title: Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer.
abstract: BACKGROUND
  MicroRNA-143 (miRNA-143) is frequently down-regulated in colorectal cancer (CRC) and may influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of miRNA-143. However, the prognostic significance of miRNA-143 expression and the ability to predict patient response to epidermal growth factor receptor (EGFR)-targeted agents have not yet been explored.
  
  
  METHODS
  We examined 77 CRC patients who were identified by pyrosequencing to have wild-type KRAS and were subsequently treated with EGFR-targeted therapy with the monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured in CRC tissue and corresponding non-neoplastic colon tissue by RT-PCR and its expression level was correlated with clinico-pathological characteristics. Univariate and multivariate analyses were used to calculate cancer-specific survival (CSS). The progression-free survival (PFS) and objective response rates on EGFR-targeted therapy were also evaluated.
  
  
  RESULTS
  Down-regulation of miRNA-143 was observed in 47 out of 77 (61%) tumours. Multivariate Cox regression analysis identified low levels of miRNA-143 expression as an independent prognostic factor with respect to CSS (hazard ratio=1.92, confidence interval=1.1-3.4, P=0.024). A significant difference was also observed with regard to PFS on EGFR-targeted therapy (P=0.031), but there were no significant differences with regard to the objective response rates.
  
  
  CONCLUSIONS
  Our data indicate that miRNA-143 expression levels serve as an independent prognostic biomarker for CRC in KRAS wild-type patients. No role for miRNA-143 expression as a predictive biomarker for EGFR-targeted agents could be identified. Given its negative impact on CSS and PFS, miRNA-143 represents a novel prognosticator and a promising drug target for patients with CRC.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Auenbruggerplatz 15, Graz, Austria. martin.pichler@medunigraz.at
authors.forename: M
authors.initials: M
authors.lastname: Pichler
authors.forename: E
authors.initials: E
authors.lastname: Winter
authors.forename: M
authors.initials: M
authors.lastname: Stotz
authors.forename: K
authors.initials: K
authors.lastname: Eberhard
authors.forename: H
authors.initials: H
authors.lastname: Samonigg
authors.forename: S
authors.initials: S
authors.lastname: Lax
authors.forename: G
authors.initials: G
authors.lastname: Hoefler
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D000077544:Panitumumab; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab