 , 1992, Nature Genetics.

[33]  R. Salgia,et al.  Paxillin expression and amplification in early lung lesions of high-risk patients, lung adenocarcinoma and metastatic disease , 2010, Journal of Clinical Pathology.

[34]  Manami Inoue,et al.  Comparative epidemiology of gastric cancer between Japan and China. , 2011, World journal of gastroenterology.

[35]  D. Xie,et al.  Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma. , 2005, World journal of gastroenterology.

[36]  G. Raj,et al.  Paxillin Regulates Androgen- and Epidermal Growth Factor-induced MAPK Signaling and Cell Proliferation in Prostate Cancer Cells* , 2010, The Journal of Biological Chemistry.

[37]  D. Lallemand,et al.  Down-regulation of AP1 activities after polarization of vas deferens epithelial cells correlates with androgen-induced gene expression , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[38]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[39]  R. Xu,et al.  L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer , 2013, Journal of Hematology & Oncology.

[40]  Ya‐Wen Cheng,et al.  Paxillin predicts survival and relapse in non-small cell lung cancer by microRNA-218 targeting. , 2010, Cancer research.

[41]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  J. Krosl,et al.  AP-1 complex is effector of Hox-induced cellular proliferation and transformation , 2000, Oncogene.

[43]  R. Salgia,et al.  c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. , 2003, Cancer research.

[44]  C. Turner,et al.  Paxillin: adapting to change. , 2004, Physiological reviews.

[45]  M. Blanca Piazuelo,et al.  Gastric cáncer: Overview , 2013, Colombia medica.

[46]  Zhiwei Wang,et al.  Effects of paxillin on HCT-8 human colorectal cancer cells. , 2011, Hepato-gastroenterology.

[47]  R. Salgia,et al.  The Bovine Papillomavirus E6 Protein Binds to the LD Motif Repeats of Paxillin and Blocks Its Interaction with Vinculin and the Focal Adhesion Kinase* , 1997, The Journal of Biological Chemistry.

[48]  M. Orringer,et al.  Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. , 2013, Journal of the National Comprehensive Cancer Network : JNCCN.

[49]  Karin Milde-Langosch,et al.  The Fos family of transcription factors and their role in tumourigenesis. , 2005, European journal of cancer.

[50]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[51]  S. Lo,et al.  Molecular Cloning Of Human Paxillin, a Focal Adhesion Protein Phosphorylated by P210BCR/ABL(*) , 1995, The Journal of Biological Chemistry.

[52]  C. Zahnow,et al.  Composite response elements mediate hormonal and developmental regulation of milk protein gene expression. , 1998, Biochemical Society symposium.

[53]  M. Orringer,et al.  Gastric Cancer, Version 2.2013 , 2013 .

[54]  S. Kanner,et al.  Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway. , 2001, European journal of immunology.

[55]  Ming Fang,et al.  Paxillin expression levels are correlated with clinical stage and metastasis in salivary adenoid cystic carcinoma. , 2010, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

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

[57]  M. Basson,et al.  Pressure activates colon cancer cell adhesion via paxillin phosphorylation, Crk, Cas, and Rac1 , 2008, Cellular and Molecular Life Sciences.

[58]  P. Angel,et al.  AP-1 subunits: quarrel and harmony among siblings , 2004, Journal of Cell Science.

[59]  R. Bravo,et al.  c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. , 1991, Oncogene.

[60]  D. Bikle,et al.  Requirement of an AP-1 Site in the Calcium Response Region of the Involucrin Promoter* , 2000, The Journal of Biological Chemistry.

[61]  Hsin-Yi Chen,et al.  Brk Activates Rac1 and Promotes Cell Migration and Invasion by Phosphorylating Paxillin , 2004, Molecular and Cellular Biology.