MicroRNA expression profiles identify biomarkers for predicting the response to chemoradiotherapy in rectal cancer

摘要

Neoadjuvant chemoradiotherapy (nCRT) following surgery significantly improves the survival rate of patients with rectal cancer. However, nCRT is associated with significant adverse symptoms and high medical costs. Therefore, it is important to investigate potential biomarkers for the prediction of the response to nCRT in patients with rectal cancer. The present study identified candidate biomarkers for predicting a complete response (CR) to nCRT in patients with rectal cancer and investigated the associated mechanisms. Microarray data (accession no. GSE29298) was downloaded from the Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs/miR) were screened between the pathological CR (pCR) group and no pCR (incomplete response) group. miRNA target genes were predicted using the miRWalk 2.0 online tool and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, a miRNA co-regulatory network was constructed and disease-associated genes were predicted. The results demonstrated that a total of 36 upregulated and 5 downregulated miRNAs were identified between the two groups. Among these differentially expressed miRNAs, miR-548c-5p, miR-548d-5p and miR-663a were significantly associated with a CR to nCRT. The co-regulatory network and pathway analysis indicated that miR-548c-5p and miR-548d-5p may function together through stem cell pluripotency and ubiquitin-mediated proteolysis signaling pathways. Furthermore, the prediction of disease-associated genes demonstrated that miR-548c-5p/miR-548d-5p and miR-663a may regulate genes associated with rectal cancer, including mutated in colorectal cancers (MCC) and adenomatous polyposis coli (APC), and colorectal neoplasms, including interleukin-6 signal transducer (IL6ST), cell cycle checkpoint kinase 2 (CHEK2), marker of proliferation Ki-67 (MKI67), cadherin 7 (CDH7), calreticulin (CALR) and transforming growth factor β1 (TGFB1). Therefore, miR-548c-5p, miR-548d-5p and miR-663a are promising candidate biomarkers for predicting a CR to nCRT. miR-548c-5p/miR-548d-5p may be associated with a CR by regulating IL6ST, CHEK2, MKI67 and MCC. In addition, it may function through the pluripotency of stem cells and ubiquitin-mediated proteolysis signaling pathways. miR-663a may be associated with a CR to nCRT by targeting CDH7, CALR, APC and TGFβ1. Thus, the miRNA biomarkers investigated in the present study may represent novel therapeutic targets for the prediction and eventual improvement of the response to nCRT in patients with rectal cancer.