Journal Article

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

Moreno-Rubio, J., Sanchez-Prieto, R., Bargiela-Iparraguirre, J., Muñoz-Fernandez, M., Perona, R., Sanchez-Perez, I., Fernandez-Fuente, M., Gutierrez-González, A., Prado-Marchal, L., Sereno, M.

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 13/89 / 13/95 / 38 / 38/109 / 38/77 / 631/337 / 631/67/1857 / 96 / Bleomycin / Bleomycin - pharmacology / Cell Line, Tumor / Checkpoint Kinase 1 - biosynthesis / Checkpoint Kinase 1 - genetics / Chemoradiotherapy / CHK1 protein / E2F1 Transcription Factor - genetics / E2F1 Transcription Factor - metabolism / Gastric cancer / Gene Expression Regulation, Enzymologic - drug effects / Gene Expression Regulation, Enzymologic - radiation effects / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - radiation effects / Genotoxicity / Humanities and Social Sciences / Humans / miRNA / multidisciplinary / p53 Protein / Post-transcription / Radiation therapy / Retinoblastoma / Retinoblastoma Binding Proteins - genetics / Retinoblastoma Binding Proteins - metabolism / Science / Science (multidisciplinary) / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - pathology / Stomach Neoplasms - therapy / Surgery / Transcription / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism