Abstract
BackgroundAccumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the post-transcriptional level; this mechanism is believed to occur in various cancers. However, the expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown.MethodsqRT-PCR was used to detect the expression of circ_001680 and miR-340 in human CRC tissues and their matched normal tissues. Bioinformatics analyses and dual-fluorescence reporter assays were used to evaluate whether circ_001680 could bind to miR-340. Circ_001680 overexpression and knockdown cell lines were constructed to investigate the proliferation and migration abilities in vivo and in vitro through function-based experiments, including CCK8, plate clone formation, transwell, and wounding healing assays. The relationships among circ_001680, miR-340 and BMI1 were investigated by bioinformatics analyses, dual-fluorescence reporter system, FISH, RIP and RNA pull down assays. Sphere forming assays and flow cytometry analyses were used to assess the effect of circ_001680 on the stemness characteristics of CRC cells.ResultsCirc_001680 was more highly expressed in of CRC tissue than in matched adjacent normal tissues from the same patients. Circ_001680 was observed to enhance the proliferation and migration capacity of CRC cells. Furthermore, dual-fluorescence reporter assays confirmed that circ_001680 affects the expression of BMI1 by targeting miR-340. More importantly, we also found that circ_001680 could promote the cancer stem cell (CSC) population in CRC and induce irinotecan therapeutic resistance by regulating the miR-340 target gene BMI1.ConclusionsOur results demonstrated that circ_001680 is a part of a novel strategy to induce chemotherapy resistance in CRC through BMI1 upregulation. Moreover, circ_001680 may be a promising diagnostic and prognostic marker to determine the success of irinotecan-based chemotherapy.
Highlights
Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide; the number of CRC cases increases every year, and CRC poses a serious threat to human life and health [1]
To assess the influence of circ_001680 on CRC, we examined its expression in 42 pairs of CRC tissues and adjacent normal tissues via qRT-PCR
The results showed that compared to the matched adjacent normal tissues, CRC tissues had circ_001680 overexpression in 71.4% (30/42) of the tissues (T/N > 1.5-fold) from the same patients (Fig. 1c)
Summary
Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide; the number of CRC cases increases every year, and CRC poses a serious threat to human life and health [1]. An increasing number of studies have identified circRNAs that play crucial roles in tumor carcinogenesis by sponging microRNA (miRNAs) [6]. The well-known circRNA ciRS7 abrogates the tumor suppressive effect of miR-7 to promote the progression of esophageal squamous cell carcinoma [7] and colorectal cancers [8]. Circ_0039569 promotes renal cell carcinoma growth and metastasis by regulating miR-34a5p/CCL22 [9]. Accumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the post-transcriptional level; this mechanism is believed to occur in various cancers. The expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown
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