Abstract
BackgroundResistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients. Microarray profiling in this study revealed the differentially expressed forkhead box Q1 (FOXQ1) in CRC, and thus we aimed to illustrate the role of FOXQ1 in CRC by modulating stemness and radio-resistance of CRC cells.MethodsCRC and adjacent normal tissues were collected from CRC patients, and the correlation between FOXQ1 expression and CRC prognosis was analyzed. Subsequently, we determined the expression of FOXQ1, sirtuin 1 (SIRT1) and β-catenin in CRC tissues and cell lines. The binding affinity between FOXQ1 and SIRT1 and that between SIRT1 and β-catenin were validated with luciferase reporter gene, Co-IP and ChIP assays. Following a metagenomics analysis of CRC intestinal microbiota, the effects of the FOXQ1/SIRT1/β-catenin axis on CRC stem cell phenotypes and radio-resistance was evaluated in vitro and in vivo through manipulation of gene expression. Besides, mouse feces were collected to examine changes in intestinal microbiota.ResultsFOXQ1 was highly expressed in CRC tissues and cells and positively correlated with poor prognosis of CRC patients. FOXQ1 overexpression contributed to resistance of CRC cells to radiation. Knockdown of FOXQ1 inhibited the stemness of CRC cells and reversed their radio-resistance. FOXQ1 enhanced the transcriptional expression of SIRT1, and SIRT1 enhanced the expression and nuclear translocation of β-catenin. Knockdown of FOXQ1 repressed SIRT1 expression, thus reducing the stemness and radio-resistance of CRC cells. Moreover, FOXQ1 knockdown suppressed CRC xenograft formation in xenograft-bearing nude mice through inhibiting SIRT1 and β-catenin to reduce the content of pathological bacteria that were up-regulated in CRC.ConclusionFOXQ1-mediated SIRT1 upregulation augments expression and nuclear translocation of β-catenin and benefits CRC-related intestinal pathological bacterial, thereby enhancing the stemness and radio-resistance of CRC cells.
Highlights
Resistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients
forkhead box Q1 (FOXQ1) overexpression occurred in CRC samples in CRC‐related microarray datasets Through bioinformatics analysis based on CRC-related microarray datasets (GSE21510 and GSE156355) retrieved from GEO database, we identified three differentially expressed genes (DEGs) of up-regulated expression and 12 DEGs of down-regulated expression in CRC tissue samples in GSE21510 microarray (Fig. 1A, B) as well as 18 DEGs of up-regulated expression and 24 DEGs of down-regulated expression in CRC tissue samples in GSE156355 microarray (Fig. 1C, D)
FOXQ1 was highly expressed in CRC tissues and cells and was positively correlated with the poor prognosis of CRC patients Following bioinformatics analysis, we explored the expression of FOXQ1 in clinical CRC tissues and CRC cells
Summary
Resistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients. In spite of progress made in regard of the prevention and treatment for CRC, many patients still experience tumor recurrence and metastasis with existing therapies, including radiotherapy and chemotherapy [2,3,4]. It has been demonstrated by genomic studies that CRC shows obvious heterogeneity, and that various epigenetic modifications regarding the heterogeneity of CRC stem cells occur in the pathogenesis of CRC [5]. Understanding the mechanisms underlying the stemness and radio-resistance in CRC cells is imperative for the development of strategies targeting CRC stem cells, and to prevent CRC recurrence and enhance the prognosis in CRC patients
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