title: ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer.
abstract: OBJECTIVE
  Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels.
  
  
  METHODS
  We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines.
  
  
  RESULTS
  We found up-regulation of ARNTL2 (P = 0.004) and SERPINE1 (P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion (P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement (P < 0.001), between high SERPINE1 expression and grading (P < 0.001) and between high SERPINE1 expression and MSI H-L (P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 (P < 0.001) and SERPINE1 (P = 0.001).
  
  
  CONCLUSIONS
  ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness.
authors.affiliation: Division of Internal Medicine and Chronobiology Unit, IRCCS Casa Sollievo della Sofferenza, Research Hospital, San Giovanni Rotondo, FG, Italy. g.mazzoccoli@tin.it
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Valvano
authors.forename: Giorgia
authors.initials: G
authors.lastname: Benegiamo
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
mesh_terms: D056930:ARNTL Transcription Factors / Q000032:analysis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000097:blood / Q000235:genetics; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D056930:ARNTL Transcription Factors; C486615:BMAL2 protein, human; D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human