title: Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment.
abstract: OBJECTIVE
  The clinical management of colorectal cancer patients has significantly improved because of the identification of novel therapeutic targets such as EGFR and VEGF. Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify novel candidate therapeutic targets.
  
  
  METHODS
  The doubling time of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. We then investigated the potential of genes highly expressed in cancer cells with faster growth as new therapeutic targets.
  
  
  RESULTS
  Faster proliferation rates were associated with microsatellite instability and poorly differentiated histology. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing, and protein transport. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPOX) were shown to have higher expression in faster growing cell lines and primary tumors. Pharmacologic or siRNA-based inhibition of GAPDH or PPOX reduced the growth of colon cancer cells in vitro. Moreover, using a mouse xenograft model, we show that treatment with the specific PPOX inhibitor acifluorfen significantly reduced the growth of three of the seven (42.8%) colon cancer lines investigated.
  
  
  CONCLUSIONS
  We have characterized at the transcriptomic level the differences between colorectal cancer cells that vary in their growth rates, and identified novel candidate chemotherapeutic targets for the treatment of colorectal cancer.
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bazzocco
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Higinio
authors.initials: H
authors.lastname: Dopeso
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Carton-Garcia
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Irati
authors.initials: I
authors.lastname: Macaya
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Andretta
authors.affiliation: Ludwig Institute for Cancer Research Melbourne-Austin Branch and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Chionh
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Garrido
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Hafid
authors.initials: H
authors.lastname: Alazzouzi
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Nieto
authors.affiliation: Unitat d'Estadística i Bioinformàtica, Vall d'Hebron University Hospital Research Institute (VHIR), Barcelona, Spain. Departament d'Estadística, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain. Group of Drug Delivery and Targeting, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Simo
authors.initials: S
authors.lastname: Schwartz
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
authors.forename: Josipa
authors.initials: J
authors.lastname: Bilic
authors.affiliation: Ludwig Institute for Cancer Research Melbourne-Austin Branch and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.affiliation: Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain. diego.arango@vhir.org.
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005420:Flavoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009579:Nitrobenzoates / Q000008:administration & dosage; D021381:Protein Transport / Q000235:genetics; D050768:Protoporphyrinogen Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D034741:RNA, Small Interfering; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009579:Nitrobenzoates; D034741:RNA, Small Interfering; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase; C018425:acifluorfen