title: CD81 is a candidate tumor suppressor gene in human gastric cancer.
abstract: BACKGROUND
  CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus. In addition, CD81 has been suggested to be involved in a broad range of other cellular functions. Its putative implication in tumorigenesis has so far, however, remained largely unexplored. To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development, we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines.
  
  
  METHODS
  The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated.
  
  
  RESULTS
  CD81 mRNA levels were found to be low in 16 of 40 (40 %) primary tumors and 9 of 14 (64.2 %) cell lines, and these low expression levels were found to correlate with the stage and grade of the tumors. Genomic alterations of CD81 were not encountered, whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment. Bisulfite DNA sequencing analysis of 10 CpG sites within the 5' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation. Subsequent restoration of CD81 expression induced a G1 cell cycle arrest and apoptosis, whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli. Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation, respectively. CD81 was found to inhibit p38 (but not ERK, JNK and AKT) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation.
  
  
  CONCLUSIONS
  From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells, at least partially through p38 signaling.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, 136-701, Seoul, Republic of Korea.
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Yoo
authors.forename: Byung-Kyu
authors.initials: BK
authors.lastname: Ryu
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Sung-Gil
authors.initials: SG
authors.lastname: Chi
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018450:Disease Progression; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060225:Tetraspanin 28 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C554798:CD81 protein, human; D060225:Tetraspanin 28; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D048051:p38 Mitogen-Activated Protein Kinases; D001374:Azacitidine