1. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, PR China;
2. Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou City, Guangdong Province, PR China;
3. Department of Breast Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, PR China.
* These authors contributed equally to this work.
Background and Aim: Hairy enhancer of split-1 (HES1) is a downstream transcriptional factor of Notch signaling pathway, which was found to be related to chemoresistance. This study was aimed to investigate the role of HES1 in chemoresistance of colorectal cancer (CRC).
Methods: Tissue microarray was used to analyze the clinical significance of HES1 in radical resected (R0) stage II/III CRC patients that received adjuvant chemotherapy. 5-fluorouracil (5-Fu) chemoresistance was examined in CRC cell lines (RKO and HCT8, LOVO) with stable over-expression and inhibition of HES1 gene by cytotoxicity test. Gene expression microarray was used to investigate the enriched pathways and different expressed of genes in cells with over-expressed HES1. Expression changes of the chemoresistance related genes were confirmed by qPCR and western blot analysis.
Results: Stage II CRC patients with higher HES1 expression showed higher recurrence rate after chemotherapy. Colon cancer cell lines which over-expressed HES1 were more resistant to 5-Fu treatment in vitro. Gene expression microarray revealed that HES1 was related to the signaling pathways of epithelial-mesenchymal transition (EMT) and drug metabolism. Immunofluorescence assay showed HES1 over-expression lead to depressed E-cadherin and elevated N-cadherin. QPCR and western blot analysis confirmed that ABCC1, ABCC2 and P-gp1 were induced after HES1 over-expression.
Conclusions: HES1 promotes chemoresistance to 5-Fu by prompting EMT and inducing of several ABC transporter genes. HES1 might be a novel therapeutic target in CRC treatment.
Keywords: HES1, colorectal cancer, chemoresistance, EMT, ABC transporter proteins.