title: Hepatocellular carcinoma with persistent hepatitis B virus infection shows unusual downregulation of Ras expression and differential response to Ras mediated signaling.
abstract: OBJECTIVE
  Persistent infection with hepatitis B virus (HBV) is a major etiological risk factor for hepatocellular carcinoma (HCC). The host cellular components involved in the progression of the carcinoma are still unclear. In the present study we aimed to evaluate Ras mediated signaling in hepatocellular carcinoma with persistent HBV infection.
  
  
  METHODS
  To gain insight into the role of Ras mediated signaling in HBV mediated carcinogenesis we evaluated Ras functionality by mutation analysis, reverse transcription-polymerase chain reaction, immunohistochemistry (IHC), Ras-guanosine triphosphate bound functionality assay and Ras-mediated downstream signaling in a cohort of primary HCC tissues positive for HBV-DNA.
  
  
  RESULTS
  Mutation in codon 12 of K-ras appeared to be an uncommon event in the pathogenesis of HCC. We found unusually low levels of Ras expression in HCC compared with those with normal liver and chronic liver disease (cirrhosis and chronic hepatitis). Considerable heterogeneity was found with respect to Ras-mediated signaling events (pRaf, pMAPK and pAKT). The hepatoma cell line (Hep3B) with integrated HBV showed upregulation in expression and activation of Ras and its downstream signaling in comparison to HBV a negative cell line (HepG2). The contrasting result between the cell lines and primary tumors is worthy of note.
  
  
  CONCLUSIONS
  The unusual finding on downregulation of Ras expression in primary HCC tumors in the present study together with tumor heterogeneity with respect to Ras-mediated signaling events prompts a new role of the wild type K-Ras as a possible growth suppressor and a stochastic model for progression of hepatic cancer.
authors.affiliation: Department of Gastroenterology, G.B. Pant Hospital, Delhi, India.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Bose
authors.forename: Puja
authors.initials: P
authors.lastname: Sakhuja
authors.forename: Lavanaya
authors.initials: L
authors.lastname: Bezawada
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Seyed N
authors.initials: SN
authors.lastname: Kazim
authors.forename: Luqman A
authors.initials: LA
authors.lastname: Khan
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sarin
authors.forename: Gayatri
authors.initials: G
authors.lastname: Ramakrishna
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D003062:Codon; D015536:Down-Regulation; D005260:Female; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007194:India; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003062:Codon; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins