title: CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response.
abstract: Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient's samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1's expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.
authors: Dpto.Bioquímica. Fac. Medicina. Instituto de Investigaciones Biomédicas Madrid CSIC-UAM; Madrid, Spain.
authors: J
authors: J
authors: Bargiela-Iparraguirre
authors: Dpto.Bioquímica. Fac. Medicina. Instituto de Investigaciones Biomédicas Madrid CSIC-UAM; Madrid, Spain.
authors: L
authors: L
authors: Prado-Marchal
authors: The Royal Veterinary College. University of London; London, UK.
authors: M
authors: M
authors: Fernandez-Fuente
authors: Dpto.Bioquímica. Fac. Medicina. Instituto de Investigaciones Biomédicas Madrid CSIC-UAM; Madrid, Spain.
authors: A
authors: A
authors: Gutierrez-González
authors: Medical Oncology Department, Infanta Sofía University Hospital, San Sebastian de los Reyes, Madrid, 28702; Spain.|IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain.
authors: J
authors: J
authors: Moreno-Rubio
authors: Pathology Department, Infanta Sofía University Hospital, San Sebastián de los Reyes, 28702, Madrid.
authors: M
authors: M
authors: Muñoz-Fernandez
authors: Medical Oncology Department, Infanta Sofía University Hospital, San Sebastian de los Reyes, Madrid, 28702; Spain.
authors: M
authors: M
authors: Sereno
authors: Unidad de Medicina Molecular, laboratorio de Oncología, CRIB/FPCYT C-LM. Universidad de Castilla-La Mancha, Av. Almansa 14, 02006, Albacete, Spain.|Unidad asociada de Biomedicina UCLM-CSIC, Arturo Duperier 4, Madrid Spain.
authors: R
authors: R
authors: Sanchez-Prieto
authors: Dpto.Bioquímica. Fac. Medicina. Instituto de Investigaciones Biomédicas Madrid CSIC-UAM; Madrid, Spain.|CIBER for Rare Diseases (CIBERER); Valencia, Spain.|Biomarkers and Experimental Therapeutics Group; IdiPAZ; University Hospital La Paz; Madrid, Spain.
authors: R
authors: R
authors: Perona
authors: Dpto.Bioquímica. Fac. Medicina. Instituto de Investigaciones Biomédicas Madrid CSIC-UAM; Madrid, Spain.|Unidad asociada de Biomedicina UCLM-CSIC, Arturo Duperier 4, Madrid Spain.|CIBER for Rare Diseases (CIBERER); Valencia, Spain.|Biomarkers and Experimental Therapeutics Group; IdiPAZ; University Hospital La Paz; Madrid, Spain.
authors: I
authors: I
authors: Sanchez-Perez
mesh_terms: D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D059248:Chemoradiotherapy; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001761:Bleomycin; D044767:Ubiquitin-Protein Ligases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1