Abstract
Preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, CRC cells often develop chemoradiation resistance (CRR). Recent studies have shown that long non-coding RNA (lncRNA) plays critical roles in a myriad of biological processes and human diseases, as well as chemotherapy resistance. Since the roles of lncRNAs in 5-FU-based CRR in human CRC cells remain unknown, they were investigated in this study. A 5-FU-based concurrent CRR cell model was established using human CRC cell line HCT116. Microarray expression profiling of lncRNAs and mRNAs was undertaken in parental HCT116 and 5-FU-based CRR cell lines. In total, 2,662 differentially expressed lncRNAs and 2,398 mRNAs were identified in 5-FU-based CRR HCT116 cells when compared with those in parental HCT116. Moreover, 6 lncRNAs and 6 mRNAs found to be differentially expressed were validated by quantitative real time PCR (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated involvement of many, such as Jak- STAT, PI3K-Akt and NF-kappa B signaling pathways. To better understand the molecular basis of 5-FU-based CRR in CRC cells, correlated expression networks were constructed based on 8 intergenic lncRNAs and their nearby coding genes. Changes in lncRNA expression are involved in 5-FU-based CRR in CRC cells. These findings may provide novel insight for the prognosis and prediction of response to therapy in CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common cancers in the world, with more than one million new cases every year (Haggar and Boushey, 2009; Chen et al, 2013; Chen et al, 2014)
Cell culture and reagents The human colorectal cancer (CRC) cell line HCT116 was maintained in RPMI medium supplemented with 10% heatinactivated fetal bovine serum (FBS) and 1% penicillin/ streptomycin in a humidified incubator at 37 ̊C with 5% CO2 atmosphere. 5-FU was purchased from SigmaAldrich
The chemoradiation resistance (CRR)-HCT116 cells showed a significant increase in resistance to chemoradiation compared with their parental HCT116 cells (Figure 2A, B)
Summary
Colorectal cancer (CRC) is one of the most common cancers in the world, with more than one million new cases every year (Haggar and Boushey, 2009; Chen et al, 2013; Chen et al, 2014). The H19 gene could induce P-glycoprotein expression and MDR1associated drug resistance in liver cancer cells via the regulation of MDR1 promoter methylation (Tsang and Kwok, 2007). Identifying lncRNAs associated with resistance to 5-FU-based concurrent chemoradiation should be of great importance to treatment of CRC patients. We developed 5-FU-based chemoradiation resistance (CRR) cell model from human CRC cell line HCT116, and performed colony formation validation. In order to identify the functional contributions of lncRNAs to 5-FU-based CRR in human CRC cells, we profiled lncRNAs and mRNAs expression in parental HCT116 and 5-FU-based CRR HCT116, and the latter was designated CRR-HCT116 in this study. Correlated expression networks between 8 intergenic lncRNAs and their nearby mRNAs were constructed to study genes that may be responsible for 5-FU-based CRR in CRC cells. The SF2 value (surviving fraction at 2 Gy) and D0 value (dose to reduce survival to 37%) were calculated
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