title: Inactivation of both FHIT and p53 cooperate in deregulating proliferation-related pathways in lung cancer.
abstract: BACKGROUND
  FHIT and p53 are the two most commonly altered tumor suppressor genes in lung cancer, and their molecular status regulates sensitivity to anticancer drugs. Although their functions are independent, there is evidence that their pathways might be interconnected, but little is known at the molecular level.
  
  
  METHODS
  Microarray profiling of FHIT-transduced lung cancer cells and modulation of FHIT levels by RNA interference in human bronchial cells were used to generate a signature of FHIT-regulated transcripts. Expression of these genes was evaluated by real-time polymerase chain reaction in 55 primary lung cancer samples characterized for FHIT and p53 expression by immunehistochemistry.
  
  
  RESULTS
  A signature of FHIT-transcripts, particularly enriched in genes involved in cell cycle control, was identified. This signature showed overlap with p53-regulated genes, indicating possible crosstalk between these proteins. Consistently, transcriptional deregulation after FHIT modulation was higher in p53-negative cells. In primary lung cancers, inactivation of either gene was detected in 48 of 55 cases (87%) and both genes in 23 of 55 (42%) cases, confirming the central role of these pathways. Primary tumors with inactivation of both FHIT and p53 displayed the strongest deregulation of growth-related pathways with high levels of expression of CCNB1, BUB1, CDC6, TOP2A, MCM6, and CENPF.
  
  
  CONCLUSIONS
  FHIT and p53 seem to rely on common mediators, and inactivation of both genes results in prominent deregulation of growth-related pathways in lung cancer cell lines and primary tumors. This reveals crosstalk between these proteins and suggests a possible distinctive phenotype for tumors with inactivation of both genes.
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Andriani
authors.forename: Elena
authors.initials: E
authors.lastname: Roz
authors.forename: Roberto
authors.initials: R
authors.lastname: Caserini
authors.forename: Davide
authors.initials: D
authors.lastname: Conte
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D000099170:Bis(5'-adenosyl)triphosphatase; C495901:TP53 protein, human