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  • br Acknowledgements br Introduction Colorectal


    Introduction Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world, and its burden is expected to increase by 60% to more than 2.2 million new cases and 1.1 million cancer deaths by 2030 [1]. The 5-year survival rate is 90.3% for patients diagnosed at an early stage but that rate decreases to 12.5% for patients diagnosed in advanced stages [2]. To date, several accepted diagnostic tools for CRC, such as fecal occult blood test (FOBT), stool DNA test, computed tomography (CT), and colonoscopy, are available. However, the invasive, unpleasant, and inconvenient nature of the current diagnostic procedures limits their application [3]. Carcinoembryonic antigen (CEA) has been applied as a serum marker for CRC screening and prognosis [4,5], but CEA testing exhibits relatively low sensitivity and specificity and is thus inappropriate for screening large asymptomatic patients. Therefore, detection of CRC is challenging owing to the lack of a specific noninvasive markers. The discovery of microRNAs (miRNAs) found in plasma or serum has opened a new pathway for diagnosing CRC. miRNAs are small noncoding (19–25 nucleotides in length), endogenous, and single-stranded RNAs that play important roles in regulating gene expression; they are also associated with numerous important pathways, including developmental and oncogenic pathways [6]. Several recent studies indicated differential CRC miRNA P 22077 profiles in plasma or serum versus healthy individuals, such as miR-141, miR-21, miR-142-3p, miR-26a-5p, miR-1914*, and miR-1915 [[7], [8], [9], [10]], which provide the foundation for studying the potentially diagnostic roles of miRNAs in CRC. Genome-wide miRNA and mRNA expression analyses have been used to identify the functional involvement of miRNAs in the progression of cancers [11]. Possible miRNA–mRNA interactions can be predicted using new computer algorithms and techniques [[12], [13], [14]], which enabled detailed analysis and prediction [15] and improved knowledge on cancer development and pathogenesis. Currently, two major qPCR-based tools are used for miRNA quantification assay, namely, the poly(A) [[16], [17], [18], [19]] and stem-loop methods [[20], [21], [22]]. Although the poly(A) method can determine miRNA expression in a high-throughput manner, the approach is less specific than others due to the nonspecific reverse transcription (RT). The stem-loop method requires individual miRNA-specific hydrolytic Taqman probes and is thus too costly for high-throughput miRNA expression profiling [23]. Moreover, given the limited number (usually six) of bases guiding the binding of the 3′ end of the step-loop primer to the target miRNAs, the efficiency of the stem-loop method is relatively low even with a pulse RT reaction [21]. In the present study, we first performed a powerful qPCR-based assay, the S-Poly(T) Plus real-time PCR assay, which exhibits superior sensitivity, specificity, and efficiency [24], to select and validate differentially expressed plasma miRNAs from a sample set including 101 CRC patients, 20 patients with colorectal noncancerous polyps (NCP), and 134 healthy controls. After the two-phase selection and validation process, we identified a miRNA panel (miR-144-3p, miR-425-5p, and miR-1260b) with high CRC diagnostic efficiency. Furthermore, we integrated predicted or validated targets of the three miRNAs and analyzed their overrepresented pathways by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome database. Therefore, we demonstrated a plasma 3-miRNA panel that may serve as novel noninvasive biomarker to diagnose CRC and may be related to CRC development. r>