title: MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1.
abstract: OBJECTIVE
  We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.
  
  
  METHODS
  We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.
  
  
  RESULTS
  We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.
  
  
  CONCLUSIONS
  This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.
authors.affiliation: Università di Napoli "Federico II", Istituto per l'Endocrinologia e l'Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche , Naples , Italy +39 081 7464547 ; +39 081 7463749 ; +39 081 2296674 ; daniela.dangelo@unina.it ; alfusco@unina.it.
authors.forename: Paula
authors.initials: P
authors.lastname: Mussnich
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosa
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005819:Genetic Markers; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D005819:Genetic Markers; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C531408:mirn199 microRNA, human; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D000068818:Cetuximab
keywords: colon cancer; drug resistance; miR-199a-5p; miR-375